1. Name Of The Medicinal Product
2. Qualitative And Quantitative Composition
One ml contains 10 mg ranibizumab. Each vial contains 2.3 mg of ranibizumab in 0.23 ml solution.
Ranibizumab is a humanised monoclonal antibody fragment produced in Escherichia coli cells by recombinant DNA technology.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection
Sterile, clear, colourless to pale yellow aqueous solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Lucentis is indicated in adults for:
• the treatment of neovascular (wet) age-related macular degeneration (AMD) (see section 5.1).
• the treatment of visual impairment due to diabetic macular oedema (DME) (see section 5.1).
• the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO) (see section 5.1).
4.2 Posology And Method Of Administration
Single-use vial for intravitreal use only.
Lucentis must be administered by a qualified ophthalmologist experienced in intravitreal injections.
Treatment of wet AMD
In wet AMD, the recommended dose for Lucentis is 0.5 mg given monthly as a single intravitreal injection. This corresponds to an injection volume of 0.05 ml.
Treatment is given monthly and continued until maximum visual acuity is achieved i.e. the patient`s visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment.
Thereafter patients should be monitored monthly for visual acuity.
Treatment is resumed when monitoring indicates loss of visual acuity due to wet AMD. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month.
Treatment of visual impairment due to either DME or macular oedema secondary to RVO (see also section 5.1)
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.
Treatment is given monthly and continued until maximum visual acuity is achieved i.e the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment. If there is no improvement in visual acuity over the course of the first three injections, continued treatment is not recommended.
Thereafter patients should be monitored monthly for visual acuity.
Treatment is resumed when monitoring indicates loss of visual acuity due to DME or to macular oedema secondary to RVO. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month.
Lucentis and laser photocoagulation in DME and in macular oedema secondary to BRVO
There is some experience of Lucentis administered concomitantly with laser photocoagulation (see section 5.1). 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.
Method of administration
As with all medicinal products for parenteral use, Lucentis should be inspected visually for particulate matter and discoloration prior to administration.
Before treatment, the patient should be instructed to self-administer antimicrobial drops (four times daily for 3 days before and following each injection).
The injection procedure should be carried out under aseptic conditions, which includes the use of surgical hand disinfection, sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent) and the availability of sterile paracentesis (if required). The patient's medical history for hypersensitivity reactions should be carefully evaluated prior to performing the intravitreal procedure (see section 4.4). The periocular skin, eyelid and ocular surface should be disinfected and adequate anaesthesia and a broad-spectrum topical microbicide should be administered prior to the injection.
For information on preparation of Lucentis, see section 6.6.
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. The injection volume of 0.05 ml is then delivered; a different scleral site should be used for subsequent injections.
Additional information on special populations
Hepatic impairment
Lucentis has not been studied in patients with hepatic impairment. However, no special considerations are needed in this population.
Renal impairment
Dose adjustment is not needed in patients with renal impairment (see section 5.2).
Paediatric population
Lucentis is not recommended for use in children and adolescents due to a lack of data on safety and efficacy in these sub-populations.
Elderly
No dose adjustment is required in the elderly. There is limited experience in patients older than 75 years with DME.
Ethnicity
Experience with treatment is limited in groups other than Caucasians.
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 severe intraocular inflammation.
4.4 Special Warnings And Precautions For Use
Treatment with Lucentis is for intravitreal injection only.
Intravitreous injections, including those with Lucentis, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see section 4.8). Proper aseptic injection techniques must always be used when administering Lucentis. In addition, patients should be monitored 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. Sustained IOP increases have also been identified (see section 4.8). Both intraocular pressure and the perfusion of the optic nerve head must be monitored and managed appropriately.
The safety and efficacy of Lucentis therapy administered to both eyes concurrently have not been studied. If bilateral treatment is performed at the same time this could lead to an increased systemic exposure, which could increase the risk of systemic adverse events.
As with all therapeutic proteins, there is a potential for immunogenicity with Lucentis. Since there is a potential for an increased systemic exposure in subjects with DME, an increased risk for developing hypersensitivity in this patient population cannot be excluded. Patients should also be instructed to report if an intraocular inflammation increases in severity, which may be a clinical sign attributable to intraocular antibody formation.
Lucentis should not be administered concurrently with other anti-VEGF (vascular endothelial growth factor) agents (systemic or ocular).
The dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of:
• a decrease in best-corrected visual acuity (BCVA) of
• an intraocular pressure of
• a retinal break;
• a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is
• performed or planned intraocular surgery within the previous or next 28 days.
Risk factors associated with the development of a retinal pigment epithelial tear after anti-VEGF therapy for wet AMD, include a large and/or high pigment epithelial retinal detachment. When initiating Lucentis therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.
Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.
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, proliferative diabetic retinopathy, 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 are limited data on safety in the treatment of DME and macular oedema due to RVO patients with prior history of stroke or transient ischaemic attacks. Since there is a potential risk of arterial thromboembolic events following intravitreal use of VEGF (vascular endothelial growth factor) inhibitors caution should be exercised when treating such patients (see section 4.8).
There is limited experience with treatment of patients with prior episodes of RVO and of patients with ischaemic branch RVO (BRVO) and central RVO (CRVO). In patients with RVO presenting with clinical signs of irreversible ischaemic visual function loss, treatment is not recommended.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No formal interaction studies have been performed.
For the adjunctive use of verteporfin photodynamic therapy (PDT) and Lucentis in wet AMD, see section 5.1.
For the adjunctive use of laser photocoagulation and Lucentis in DME and BRVO, see sections 4.2 and 5.1.
4.6 Pregnancy And Lactation
Women of childbearing potential/contraception in females
Women of childbearing potential should use effective contraception during treatment.
Pregnancy
For ranibizumab no clinical data on exposed pregnancies are available. Studies in cynomolgus monkeys do not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/foetal development (see section 5.3). The systemic exposure to ranibizumab is low after ocular administration, but due to its mechanism of action, ranibizumab must be regarded as potentially teratogenic and embryo-/foetotoxic. Therefore, ranibizumab should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus. 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.
Breast-feeding
It is unknown whether Lucentis is excreted in human milk. Breast-feeding is not recommended during the use of Lucentis.
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). Patients who experience these signs must not drive or use machines until these temporary visual disturbances subside.
4.8 Undesirable Effects
Wet AMD population
In wet AMD a total of 1,315 patients constituted the safety population in the three phase III studies with 24 months exposure to Lucentis and 440 patients were treated with the recommended dose of 0.5 mg.
Serious adverse events related to the injection procedure included endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see section 4.4).
Other serious ocular events observed among Lucentis-treated patients included intraocular inflammation and increased intraocular pressure (see section 4.4).
The adverse events listed below 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 or verteporfin PDT) in the three controlled wet AMD phase III studies FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER). These were therefore considered potential adverse drug reactions. The safety data described below also include all adverse events (in at least 0.5 percentage points of patients) suspected to be at least potentially related to the injection procedure or medicinal product in the 440 patients of the combined 0.5 mg treatment groups in wet AMD.
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). The event of urinary tract infection, in the common frequency category, met the adverse reaction criteria for the table below; 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.
RVO population
The safety of Lucentis was studied in two 12-month trials (BRAVO and CRUISE) conducted in 264 and 261 ranibizumab-treated patients with visual impairment due to macular oedema secondary to BRVO and CRVO, respectively (see section 5.1). 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.
The adverse events are listed by system organ class and frequency using the following convention: very common (
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* observed only in DME population
Product-class-related adverse reactions: In the wet AMD phase III studies, the overall frequency of non-ocular haemorrhages, an adverse event potentially related to systemic VEGF (vascular endothelial growth factor) inhibition, was slightly increased in ranibizumab-treated patients. However, there was no consistent pattern among the different haemorrhages. There is a theoretical risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. A low incidence rate of arterial thromboembolic events was observed in the Lucentis clinical trials in patients with AMD, DME and RVO and there were no major differences between the groups treated with ranibizumab compared to control.
4.9 Overdose
Cases of accidental overdose have been reported from the clinical studies in wet AMD and post-marketing data. Adverse reactions 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antineovascularisation agents, ATC code: S01LA04
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, all of which are thought to contribute to the progression of the neovascular form of age-related macular degeneration or to visual impairment caused by either diabetic macular oedema or macular oedema secondary to RVO.
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 of 24 months duration in patients with neovascular AMD. A total of 1,323 patients (879 active and 444 control) were enrolled in these studies.
In study FVF2598g (MARINA), 716 patients with minimally classic or occult with no classic choroidal neovascularisation (CNV) received monthly intravitreal injections of Lucentis 0.3 mg (n=238) or 0.5 mg (n=240) or sham (n=238) injections.
In study FVF2587g (ANCHOR), 423 patients with predominantly classic CNV lesions received either: 1) monthly intravitreal injections of Lucentis 0.3 mg and sham PDT (n=140); 2) monthly intravitreal injections of Lucentis 0.5 mg and sham PDT (n=140); or 3) sham intravitreal injections and active verteporfin PDT (n=143). Sham or active verteporfin PDT was given with the initial Lucentis injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of vascular leakage.
Key outcome measures are summarised in Tables 1, 2 and Figure 1.
Table 1 Outcomes at Month 12 and Month 24 in study FVF2598g (MARINA)
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Table 2 Outcomes at Month 12 and Month 24 in study FVF2587g (ANCHOR)
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Figure 1 Mean change in visual acuity from baseline to Month 24 in study FVF2598g (MARINA) and study FVF2587g (ANCHOR)
Results from both trials indicated that continued ranibizumab treatment may also be of benefit in patients who lost
The use of Lucentis beyond 36 months has not been studied.
Study FVF3192g (PIER) was a randomised, double-masked, sham-controlled study designed to assess the safety and efficacy of Lucentis in 184 patients with all forms of neovascular AMD. Patients received Lucentis 0.3 mg (n=60) or 0.5 mg (n=61) intravitreal injections or sham (n=63) injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months. From Month 14 of the study, sham-treated patients were allowed to cross over to receive ranibizumab and from Month 19, more frequent treatments were possible. Patients treated with Lucentis in PIER received a mean of 10 total treatments.
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' visual acuity declined with quarterly dosing, returning to baseline at Month 12 and this effect was maintained in most ranibizumab-treated patients (82%) at Month 24. Data from a limited number of subjects that crossed over to receive ranibizumab after more than a year of sham-treatment suggested that early initiation of treatment may be associated with a better preservation of visual acuity.
Data from an open label study (PROTECT) in 32 patients followed for 9 months in which the safety of same-day administration of verteporfin PDT and Lucentis 0.5 mg was evaluated showed that the incidence of intraocular inflammation following the initial treatment was 6.3% (2 of 32 patients).
In both the MARINA and ANCHOR studies, the improvement in visual acuity seen with Lucentis 0.5 mg at 12 months was accompanied by patient-reported benefits as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) scores. The differences between Lucentis 0.5 mg and the two control groups were assessed with p-values ranging from 0.009 to <0.0001.
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. A total of 496 patients (336 active and 160 control) were enrolled in these studies, the majority had type II diabetes, 28 ranibizumab-treated patients had type I diabetes.
In the phase II study D2201 (RESOLVE), 151 patients 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. Laser photocoagulation was allowed as rescue treatment from Month 3 in both treatment arms. The study had two parts: an exploratory part (the first 42 patients analysed at Month 6) and a confirmatory part (the remaining 109 patients analysed at Month 12).
Key outcome measures from the confirmatory part of the study (2/3 of patients) are summarised in Table 3.
Table 3 Outcomes at Month 12 in study D2201 (RESOLVE) (overall study population)
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ap<0.0001
In the phase III study D2301 (RESTORE), 345 patients with visual impairment due to macular oedema were randomised to receive either 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 a reduction in BCVA due to DME progression was observed. Laser photocoagulation was administered at baseline on the same day, at least 30 minutes before injection of ranibizumab, and then as needed based on ETDRS criteria.
Key outcome measures are summarised in Table 4 and Figure 2.
Table 4 Outcomes at Month 12 in study D2301 (RESTORE)
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ap<0.0001
Figure 2 Mean change in visual acuity from baseline over time in study D2301 (RESTORE)
BL=baseline; SE=standard error of mean
* Difference in least square means, p<0.0001/0.0004 based on two-sided stratified Cochran-Mantel-Haenszel test
The effect was consistent in most subgroups. However, subjects with a fairly good baseline BCVA (>73 letters) together with macular oedema with central retinal thickness of <300 μm did not appear to benefit from treatment with ranibizumab compared to laser photocoagulation.
The improvement in visual acuity seen with Lucentis 0.5 mg at 12 months was accompanied by patient-reported benefits with regards to most vision-related functions as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) scores. For other subscales of this questionnaire no treatment differences could be established. The difference between Lucentis 0.5 mg and the control group was assessed with p-values of 0.0137 (ranibizumab mono) and 0.0041 (ranibizumab+laser) for the VFQ-25 composite score.
In both studies, the improvement of vision was accompanied by a continuous decrease in the macular oedema as measured by central retinal thickness (CRT).
Treatment of visual impairment due to macular oedema secondary to RVO
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 0.3 mg or 0.5 mg intravitreal ranibizumab or sham injections. After 6 months, patients in the sham-control arms were crossed over to 0.5 mg ranibizumab. In BRAVO, laser photocoagulation as rescue was allowed in all arms from Month 3.
Key outcome measures from BRAVO and CRUISE are summarised in Tables 5 and 6 and Figures 3 and 4.
Table 5 Outcomes at Month 6 and 12 (BRAVO)
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ap<0.0001
Figure 3 Mean change from baseline BCVA over time to Month 6 and Month 12 (BRAVO)
BL=baseline; SE=standard error of mean
Table 6 Outcomes at Month 6 and 12 (CRUISE)
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ap<0.0001
Figure 4 Mean change from baseline BCVA over time to Month 6 and Month 12 (CRUISE)
BL=baseline; SE=standard error of mean
In both studies, the improvement of vision was accompanied by a continuous and significant reduction in the macular oedema as measured by central retinal thickness.
In patients with BRVO (BRAVO and extension study HORIZON): After 2 years, subjects that were treated with sham in the first 6 months and subsequently crossed over to ranibizumab treatment had achieved comparable gains in VA (~15 letters) compared to subjects that were treated wit
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