Consumer medicine information

Lucentis

Ranibizumab

BRAND INFORMATION

Brand name

Lucentis

Active ingredient

Ranibizumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lucentis.

What is in this leaflet

This leaflet answers some common questions about Lucentis.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up-to-date information on the medicine. You can also download the most up-to-date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Lucentis against the benefits they expect it will have for you.

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

Keep this leaflet. You may need to read it again.

What Lucentis is used for

Lucentis is used to treat adults with damage to the retina (light-sensitive layer at the back of the eye) caused by growth of leaky, abnormal blood vessels (choroidal neovascularization, CNV) in diseases that may cause decreased vision such as:

  • Wet age related macular degeneration (wet AMD)
  • Diabetic macular oedema (DME), or oedema due to retinal vein occlusion (RVO) where fluid accumulates into the back of the eye.
  • Proliferative diabetic retinopathy (PDR)
  • CNV secondary to pathologic myopia (PM)
  • CNV due to other causes, such as angioid streaks, post-inflammatory retinochoroidopathy, central serous chorioretinopathy, and inflammatory CNV.

Lucentis contains the active substance ranibizumab, which is part of an antibody. Antibodies are proteins which specifically recognise and bind to other unique proteins in the body. Ranibizumab binds selectively to a protein called human vascular endothelial growth factor A (VEGF-A), which is present in the retina. It inhibits both the growth and leakage of new blood vessels in the eye, abnormal processes that contribute to several eye diseases that may cause decreased vision.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor's prescription.

There is not enough information to recommend the use of this medicine for children or adolescents.

Before you are given Lucentis

When you must not be given it

You must not be given Lucentis if you have an allergy to:

  • any medicine containing ranibizumab
  • any of the ingredients listed at the end of this leaflet.

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 this medicine if you have or suspect you may have an infection in or around your eye or if you have any pain or redness in your eye.

You must not be given this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you have the potential to become pregnant. It is recommended that you use effective contraception during Lucentis treatment and for at least three months after the last injection of Lucentis.

Tell your doctor if you are breast-feeding or planning to breast-feed. Lucentis is not recommended during breast-feeding as it is not known whether Lucentis passes into breast milk.

Tell your doctor if you have ever had a stroke or have experienced short-lasting signs of a stroke (weakness or paralysis of limbs or face, difficulty speaking or understanding). This information will be taken into account to evaluate if Lucentis is the appropriate treatment for you.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Your doctor and pharmacist have more information on medicines to be careful with or avoid when you are given this medicine.

How Lucentis is given

Lucentis is given by your ophthalmologist (eye doctor) as an injection into your eye under a local anaesthetic.

Follow the directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor for help.

It is important to see your doctor regularly when on treatment with Lucentis.

How much is given

The usual dose is 0.05 mL (equivalent to 0.5mg). The time between two doses injected into the same eye should not be shorter than one month.

The treatment is started with one injection of Lucentis per month. Your doctor will check the condition of your eye. Depending on how you respond to the treatment, your doctor will decide whether and when you need to receive the next injection of Lucentis.

How it is given

Lucentis is given as a single injection into your eye. Before the injection you will be given an eye drop to numb the eye. Before the injection you will also be treated with an eye drop that can kill germs on the eye and on the skin around the eye.

After the Lucentis injection, your doctor may perform some additional tests to make sure there are no complications. Eye injections like those with Lucentis can increase eye pressure. This is something you would not notice.

When it is given

Your doctor will decide when you will be given Lucentis.

How long to continue treatment

Continue treatment with this medicine for as long as your doctor tells you.

If you forget a treatment

If you miss a Lucentis treatment, you need to contact your doctor to arrange another appointment as soon as possible.

If you stop Lucentis treatment, your eye disease may get worse.

If you are given too much (overdose)

If you are given more Lucentis than you need, your doctor will check the pressure in your eye and may need to treat it if it is increased.

While you are being given Lucentis

Things you must do

If you experience any problems during the treatment, tell your doctor.

Tell your doctor immediately if you develop signs of inflammation and/or infection of the eye such as redness of the eye, eye pain, light sensitivity and/or vision changes, seeing flashes of light with floaters (seeing cobwebs), progressing to a loss of sight or blurred vision. A serious eye infection or eye disorder can sometimes develop after an injection into the eye.

If you are treated for visual impairment due to macular oedema in diabetes or in RVO tell your doctor if you think that the effect of the treatment is being lost.

If you become pregnant while being treated with this medicine, tell your doctor immediately.

Things you must not do

Do not drive or operate machinery if your vision is poor, either because of your disease or because of the treatment. This medicine may cause temporary problems with vision in some people. If you are affected, do not drive, operate machinery or do anything else that could be dangerous until your vision is normal.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are being treated with Lucentis.

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • eye irritation, clouding of the lens, a feeling of having something in the eye, dry eye, abnormal sensation in the eye
  • eye discomfort, pain or irritation at the site of the injection, increased tear production, redness or itching of the eye, small particles or spots in your vision (floaters)
  • sore throat, headache, joint pain, flu-like symptoms, fatigue, general feeling of being unwell, anxiety, cough, nausea, allergic reactions (rash, itching, redness of the skin).

The above list includes side effects of your medicine which are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • bloodshot eye, bleeding in the eye, inflammation or infection of the eyelid margins, visual disturbance, blurred or decreased sharpness of vision, blindness (temporary or otherwise)
  • discharge of the eye with itching, redness and swelling (conjunctivitis)
  • small marks on the surface of the eye, swelling of a section of the eye (cornea, uvea), swelling or irritation of the eyelid, eyelid pain, sac of pus on the eye.
  • symptoms of a urinary tract infection, including burning, stinging, pain or increased urgency to pass water.

The above list includes serious side effects which may require medical attention. Serious side effects are rare.

Tell your doctor immediately if you experience any of the following:

  • signs of inflammation or infection of the eye such as redness of the eye, eye pain, sensitivity to light or vision changes
  • seeing flashes of light with floaters (seeing spots or cobwebs), progressing to blurred vision or loss of sight.

Go to your nearest emergency room immediately if you experience signs of a stroke, such as weakness or paralysis of limbs or face, difficulty speaking or understanding. If you experience any of these signs, immediate medical care is needed.

The above are serious side effects which might need immediate medical attention.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people. Some of these side effects (e.g. an increase in the pressure inside your eye) can only be found when your doctor does tests to check your progress.

After you are given Lucentis

Storage

It is unlikely you will have to store Lucentis at home.

If you do have to store it:

Vial

  • Keep it in a refrigerator (2°C to 8°C). Do not freeze it.
  • Keep the vial in the outer carton in order to protect it from light.
  • Prior to usage, the unopened vial may be kept at room temperature (25°C) for up to 24 hours.

Pre-filled syringe

  • Keep it in a refrigerator (2°C to 8°C). Do not freeze it.
  • Keep the pre-filled syringe in its sealed tray in the carton in order to protect it from light.
  • Prior to usage, the unopened tray may be kept at room temperature (25°C) for up to 24 hours.

Do not store Lucentis or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on a window sill. Heat and dampness can destroy some medicines.

Keep the medicine where children cannot reach it.

Each Lucentis vial and associated needles and syringe are to be used for one injection only and then discarded.

Product description

What it looks like

Vial pack

Lucentis is supplied as packs containing one glass vial containing 0.23mL of solution, one filter needle for withdrawal of the vial contents, one injection needle and one syringe for intravitreal injection.

Lucentis is a solution for injection supplied in a clear, colourless glass vial. The vial contains 0.23mL of a sterile, clear, colourless to pale yellow aqueous solution.

Vial with filter needle*

Lucentis is supplied as packs containing one glass vial of ranibizumab and one filter needle for withdrawal of the vial contents.

Lucentis is a solution for injection supplied in a clear, colourless glass vial. The vial contains 0.23 mL of a sterile, clear, colourless to pale yellow aqueous solution.

Vial*

Lucentis is supplied as packs containing one glass vial of ranibizumab.

Lucentis is a solution for injection supplied in a clear, colourless glass vial. The vial contains 0.23 mL of a sterile, clear, colourless to pale yellow aqueous solution.

Pre-filled syringe

Lucentis is supplied as packs containing one sterile pre-filled syringe in a sealed tray.

Lucentis is a solution for injection supplied in a pre-filled syringe. The pre-filled syringe contains 0.165 mL of a sterile, clear, colourless to pale yellow aqueous solution.

*Not all presentations may be marketed.

Ingredients

Lucentis vial contains 2.3mg ranibizumab as the active ingredient.

Lucentis pre-filled syringe contains 0.165 mg ranibizumab as the active ingredient.

The vial and pre-filled syringe also contains:

  • trehalose dihydrate
  • histidine hydrochloride monohydrate
  • histidine
  • polysorbate 20
  • water for injections.

Sponsor

Lucentis is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1-800-671-203
Web site: www.novartis.com.au

Date of preparation

This leaflet was prepared in March 2020.

Vial: AUST R 148325 (2.3mg/0.23mL)

Pre-filled syringe: AUST R 212387 (1.65mg/0.165mL)

®= Registered trademark

© Copyright 2020.

Internal document code:

luc270320c based on PI luc270320i.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Lucentis

Active ingredient

Ranibizumab

Schedule

S4

 

1 Name of Medicine

Ranibizumab (rbe).

6.7 Physicochemical Properties

Active ingredient: Ranibizumab.

Chemical structure.

Ranibizumab is the Fab moiety of a high affinity version of recombinant humanised monoclonal antibody rhuMAb vascular endothelial growth factor (VEGF). It consists of a 214-residue light chain linked by a disulfide bond at its C-terminus to the 231-residue N-terminal segment of the heavy chain. The expected amino acid sequences of the heavy and light chains are shown below.
Chemical name: Immunoglobulin G1, anti-(human vascular endothelial growth factor) Fab fragment (human-mouse monoclonal rhuFab V2 γ1-chain), disulfide with human-mouse monoclonal rhuFab V2 κ-chain.
Molecular weight: Approximately 48 kDa.

CAS number.

347396-82-1.

2 Qualitative and Quantitative Composition

Lucentis is supplied in a vial or a pre-filled syringe.

Vial.

Each vial contains 2.3 mg of ranibizumab in 0.23 mL solution for intravitreal injection.

Pre-filled syringe.

Each pre-filled syringe contains 1.65 mg of ranibizumab in 0.165 mL solution.
Ranibizumab is a humanised monoclonal antibody fragment produced in Escherichia coli cells by recombinant DNA technology.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.

Vial.

The solution is sterile, clear, colourless to pale yellow, aqueous and preservative free.

Pre-filled syringe.

The solution is sterile, clear, colourless to pale yellow, aqueous and preservative free.

5 Pharmacological Properties

Pharmacotherapeutic group, ATC.

Antineovascularisation agents. ATC code: S01LA04.

5.1 Pharmacodynamic Properties

Mechanism of action.

Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A (VEGF-A). It binds with high affinity to the VEGF-A isoforms (e.g. VEGF110, VEGF121 and VEGF165), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2.
Binding of VEGF-A to its receptors leads to endothelial cell proliferation and neovascularisation, as well as vascular leakage, which are thought to contribute to the progression of the neovascular form of age related macular degeneration, to the development of choroidal neovascularisation (CNV), including CNV secondary to pathologic myopia or to the macular oedema causing visual impairment in diabetes and retinal vein occlusion.

Clinical trials.

Treatment of wet AMD.

In wet AMD, the clinical safety and efficacy of Lucentis have been assessed in three randomised, double-masked, sham**- or active-controlled studies in patients with neovascular age-related macular degeneration (AMD) (FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER)). A total of 1,323 patients (879 active and 444 control) was enrolled in these studies.

Study FVF2598g (MARINA) and study FVF2587g (ANCHOR).

In the 24-month study FVF2598g (MARINA), patients with minimally classic or occult with no classic choroidal neovascularisation (CNV) received monthly intravitreal injections of Lucentis 0.3 mg or 0.5 mg or sham injections. A total of 716 patients was enrolled in this study (sham, 238; Lucentis 0.3 mg, 238; Lucentis 0.5 mg, 240). A total of 664 subjects (92.7%) completed month 12 (defined as having a visual acuity score for the study eye at month 12) and a total of 615 subjects (85.9%) completed the 2-year study period.
In the 24-month study FVF2587g (ANCHOR), patients with predominantly classic CNV lesions received either: 1) monthly intravitreal injections of Lucentis 0.3 mg and sham photodynamic therapy (PDT); 2) monthly intravitreal injections of Lucentis 0.5 mg and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Verteporfin (or sham) PDT was given with the initial Lucentis (or sham) injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of vascular leakage. A total of 423 patients was enrolled in this study (Lucentis 0.3 mg, 140; Lucentis 0.5 mg, 140; Verteporfin PDT, 143). A total of 386 subjects (91.3%) completed month 12 of the study and 343 subjects (81.1%) completed month 24 of the study.
** The sham Lucentis injection control procedure involved anesthetising the eye in a manner identical to a Lucentis intravitreal injection. The tip of a needleless syringe was then pressed against the conjunctiva and the plunger of the needleless syringe depressed.
In MARINA, the visual acuity gain with ranibizumab is present at 1 month, continues to increase up to month 3, and is maintained up to month 24, compared to a gradual deterioration in the sham treatment group, as shown in Figure 1.
In ANCHOR, the visual acuity gain with ranibizumab is present at 1 month, continues to increase up to month 3, and is maintained up to month 12 compared to a gradual deterioration in the verteporfin treatment group, as shown in Figure 1.
Detailed results are shown in Tables 2 and 3.
Patients in the group treated with Lucentis had minimal observable CNV lesion growth, on average. At month 12, the mean change in the total area of the CNV lesion was 0.1 to 0.3 DA for Lucentis versus 2.3 to 2.6 DA for the control arms.
The use of Lucentis beyond 24 months has not been studied.
In MARINA, at month 12, patients treated with Lucentis reported, on average, a statistically and clinically meaningful improvement in their ability to perform activities related to near vision, distance vision and vision-specific dependency, as measured by the NEI VFQ-25, while sham-treated patients reported a decrease in their ability to perform these activities. On the near activities scale, patients treated with Lucentis 0.5 mg reported a +10.4 point increase (0.3 mg: +9.4), while sham-treated patients had a -2.6 point decrease (p < 0.01). On the distance activities scale, Lucentis 0.5 mg-treated patients had a +7.0 point increase (0.3 mg: +6.7), while sham-treated patients had a -5.9 point decrease (p < 0.01). On the vision-specific dependency scale, Lucentis 0.5 mg-treated patients experienced +6.8 point increase (0.3 mg: +3.6), while sham-treated patients reported a decrease of -4.7 points (p < 0.01).
This increase from baseline in each of these three VFQ-25 subscales at month 12 was maintained at month 24 for Lucentis-treated patients, while in the sham-injection group the mean change from baseline decreased further from month 12 to month 24 in each of these subscales. Therefore, the treatment benefit of Lucentis over the sham control at month 24 was greater than that at month 12.
In ANCHOR, at month 12, patients treated with Lucentis reported a statistically and clinically meaningful improvement in their ability to perform activities related to near vision, distance vision and vision-specific dependency compared to patients receiving verteporfin PDT treatment. On the near activities scale, patients treated with Lucentis 0.5 mg reported a +9.1 point increase (0.3 mg: +6.6), while verteporfin PDT-treated patients had a +3.7 point increase (p < 0.01). On the distance activities scale, Lucentis 0.5 mg-treated patients reported a +9.3 point increase (0.3 mg: +6.4), while verteporfin PDT-treated patients had a +1.7 point increase (p < 0.01). On the vision-specific dependency scale, Lucentis 0.5 mg-treated patients reported a +8.9 point increase (0.3 mg: +7.6), while verteporfin PDT-treated patients had a -1.4 point decrease (p < 0.01). In the verteporfin PDT group, the mean improvement from baseline in the near activities and distance activities subscale scores at month 12 were lost at month 24, while the mean decrease from baseline in the vision-specific dependency subscale score at month 12 was maintained at month 24. These changes between months 12 and 24 within each treatment group resulted in either maintained or greater treatment benefit of ranibizumab over verteporfin PDT compared with month 12, while the treatment benefit of ranibizumab in the vision-specific dependency subscale was smaller at month 24 compared with month 12 (p-values ranging from 0.0023 to 0.0006).

Study FVF3689g (SAILOR).

Study FVF3689g (SAILOR) was a Phase IIIb, single-masked, one-year multicentre study in naïve and previously treated subjects with CNV secondary to AMD. The primary study objective was to estimate the incidence of ocular and non-ocular serious adverse events in subjects treated for 12 months. Overall, 2378 patients were randomised in a 1:1 ratio to receive one intravitreal injection of ranibizumab 0.3 mg or 0.5 mg every month for three consecutive months followed by re-treatment as-needed not more often than monthly.
Overall, no imbalances between the two dose groups were observed in the frequency of ocular and non-ocular adverse events. There was a statistically non-significant trend towards a higher stroke rate in the 0.5 mg group compared to the 0.3 mg group. The respective 95% CIs for the overall stroke rate were wide (0.3% to 1.3% for the 0.3 mg group vs. 0.7% to 2.0% for the 0.5 mg group). The number of strokes was small in both dose groups, and there is not sufficient evidence to conclude (or rule out) that there is a true difference in stroke rates among the treatment groups. The difference in stroke rates may be greater in patients with known risk factors for stroke, including history of prior stroke and transient ischaemic attack.

Study FVF3192g (PIER).

Quarterly dosing after three consecutive monthly doses.

Study FVF3192g (PIER) was a randomised, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of Lucentis in patients with neovascular AMD (with or without a classic CNV component). Data are available up to the end of month 12. Patients received Lucentis 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for three consecutive doses, followed by a dose administered once every 3 months. A total of 184 patients was enrolled in this study (Lucentis 0.3 mg, 60; Lucentis 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study. Patients treated with Lucentis in PIER received a mean of 6 total treatments out of possible 6 from day 0 to month 12.
In PIER, the primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline. After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every three months with Lucentis lost the initial visual acuity gain, returning to baseline at month 12. In PIER, almost all Lucentis-treated patients (90%) maintained their visual acuity at month 12.

Interpretation of PIER.

Although less effective, treatment might be reduced to one injection every 3 months after the first three injections (e.g. if monthly injections are not feasible) but, compared to continued monthly doses, dosing every 3 months may lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following nine months. Patients should be evaluated regularly.

Study A2412 (EVEREST II).

Study A2412 (EVEREST II) is a two-year, randomised, double-masked, multi-centre study designed to evaluate the efficacy and safety of Lucentis 0.5 mg monotherapy vs. Lucentis 0.5 mg in combination with verteporfin photodynamic therapy (vPDT) in 322 Asian patients with symptomatic macular polypoidal choroidal vasculopathy (PCV), a subtype of wet AMD. Patients in both study arms initiated treatment with three monthly Lucentis injections, plus sham or active vPDT given with the first Lucentis injection only. Following treatment initiation, Lucentis monotherapy and Lucentis administered with vPDT were given pro re nata (PRN) based on ocular clinical assessments, including imaging techniques (e.g. OCT, FA, ICGA). Primary results at Month 12 demonstrated that Lucentis administered with vPDT was superior to Lucentis monotherapy with respect to the BCVA change from baseline (8.3 letters versus 5.1 letters, p=0.013) and complete polyp regression (69.3% versus 34.7%, p < 0.001). Patients administered Lucentis with vPDT received on average 2.3 Lucentis injections less than patients administered Lucentis monotherapy (5.1 vs. 7.4 injections).
Superiority of Lucentis with vPDT compared to Lucentis monotherapy was confirmed at Month 24 with respect to BCVA change from baseline (9.6 letters vs. 5.5 letters, p=0.005) and complete polyp regression (56.6% versus 26.7%, p < 0.0001). Patients administered Lucentis with vPDT received on average 4.2 Lucentis injections less than patients administered Lucentis monotherapy (8.1 vs. 12.3 injections).

Treatment of visual impairment due to DME.

The efficacy and safety of Lucentis have been assessed in two randomised, double-masked, sham- or active controlled studies of 12 months duration in patients with visual impairment due to diabetic macular oedema (Study D2301 (RESTORE) and D2201 (RESOLVE)). A total of 496 patients (336 active and 160 control) was enrolled in these studies, the majority had type II diabetes, 28 patients treated with ranibizumab had type I diabetes.

Study D2301 (RESTORE).

In study D2301 (RESTORE), a total of 345 patients with visual impairment due to macular oedema was randomised to receive either initial intravitreal injection of ranibizumab 0.5 mg as monotherapy and sham laser photocoagulation (n=116), combined ranibizumab 0.5 mg and laser photocoagulation (n=118), or sham** injection and laser photocoagulation (n=111). Treatment with ranibizumab was started with monthly intravitreal injections and continued until visual acuity was stable for at least three consecutive monthly assessments. The treatment was reinitiated when there was a reduction in best corrected visual acuity (BCVA) due to DME progression. Laser photocoagulation was administered at baseline on the same day, at least 30 minutes before the injection of ranibizumab, and then as needed based on Early Treatment Diabetic Retinopathy Study (ETDRS) criteria.
Key outcomes are summarised in Tables 4 and 5 and Figure 2.

Study D2301E1 (RESTORE extension).

Study D2301E1 (RESTORE Extension) was an open-label, multi-centre, 24-month extension study. 240 patients who had completed the 12-month core study entered the extension study and were treated with ranibizumab 0.5 mg pro re nata (PRN) in the same eye that was selected as the study eye in the core study. Treatment was re-initiated at monthly intervals upon a decrease in BCVA due to DME and continued until stable BCVA was reached. In addition, laser treatment was administered, if deemed necessary by the investigator, and based on ETDRS guidelines.
On average, 6.4 ranibizumab injections were administered per patient in the 24-month extension period in patients who were treated with ranibizumab, with or without laser treatment, in study D2301. Of the 74 patients from the core study laser treatment arm, 59 (80%) patients received ranibizumab at some point during the extension phase. On average, these 59 patients received 8.1 ranibizumab injections per patient over the 24 months of the extension study. The proportions of patients who did not require any ranibizumab treatment during the extension phase were 19%, 25% and 20% in the prior ranibizumab, prior ranibizumab + laser, and prior laser group, respectively.
Secondary outcome measures are summarized in Table 6.
The long-term safety profile of ranibizumab observed in this 24-month extension study is consistent with the known Lucentis safety profile.

Study D2201 (RESOLVE).

In a supportive, partly exploratory study D2201 (RESOLVE), a total of 151 patients with macular centre involvement in at least one eye, including those with focal or diffuse DME, causing visual impairment were treated with ranibizumab (6 mg/mL, n=51, 10 mg/mL, n=51) or sham (n=49) by monthly intravitreal injections until pre-defined treatment stopping criteria were met. The initial ranibizumab dose (0.3 mg or 0.5 mg) could be doubled at any time during the study after the first injection if at the Month 1 visit, retinal thickness in the study eye remained > 300 micrometre; or if at any monthly visit after Month 1, retinal thickness in the study eye was > 225 micrometre and reduction in retinal oedema from the previous assessment was < 50 micrometre. Laser photocoagulation rescue treatment was allowed from month 3 in both treatment arms.
The average injection doses in the 6 mg/mL group, 10 mg/mL group, and pooled group, were 0.47 mg, 0.76 mg and 0.62 mg, respectively. A total of 86% of patients in the ranibizumab treated groups received doses of 0.5 mg/injection or higher, of which 69% received doses of 0.6 mg/injection or higher.
The study was comprised of two parts: an exploratory part (the first 42 patients analysed at months 6), and a confirmatory part (the remaining 109 patients analysed at months 12).
The exploratory analysis revealed no sign of a clinically relevant response to dose doubling (in terms of efficacy neither for visual acuity nor for central retinal thickness). The results of this study therefore do not support the concept of dose doubling where response to the recommended dose is considered inadequate. Key outcomes from the confirmatory part of the study (2/3 patients) are summarised in Table 7 and Figure 3.
Patients treated with ranibizumab experienced a continuous reduction in central retina thickness. At month 12, the mean CRT change from baseline was -194 micrometres for ranibizumab versus -48 micrometres for sham control.
Overall, ocular and non-ocular safety findings in DME patients of both studies D2201 and D2301 were comparable with the previously known safety profile observed in wet AMD patients.

Study D2303 (REVEAL).

The study D2303 (REVEAL), was a 12 month, randomised, double-masked Phase IIIb trial conducted in Asian patients. Similar to the RESTORE 12 month core study in trial design and inclusion/exclusion criteria, 390 patients with visual impairment due to macular oedema were randomised to receive either ranibizumab 0.5 mg injection as monotherapy and sham laser photocoagulation (n=133), ranibizumab 0.5 mg injection and laser photocoagulation (n=129), or sham injection and laser photocoagulation (n=128). Mean change in visual acuity at Month 12 compared to baseline were +6.6 letters in the ranibizumab monotherapy group, +6.4 letters in the ranibizumab plus laser group and +1.8 letters in the laser group. Overall, the efficacy and safety results of the REVEAL study in Asian DME patients are consistent with those of the RESTORE study in Caucasian DME patients.

Study D2304 (RETAIN).

In the phase IIIb study D2304 (RETAIN), 372 patients with visual impairment due to DME were randomised to receive intravitreal injection of either:
ranibizumab 0.5 mg with concomitant laser photocoagulation on a 'treat-and-extend' (TE) regimen (n=121); or
ranibizumab 0.5 mg monotherapy on a TE regimen (n=128); or
ranibizumab 0.5 mg monotherapy on a pro re nata (PRN) regimen (n=123).
In all groups, treatment with ranibizumab was initiated with monthly intravitreal injections and continued until BCVA was stable for at least three consecutive monthly assessments. Laser photocoagulation was administered at baseline on the same day as the first ranibizumab injection and then as needed based on ETDRS criteria. On the 'treat-and-extend' (TE) regimen, ranibizumab was then administered, at scheduled treatment, at intervals of 2-3 months. On the PRN regimen, BCVA was assessed monthly and ranibizumab was then administered during the same visit, if needed. In all groups, monthly treatment was re-initiated upon a decrease in BCVA due to DME progression and continued until stable BCVA was reached again. The duration of the study was 24 months.
In the RETAIN study, after 3 initial monthly treatment visits, the number of scheduled treatment visits required by the TE regimen was 13 compared to the 20 monthly visits required by the PRN regimen. Over 24 months the mean (median) number of injections was 12.4 (12.0) in TE ranibizumab + laser, 12.8 (12.0) in TE ranibizumab alone, and 10.7 (10.0) for the PRN ranibizumab treatment groups. The addition of laser was not associated with a reduced mean number of ranibizumab injections in the TE regimen. On average, patients in both TE groups maintained BCVA over 24 months of treatment. In the TE groups, over 70% of patients had a visit frequency of ≥ 2 months.
Key outcome measures are summarised in Table 8.
There was no difference in the BCVA or CRT outcomes of patients in RETAIN study who received or did not receive concomitant thiazolidinediones.
In DME studies, the improvement in BCVA was accompanied by a reduction over time in mean CRT in all the treatment groups.
Diabetic retinopathy severity score (DRSS) was assessed in three of the clinical trials described above. Of the 875 patients of whom approximately 75% were of Asian origin. In a meta-analysis of these studies 48.8% of the 315 patients with gradable DRSS scores in the subgroup of patients with moderately severe non-proliferative DR (NDPR) or worse at baseline experienced a ≥ 2 step improvement in the DRSS at month 12 when treated with ranibizumab (n=192) vs 14.6% of patients treated with laser (n=123). The estimated difference between ranibzumab and laser was 29.9% (95% CI: [20.0, 39.7]. In the 405 DRSS gradable patients with moderate NDPR or better, a ≥ 2 step DRSS improvement was observed in 1.4% and 0.9% of the ranibizumab and laser groups respectively.

Treatment of PDR.

The clinical safety and efficacy of Lucentis in patients with PDR have been assessed in Protocol S which evaluated the treatment with ranibizumab 0.5 mg intravitreal injections compared with panretinal photocoagulation (PRP). The primary endpoint was the mean visual acuity change at year 2. Additionally, change in diabetic retinopathy (DR) severity was assessed based on fundus photographs using the DR severity score (DRSS).
Protocol S was a multicentre, randomised, active-controlled, parallel-assignment, non-inferiority phase III study in which 305 patients (394 study eyes) with PDR with or without DME at baseline were enrolled. The study compared ranibizumab 0.5 mg intravitreal injections to standard treatment with PRP. A total of 191 eyes (48.5%) were randomised to ranibizumab 0.5 mg and 203 eyes (51.5%) eyes were randomised to PRP. A total of 88 eyes (22.3%) had baseline DME: 42 (22.0%) and 46 (22.7%) eyes in the ranibizumab and PRP groups, respectively.
In this study, the baseline visual acuity was 75.0 letters in the ranibizumab group and 75.2 letters in the PRP group, the mean visual acuity change at year 2 was +2.7 letters in the ranibizumab group compared to -0.7 letters in the PRP group. The difference in least square means was 3.5 letters (95% CI: [0.2 to 6.7]).
At year 1, 41.8% of eyes experienced a ≥ 2-step improvement in the DRSS when treated with ranibizumab (n=189) compared to 14.6% of eyes treated with PRP (n=199). The estimated difference between ranibizumab and laser was 27.4% (95% CI: [18.9, 35.9]). See Table 9.
At year 1 in the ranibizumab-treated group in Protocol S, ≥ 2-step improvement in DRSS was consistent in eyes without DME (39.9%) and with baseline DME (48.8%).
An analysis of year 2 data from Protocol S demonstrated that 42.3% (n=80) of eyes in the ranibizumab-treated group had ≥ 2-step improvement in DRSS from baseline compared with 23.1% (n=46) of eyes in the PRP group. In the ranibizumab-treated group, ≥ 2-step improvement in DRSS from baseline was observed in 58.5% (n=24) of eyes with baseline DME and 37.8% (n=56) of eyes without DME.

Treatment of visual impairment due to macular oedema secondary to RVO.

Study FVF4165g (BRAVO) and study FVF4166g (CRUISE).

The clinical safety and efficacy of Lucentis in patients with visual impairment due to macular oedema secondary to RVO have been assessed in the randomised, double-masked, controlled studies BRAVO and CRUISE that recruited subjects with BRVO (n=397) and CRVO (n=392), respectively. In both studies, subjects received either ranibizumab 0.3 mg or 0.5 mg intravitreal or sham** injections. Patients were initially treated monthly for 6 months. Neither study compared a flexible versus fixed dosing regimen. Thereafter, treatment was given as needed following pre-specified re-treatment criteria. After 6 months, patients in the sham-control arms were crossed over to ranibizumab 0.5 mg. In BRAVO, laser photocoagulation as rescue was allowed in all arms from Month 3.
Laser therapy was not used as a comparative treatment. During the first six months, laser rescue treatment was administered to 27 (20.1%) patients in the ranibizumab 0.3 mg group, 28 (21.4%) in the ranibizumab 0.5 mg group and 76 (57.6%) in the sham group.
In the first six months, ranibizumab was given monthly. In the second six month period, all patients were given only ranibizumab as needed i.e. were given only active treatment as required (0.5 mg monthly if previously on sham treatment) and at monthly intervals as necessary, the latter determined by a best corrected visual acuity of 20/40 - or worse - or mean central subfield thickness ≥ 250 micrometre on optical coherence tomography.
Out of the 525 patients who received active treatment in the first 6 months, 501 patients entered into the observation period, with 87.2% (n=437) of them receiving at least one injection. Overall, patients received from 0 to 6 injections, with the lowest percentage of patients (10%) receiving 1 injection and the highest percentage of patients (20.8%) receiving 6 injections. The average number of injections was 3.3.
While numerically the better results were seen for 0.5 mg the differences between the two doses of Lucentis are not clinically significant. Key outcomes from BRAVO and CRUISE are summarised in Tables 10 and 11 and Figures 4 and 5.
In both studies, the improvement of vision was accompanied by a continuous decrease in the macular oedema as measured by central retinal thickness.
The improvement in visual acuity seen with ranibizumab treatment at 6 and 12 months was accompanied by patient-reported benefits as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) sub-scales related to near and distance activity, a pre-specified secondary efficacy endpoint. The difference between Lucentis 0.5 mg and the control group was assessed at Month 6 with p-values of 0.02 to 0.0002.
Efficacy and safety of Lucentis for treatment of visual impairment due to macular oedema secondary to RVO has not been evaluated beyond 12 months.

Treatment of visual impairment due to CNV.

Study G2301 (MINERVA).

The clinical safety and efficacy of Lucentis in patients with visual impairment due to CNV secondary to etiologies other than nAMD and PM have been assessed in the pivotal study G2301 (MINERVA), which was randomised, double-masked, sham controlled for 2 months, followed by an open label extension of 10 months. Due to the multiple baseline etiologies involved, five subgroups (angioid streaks, post-inflammatory retinochoroidopathy, central serous chorioretinopathy, idiopathic chorioretinopathy, and miscellaneous etiology) were pre-defined for analysis. In this study, 178 patients were randomised in a 2:1 ratio to one of the following arms:
ranibizumab 0.5 mg at baseline followed by an individualized dosing regimen driven by disease activity;
sham injection at baseline followed by an individualized treatment regimen driven by disease activity.
Starting at Month 2, all patients received open-label treatment with ranibizumab as needed. The primary endpoint was assessed by the best corrected visual acuity (BCVA) change from baseline to Month 2.
Key outcomes from MINERVA are summarized in Tables 12 and 13 and Figure 6.
When comparing ranibizumab versus sham control at Month 2, a statistically significant treatment effect for patients in ranibizumab arm was observed.
The improvement of vision was accompanied by a reduction in central subfield thickness over the 12-month period.
The mean number of ranibizumab injections given in the study eye over 12 months was 5.8 in the ranibizumab arm versus 5.4 in those patients in the sham with ranibizumab group. In the sham arm, 7 out of 59 patients did not receive any treatment with ranibizumab in the study eye during the 12-month period.

Paediatric patients.

Five adolescent patients aged 12 to 17 years with visual impairment secondary to CNV received open-label treatment with ranibizumab 0.5 mg at baseline followed by an individualized treatment regimen based on evidence of disease activity (e.g. VA impairment, intra/sub-retinal fluid, hemorrhage or leakage). BCVA change from baseline to Month 12 improved in all five patients, ranging from +5 to +38 letters (mean of 16.6 letters). The improvement of vision was accompanied by a stabilization or reduction in central subfield thickness over the 12-month period. The mean number of ranibizumab injections given in the study eye over 12 months was three (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM).

Study F2301 (RADIANCE).

The clinical safety and efficacy of Lucentis in patients with visual impairment due to CNV in PM have been assessed based on the 12-month data of the randomised, double-masked, controlled pivotal study F2301 (RADIANCE) which was designed to evaluate two different dosing regimens of ranibizumab 0.5 mg given as intravitreal injection in comparison to verteporfin PDT (vPDT, Visudyne photodynamic therapy).
Patients with retinal detachment, cataract, pre-retinal membrane of the macula, history of panretinal or focal/grid laser photocoagulation with involvement of the macular area, history of intraocular treatment with any anti-VEGF or vPDT, history of intra-ocular surgery or treatment with corticosteroids in preceding 3 months were excluded from the trial.
A total of 277 eligible patients participated in the trial. The mean (SD) age of all randomised patients was 55.5 (13.94) years. At baseline, the mean (SD) BCVA was 55.4 (13.11) letters. The mean (SD) axial length was 29.07 (1.892) mm and the mean refraction-sphere was -12 diopters (range -6 to ~-30) at baseline. A total of 68.6% patients had subfoveal, 23.8% patients had juxtafoveal and 4.0% patients had extrafoveal lesions. The patients were randomised to the following three treatment groups:
Group I (ranibizumab 0.5 mg, dosing regimen driven by "stability" criteria defined as no change in BCVA compared to two preceding monthly evaluations).
Group II (ranibizumab 0.5 mg, dosing regimen driven by "disease activity" criteria defined as vision impairment attributable to intra-or-subretinal fluid or active leakage due to the CNV lesion as assessed by Optical Coherence Tomography (OCT) and/or Fluorescein Tomography (FA)).
Group III (vPDT - patients were allowed to receive ranibizumab treatment as of Month 3).
Over the 12 months of the study patients received on average 4.6 injections (range 1-11) in Group I and 3.5 injections (range 1-12) in Group II. In Group II (in which patients received the recommended treatment regimen based on disease activity, see Section 4.2 Dose and Method of Administration), 50.9% of patients required 1 or 2 injections, 34.5% required 3 to 5 injections and 14.7% required 6 to 12 injections over the 12-month study period. In Group II, 62.9% of patients did not require injections in the second 6 months of the study.
Key outcomes from RADIANCE are summarised in Table 14 and Figure 7.
The improvement of vision was accompanied by a reduction in central retinal thickness.
Patient-reported benefits were observed with the ranibizumab treatment arms over vPDT (p-value < 0.05) in terms of improvement in the composite score and several subscales (general vision, near activities, mental health and dependency) of the VFQ-25.

5.2 Pharmacokinetic Properties

Absorption.

Following monthly intravitreal administration of Lucentis to patients with neovascular AMD, serum concentrations of ranibizumab were generally low. Cmax was dose proportional over the dose range of 0.05 to 1.0 mg/eye. Upon monthly intravitreal administration of Lucentis 0.5 mg/eye, serum ranibizumab Cmax, attained approximately 1 day after dosing, is predicted to generally range between 0.79 and 2.90 nanogram/mL, and Cmin is predicted to generally range between 0.07 and 0.49 nanogram/L. Maximum levels (Cmax) were generally below the ranibizumab concentration necessary to inhibit the biological activity of VEGF by 50% (11 to 27 nanogram/mL, as assessed in an in vitro cellular proliferation assay). Serum ranibizumab concentrations in RVO patients were similar to those observed in neovascular AMD patients.

Distribution and elimination.

Based on analysis of population pharmacokinetics and the disappearance of ranibizumab from serum for patients with neovascular AMD treated with the 0.5 mg dose, the average vitreous elimination half-life of ranibizumab is approximately 9 days. Serum ranibizumab exposure is predicted to be approximately 90,000-fold lower than vitreal ranibizumab exposure.

Renal impairment.

No formal studies have been conducted to examine the pharmacokinetics of Lucentis in patients with renal impairment. In a population pharmacokinetic analysis of neovascular AMD patients, 68% (136 of 200) of patients in a population pharmacokinetic analysis had renal impairment (46.5% mild [50 to 80 mL/min], 20% moderate [30 to 50 mL/min] and 1.5% severe [< 30 mL/min]). In RVO patients, 48.2% (253 of 525) had renal impairment (36.4% mild, 9.5% moderate and 2.3% severe). Systemic clearance was slightly lower, but this was not clinically significant.

Hepatic impairment.

No formal studies have been conducted to examine the pharmacokinetics of Lucentis in patients with hepatic impairment.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies were performed with ranibizumab.

Carcinogenicity.

No carcinogenicity studies were performed with ranibizumab.

4 Clinical Particulars

4.1 Therapeutic Indications

Lucentis (ranibizumab) is indicated in adults for:
the treatment of neovascular (wet) age-related macular degeneration (AMD);
the treatment of visual impairment due to diabetic macular oedema (DME);
treatment of proliferative diabetic retinopathy (PDR);
the treatment of visual impairment due to choroidal neovascularisation;
the treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM);
the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (RVO).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Patients with active or suspected ocular or periocular infections.
Patients with active intraocular inflammation.

4.4 Special Warnings and Precautions for Use

Intravitreal injection-related reactions.

Intravitreal injections, including those with Lucentis, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear, iatrogenic traumatic cataract and increased intraocular pressure (see Section 4.8 Adverse Effects (Undesirable Effects)). Symptoms of these adverse effects should be explained and the patient should be given a copy of the consumer medicine information document. The patient should be given contact details in the case of adverse effects.
Proper aseptic injection techniques must always be used when administering Lucentis. In addition, patients should be reviewed during the week following the injection to permit early treatment if an infection occurs. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above-mentioned events without delay.
Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of Lucentis (see Section 4.8 Adverse Effects (Undesirable Effects)). Sustained IOP increases have also been reported but the frequency is unclear. Both intraocular pressure and the perfusion of the optic nerve head must therefore be monitored and managed appropriately. Patients should be reviewed for IOP rise pre-injection and 60 minutes post-injection. The dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of an intraocular pressure of ≥ 30 mmHg.

Bilateral treatment.

Limited data on bilateral use of Lucentis (including same day administration) do not suggest an increased risk of systemic adverse effects compared to unilateral treatment.

Arterial thromboembolic events.

There is a potential risk of arterial thromboembolic events following intravitreal use of inhibitors of VEGF. Arterial thromboembolic events are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). In the wet AMD Phase III studies, the overall frequency of arterial thromboembolic events was similar between ranibizumab and control. A numerically higher stroke rate was observed in patients treated with ranibizumab 0.5 mg compared to ranibizumab 0.3 mg or control, however, the differences were not statistically significant. The difference in stroke rates may be greater in patients with known risk factors for stroke, including history of prior stroke or transient ischemic attack. Therefore, these patients should be carefully evaluated by their physicians as to whether Lucentis treatment is appropriate and the benefit outweighs the potential risk.

Immunogenicity.

As with all therapeutic proteins, there is a potential for immunogenicity with Lucentis.

Patient populations with limited data.

There is only limited experience in the treatment of subjects with DME due to type I diabetes. Lucentis has not been studied in patients who have previously received intravitreal injections, in patients with active systemic infections or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is also no experience of treatment with Lucentis in diabetic patients with an HbA1c over 12% and uncontrolled hypertension.
There is limited experience with treatment of patients with prior episodes of RVO and of patients with ischemic branch RVO (BRVO) and central RVO (CRVO). In patients with RVO presenting with clinical signs of irreversible ischemic visual function loss, treatment is not recommended.

Use in renal impairment.

Dose adjustment is not needed in patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

Use in hepatic impairment.

Lucentis has not been studied in patients with hepatic impairment. However, as systemic exposure is negligible, no special measures are considered necessary in this population.

Use in the elderly.

Elderly (65 years and above).

No dose adjustment is required in the elderly.

Paediatric use.

Children and adolescents (below 18 years of age).

Lucentis is not recommended for use in children and adolescents due to insufficient data on safety and efficacy in these sub-populations. Limited data on adolescent patients aged 12 to 17 years with visual impairment due to CNV is available (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Pediatric patients).

Effects on laboratory tests.

No data are available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal interaction studies have been performed (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In clinical trials for treatment of visual impairment due to DME, the outcome with regards to visual acuity or central retinal thickness in patients treated with Lucentis was not affected by concomitant treatment with thiazolidinediones (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
For the adjunctive use of laser photocoagulation and Lucentis in DME and BRVO, see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No study has been conducted to investigate the effects of ranibizumab on male or female fertility. In animal studies with bevacizumab, a closely related recombinant anti-VEGF monoclonal antibody, a reversible inhibition of ovarian function was observed in rabbits and cynomolgus monkeys following intravenous treatment. This finding is thought to be associated with inhibitory effects of bevacizumab on angiogenesis. The clinical relevance of this finding to Lucentis is unclear.
(Category D)
For ranibizumab, no clinical data on exposed pregnancies are available. The potential risk for humans is unknown.
In pregnant monkeys, intravitreal ranibizumab treatment did not elicit developmental toxicity or teratogenicity, and had no effect on weight or structure of the placenta, at doses up to 1 mg/eye/fortnight, yielding systemic exposure levels estimated to be up to 58-times those expected clinically. However, based on its pharmacological effect ranibizumab should be regarded as potentially teratogenic and embryo-foetotoxic. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving a child.
The absence of ranibizumab-mediated effects on the embryo-foetal development is plausibly related to the expected inability of the Fab fragment to cross the placenta. Nevertheless, ranibizumab was detected in a foetus coincident with high maternal ranibizumab and anti-ranibizumab antibody serum levels, possibly because the anti-ranibizumab antibody acted as a (Fc region containing) carrier protein for ranibizumab, thereby decreasing its maternal serum clearance and enabling its placental transfer.
As the embryo-foetal development investigations were performed in healthy pregnant animals and disease (such as diabetes) may modify the permeability of the placenta towards a Fab fragment, ranibizumab should be used with caution in women of child bearing potential in general, and during pregnancy in particular.

Women of childbearing potential.

Women of childbearing potential should use effective contraception during treatment.
It is not known whether ranibizumab is excreted in human milk. As a precautionary measure, breast-feeding is not recommended during the use of Lucentis.

4.8 Adverse Effects (Undesirable Effects)

Wet AMD population.

A total of 1,315 patients constituted the safety population in the three controlled phase III studies in wet AMD (FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER)) with 24 months exposure to Lucentis and 440 patients were treated with the 0.5 mg dose.
Serious adverse events related to the injection procedure included endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see Section 4.4 Special Warnings and Precautions for Use). The cumulative 2-year incidence of endophthalmitis (serious and non-serious) in the pooled pivotal trials (i.e. studies FVF2598g (MARINA), FVF2587g (ANCHOR), and FVF3192g (PIER)) was about 1%.
Other serious ocular events observed among Lucentis-treated patients included intraocular inflammation and increased intraocular pressure (see Section 4.4 Special Warnings and Precautions for Use).
The adverse events listed in Table 1 occurred at a higher rate (at least 2 percentage points) in patients receiving treatment with Lucentis 0.5 mg than in those receiving control treatment (sham injection (see Section 5.1 Pharmacodynamic Properties, Clinical trials for definition) or verteporfin photodynamic therapy (PDT)) in the pooled data of the three controlled wet AMD phase III studies. They were therefore considered potential adverse drug reactions. The safety data described below also include all adverse events suspected to be at least potentially related to the injection procedure or medicinal product in the 440 wAMD patients treated with 0.5 mg Lucentis. The adverse event rates for the 0.3 mg dose were comparable to those for 0.5 mg.

DME population.

The safety of Lucentis was studied in a one-year sham-controlled trial (RESOLVE) and in a one-year laser-controlled trial (RESTORE) conducted respectively in 102 and 235 ranibizumab-treated patients with visual impairment due to DME (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The event of urinary tract infection, in the common frequency category, met the criteria for Table 1; otherwise ocular and non-ocular events in the RESOLVE and RESTORE trials were reported with a frequency and severity similar to those seen in the wet AMD trials.

Post-registration study in DME population.

An analysis of 24-month data from two Phase III studies in DME, RIDE and RISE, is available. Both studies are randomised, sham-controlled studies of monthly intravitreal ranibizumab injections (0.5 mg or 0.3 mg) for a total of 36 months in patients with clinically significant macular oedema with centre involvement secondary to diabetes mellitus (type 1 or type 2). The patients are treated using a fixed dosing regimen which requires monthly injections as opposed to the approved individualised dosing regimen (see Section 4.2 Dose and Method of Administration). A total of 500 patients were exposed to ranibizumab treatment in the pooled studies (250 patients in each pooled ranibizumab 0.3 mg and 0.5 mg arm as well as the sham arm.
The pooled safety analysis showed a numerically higher, but not statistically significant, number of deaths and cerebrovascular events in the 0.5 mg group as compared to the 0.3 mg or sham groups. The stroke rate at 2 years was 3.2% (8/250) with ranibizumab 0.5 mg, 1.2% (3/250) with ranibizumab 0.3 mg, and 1.6% (4/250) with sham. Fatalities in the first 2 years occurred in 4.4% (11/250) of patients treated with ranibizumab 0.5 mg, in 2.8% (7/250) treated with ranibizumab 0.3 mg, and in 1.2% (3/250) of control patients.

PDR population.

The safety of Lucentis in patients with PDR was studied for up to 24 months in Protocol S, including 191 patients treated with ranibizumab 0.5 mg (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Ocular and non-ocular events observed were consistent with what would be expected in a diabetic patient population with DR, or have been reported with a frequency and severity similar to those seen in previous clinical trials with Lucentis.

RVO population.

The safety of Lucentis was studied in two 12-month trials (BRAVO and CRUISE) conducted respectively in 264 and 261 ranibizumab-treated patients with visual impairment due to macular oedema secondary to BRVO and CRVO, respectively (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Ocular and non-ocular events in the BRAVO and CRUISE trials were reported with a frequency and severity similar to those seen in the wet-AMD trials.

CNV population.

The safety of Lucentis was studied in a 12-month clinical trial (MINERVA), which included 171 ranibizumab-treated patients with visual impairment due to CNV (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The safety profile in these patients was consistent with that seen in previous clinical trials with Lucentis.

Pathologic myopia (PM) population.

The safety of Lucentis was studied in the 12-month clinical trial (RADIANCE), which included 224 ranibizumab-treated patients with visual impairment due to CNV secondary to PM (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Ocular and non-ocular events in this trial were reported with a frequency and severity similar to those seen in the wet-AMD trials.
Patients with PM have an increased risk for retinal detachment and retinal tear. No case of 'retinal detachment' was reported in the pivotal clinical trial (RADIANCE) in PM and three events coded as 'retinal tear' were reported. This incidence (1.3%) is higher than that seen in other approved indications for ranibizumab (0 to 1.1% in wet AMD, 0 to 0.8% in DME and in RVO) and consistent with the reporting rate for retinal tear described in Table 1.

Tabulated summary of adverse effects from clinical trials.

The adverse effects from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse effects are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS): 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).
A meta-analysis of pooled safety data from completed, randomised, double masked global studies showed a higher incidence rate of non-serious, non-ocular wound infection/inflammation in DME patients treated with ranibizumab 0.5 mg (1.85/100 PY; 20 events in 936 patients) compared to sham/laser treatment (0.27/100 PY; 2 events in 58 patients); HR 8.07 (95% CI 1.88, 34.74). The relationship to ranibizumab remains unknown.

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 www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage regimen.

Single-use vial for intravitreal use only. Use of more than one injection from a vial can lead to product contamination and subsequent ocular infection.
Lucentis must be administered by a qualified ophthalmologist experienced in intravitreal injections.
The recommended dose for Lucentis is 0.5 mg given as a single intravitreal injection. This corresponds to an injection volume of 0.05 mL. The interval between two doses injected into the same eye should be at least four weeks.
The recommended maximal dose (0.5 mg) should not be exceeded. Post-injection monitoring is recommended (see Section 4.4 Special Warnings and Precautions for Use).

General target population.

Treatment of wet AMD, DME, PDR, macular oedema secondary to RVO, CNV or CNV secondary to PM.

Treatment is initiated with one injection per month until maximum visual acuity is achieved and/or there are no signs of disease activity i.e. no change in visual acuity and in other signs and symptoms of the disease under continued treatment. In patients with wet AMD, DME, PDR, and RVO, initially, three or more consecutive, monthly injections may be needed.
Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity, as assessed by visual acuity and/or anatomical parameters.
If, in the physician's opinion, visual and anatomic parameters indicate that the patient is not benefiting from continued treatment, Lucentis should be discontinued.
Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography).
Treatment has been described with either fixed (e.g. monthly) or variable dosing regimens. Variable dosage regimens include 'pro re nata' (PRN) where patients are seen at regular intervals and the lesion is treated when it is active, and 'treat-and-extend' where the interval may be extended as described below.
If patients are being treated according to a treat-and-extend regimen, once maximum visual acuity is achieved and/or there are no signs of disease activity, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval should be extended by no more than two weeks at a time for wet AMD and may be extended by up to one month at a time for DME. For RVO, treatment intervals may also be gradually extended, however there are insufficient data to conclude on the length of these intervals. If disease activity recurs, the treatment interval should be shortened accordingly.
There was no sign of clinically relevant response to dose doubling (in terms of efficacy neither for visual acuity nor for central retinal thickness). The results of clinical studies do not support the concept of dose doubling where response to the recommended dose is considered inadequate (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The treatment of visual impairment due to CNV should be determined individually per patient based on disease activity. In the treatment of visual impairment due to CNV secondary to Pathologic Myopia (PM), many patients may only need one or two injections during the first year, while some patients may need more frequent treatment (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Lucentis and laser photocoagulation in DME and Branch RVO (BRVO).

Lucentis has been used concomitantly with laser photocoagulation in clinical studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials). When given on the same day, Lucentis should be administered at least 30 minutes after laser photocoagulation. Lucentis can be administered in patients who have received previous laser photocoagulation.

Lucentis and Visudyne photodynamic therapy in CNV secondary to PM.

There is no experience in using Lucentis in combination with Visudyne.

Method of administration.

As with all medicinal products for parenteral use, Lucentis should be inspected visually for particulate matter and discolouration prior to administration.
The injection procedure should be carried out under aseptic conditions, which include the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). Sterile paracentesis equipment should be available as a precautionary measure. The patient's medical history should be carefully evaluated for hypersensitivity reactions prior to performing the intravitreal procedure (see Section 4.3 Contraindications). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection.
For information on preparation of Lucentis, see Instructions for use and handling.
The injection needle should be inserted 3.5 to 4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe. The injection volume of 0.05 mL is then delivered; the scleral site should be rotated for subsequent injections.

Instructions for use and handling.

Vial.

Vials are for single use only (see Section 4.2 Dose and Method of Administration). The vial is sterile. After injection any unused product must be discarded.
Do not use the vial if the packaging is damaged. The sterility of the vial cannot be guaranteed unless the packaging seal remains intact. Do not use the vial if the solution is discoloured, cloudy, or contains particulates.
For preparation and intravitreal injection, the following single-use medical devices are needed:
a 5 micrometre filter needle (18G);
a 1 mL sterile syringe;
an injection needle (30G x ½ inch).
These medical devices are not supplied in the Lucentis pack that contains only the vial.
To prepare Lucentis for intravitreal injection, please adhere to the following instructions:
(See Manufacturer's product information for diagrams.)
1. Before withdrawal, the outer part of the rubber stopper of the vial should be disinfected.
2. Attach a 5 micrometre filter needle (18G) to a 1 mL syringe using an aseptic technique. Push the blunt filter needle into the centre of the vial stopper until the needle touches the bottom edge of the vial.
3. Withdraw all the liquid from the vial, keeping the vial in an upright position, slightly inclined to ease complete withdrawal.
4. Ensure that the plunger rod is drawn back sufficiently when emptying the vial in order to completely empty the filter needle.
5. Leave the blunt filter needle in the vial and disconnect the syringe from the blunt filter needle. The filter needle should be discarded after withdrawal of the vial contents and should not be used for the intravitreal injection.
6. Aseptically and firmly attach an injection needle (30G x ½ inch) onto the syringe.
7. Carefully remove the cap from the injection needle without disconnecting the injection needle from the syringe.

Note.

Grip at the yellow hub of the injection needle while removing the cap.
8. Carefully expel the air from the syringe and adjust the dose to the 0.05 mL mark on the syringe. The syringe is ready for injection.

Note.

Do not wipe the injection needle. Do not pull back on the plunger.
After injection, do not recap the needle or detach it from the syringe. Dispose of the used syringe together with the needle in a sharps disposal container or in accordance with local requirements.

Prefilled syringe pack.

The pre-filled syringe is for single use only (see Section 4.2 Dose and Method of Administration).
The pre-filled syringe is sterile. Do not use the pre-filled syringe if the packaging is damaged. The sterility of the pre-filled syringe cannot be guaranteed unless the tray remains sealed. Do not use the pre-filled syringe if the solution is discoloured, cloudy, or contains particulates.
For the intravitreal injection, a 30G x ½ inch injection needle should be used.
To prepare Lucentis for intravitreal administration, please adhere to the instructions for use.
(See Manufacturer's product information for diagrams.)
Read all the instructions carefully before using the pre-filled syringe.
The pre-filled syringe is for single use only. The pre-filled syringe is sterile. Do not use the product if the packaging is damaged. The opening of the sealed tray and all subsequent steps should be done under aseptic conditions.

Note.

The dose must be set to 0.05 mL.

Prepare.

1. Make sure that your pack contains: a sterile pre-filled syringe in a sealed tray.
2. Peel the lid off the syringe tray and, using aseptic technique, carefully remove the syringe.

Check syringe.

3. Check that: the syringe cap is not detached from the Luer Lock; the syringe is not damaged; the drug solution looks clear, colourless to pale yellow and does not contain any particulates.
4. If any of the above is not true, discard the pre-filled syringe and use a new one.

Remove syringe cap.

5. Snap off (do not turn or twist) the syringe cap.
6. Dispose of the syringe cap.

Attach needle.

7. Attach a 30G x ½ inch sterile injection needle firmly onto the syringe by screwing it tightly onto the Luer Lock.
8. Carefully remove the needle cap by pulling it straight off.

Note.

Do not wipe the needle at any time.

Dislodge air bubbles.

9. Hold the syringe upright.
10. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top.

Set dose.

11. Hold the syringe at eye level and carefully push the plunger until the edge below the dome of the rubber stopper is aligned with the dose mark. This will expel the air and the excess solution and set the dose to 0.05 mL.

Note.

The plunger rod is not attached to the rubber stopper - this is to prevent air being drawn into the syringe.

Inject.

The injection procedure should be carried out under aseptic conditions.
12. The injection needle should be inserted 3.5 - 4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and aiming towards the centre of the globe.
13. Inject slowly until the rubber stopper reaches the bottom of the syringe to deliver the volume of 0.05 mL.
14. A different scleral site should be used for subsequent injections.
15. After injection, do not recap the needle or detach it from the syringe. Dispose of the used syringe together with the needle in a sharps disposal container or in accordance with local requirements.
Lucentis contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.

4.7 Effects on Ability to Drive and Use Machines

The Lucentis treatment procedure may induce temporary visual disturbances, which may affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients who experience these signs must not drive or use machines until these temporary visual disturbances subside.

4.9 Overdose

Cases of accidental overdose (injection of volumes greater than the recommended 0.05 mL Lucentis) have been reported from the clinical studies in wet AMD and postmarketing data. Adverse reactions most frequently associated with these reported cases were intraocular pressure increased, transient blindness, reduced visual acuity, corneal oedema, corneal pain, and eye pain. If an overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the attending physician.
In clinical trials doses up to 2 mg of ranibizumab in an injection volume of 0.05 mL to 0.10 mL have been administered to patients with wet AMD and DME. The type and frequency of ocular and systemic adverse events were consistent with those reported for the 0.5 mg (in 0.05 mL) Lucentis dose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Trehalose dihydrate, histidine hydrochloride monohydrate, histidine, polysorbate 20, water for injections.

6.2 Incompatibilities

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

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.

Store at 2°C to 8°C (refrigerate - do not freeze). Protect from light.
Keep the vial in the outer carton in order to protect from light.
Prior to usage, the unopened tray may be kept at room temperature (25°C) for up to 24 hours.

Pre-filled syringe pack.

Store at 2°C to 8°C (refrigerate - do not freeze). Protect from light.
Keep the pre-filled syringe in its sealed tray in the carton in order to protect from light. Prior to usage, the unopened tray may be kept at room temperature (25°C) for up to 24 hours.

6.5 Nature and Contents of Container

Vial pack*.

Lucentis is supplied as 0.23 mL solution for injection in glass vials (colourless type I glass) with chlorobutyl rubber stopper. One pack contains one vial, one filter needle for withdrawal of the vial contents, one needle for intravitreal injection and one syringe for withdrawal of the vial contents and for intravitreal injection. Each vial contains 2.3 mg of ranibizumab in 0.23 mL solution.

Vial and filter needle pack.

0.23 mL Lucentis solution for injection in a glass vial (colourless type I glass) with chlorobutyl rubber stopper. One pack contains one vial and one filter needle for withdrawal of the vial content.

Vial only*.

Lucentis is supplied as 0.23 mL solution for injection in glass vials (colourless type I glass) with chlorobutyl rubber stopper. One pack contains one vial.

Pre-filled syringe pack.

Lucentis is supplied as 0.165 mL sterile solution in a pre-filled syringe (type I glass) with a bromobutyl rubber plunger stopper and a syringe cap consisting of a white, tamper-evident rigid seal with a grey bromobutyl rubber tip cap and a Luer Lock adapter. The pre-filled syringe has a plunger rod and a finger grip, and is packed in a sealed tray. One pack contains one pre-filled syringe. Each pre-filled syringe contains 1.65 mg of ranibizumab in 0.165mL solution.
* Not all presentations may be marketed.

6.6 Special Precautions for Disposal

Dispose of the used syringe together with the needle in a sharps disposal container or in accordance with local requirements.

Summary Table of Changes