Accentrix

Accentrix

ranibizumab

Manufacturer:

Novartis

Distributor:

DKSH
Full Prescribing Info
Contents
Ranibizumab.
Description
One mL contains 10 mg ranibizumab.
Each vial contains 2.3 mg of ranibizumab in 0.23 mL solution.
Ranibizumab is a humanized monoclonal antibody fragment produced in Escherichia coli cells by recombinant DNA technology.
Excipients/Inactive Ingredients: alpha, alpha-trehalose dihydrate, histidine hydrochloride, monohydrate, histidine, polysorbate 20, water for injections.
Action
Pharmacology: Mechanism of action (MOA): Ranibizumab is a humanized 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.
Pharmacodynamics (PD): 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 CNV, including CNV secondary to pathologic myopia or to the macular edema causing visual impairment in diabetes and retinal vein occlusion.
Clinical Studies: Treatment of wet AMD: In wet AMD, the clinical safety and efficacy of ranibizumab have been assessed in three randomized, double-masked, sham** or active-controlled studies in patients with neovascular AMD (FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER)). A total of 1,323 patients (879 active and 444 control) were 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 CNV received monthly intravitreal injections of ranibizumab 0.3 mg or 0.5 mg or sham injections. A total of 716 patients were enrolled in this study (sham, 238; ranibizumab 0.3 mg, 238; ranibizumab 0.5 mg, 240).
In the 24-month study FVF2587g (ANCHOR), patients with predominantly classic CNV lesions received either: 1) monthly intravitreal injections of ranibizumab 0.3 mg and sham PDT; 2) monthly intravitreal injections of ranibizumab 0.5 mg and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Verteporfin (or sham) PDT was given with the initial ranibizumab (or sham) injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of vascular leakage. A total of 423 patients were enrolled in this study (ranibizumab 0.3 mg, 140; ranibizumab 0.5 mg, 140; verteporfin PDT, 143).
** The sham Ranibizumab injection control procedure involved anesthetising the eye in a manner identical to a Ranibizumab intravitreal injection. The tip of a needleless syringe was then pressed against the conjunctiva and the plunger of the needleless syringe depressed.
Key outcomes are summarised in Tables 1, 2 and Figure 1. (See Tables 1, 2 and Figure 1.)

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Patients in the group treated with ranibizumab 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 ranibizumab versus 2.3 to 2.6 DA for the control arms.
Results from both trials indicated that continued ranibizumab-treatment may be of benefit also in patients who lost ≥15 letters of best-corrected visual acuity (BCVA) in the first year of treatment.
In both the MARINA and ANCHOR studies, the improvement in visual acuity seen with ranibizumab 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 ranibizumab 0.5 mg and the two control groups were assessed with p-values ranging from 0.009 to <0.0001.
Study FVF3192g (PIER): Study FVF3192g (PIER) was a randomized, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of ranibizumab in 184 patients with neovascular AMD (with or without a classic CNV component). Patients received ranibizumab 0.3 mg or 0.5 mg intravitreal injections or sham 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 ranibizumab in PIER received a mean of 10 treatments during the study. The primary efficacy endpoint was mean change in visual acuity at Month 12 compared with baseline. After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every three months with ranibizumab lost visual acuity, returning to baseline at Month 12. 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.
Study FVF3689g (SAILOR): Study FVF3689g (SAILOR) was a Phase IIIb, single-masked, one-year multicenter 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 randomized in a 1:1 ratio to receive one intravitreal injection of 0.3 mg or 0.5 mg ranibizumab 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 ischemic attack.
Study A2412 (EVEREST II): Study A2412 (EVEREST II) is a two-year, randomized, double-masked, multicenter study designed to evaluate the efficacy and safety of Accentrix 0.5 mg monotherapy vs. Accentrix 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 Accentrix injections, plus sham or active vPDT given with the first Accentrix injection only. Following treatment initiation, Accentrix monotherapy and Accentrix 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 Accentrix administered with vPDT was superior to Accentrix 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 Accentrix with vPDT received on average 2.3 Accentrix injections less than patients administered Accentrix monotherapy (5.1 vs. 7.4 injections).
Superiority of Accentrix with vPDT compared to Accentrix 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 Accentrix with vPDT received on average 4.2 Accentrix injections less than patients administered Accentrix monotherapy (8.1 vs. 12.3 injections).
The safety profile in these patients was consistent with that seen in previous clinical trials with Accentrix monotherapy.
Treatment of visual impairment due to DME: The efficacy and safety of ranibizumab have been assessed in two randomized, double-masked, sham- or active controlled studies of 12 months duration in patients with visual impairment due to diabetic macular edema (Study D2301 (RESTORE) and D2201 (RESOLVE)). A total of 496 patients (336 active and 160 control) were 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 edema were randomized 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 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 Table 3 and Figure 2. (See Table 3 and Figure 2.)

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Study D2301E1 (RESTORE Extension): Study D2301E1 (RESTORE Extension) was an open-label, multi-center, 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 administered monthly upon a decrease in BCVA due to DME 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 in the core study. Of the 74 patients from the core study laser treatment arm, 59 (79%) 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.
Key outcome measures are summarized in Table 4. (See Table 4.)

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The long-term safety profile of ranibizumab observed in this 24-month extension study is consistent with the known ranibizumab safety profile.
Study D2201 (RESOLVE): In study D2201 (RESOLVE), a total of 151 patients with macular center involvement 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 the investigator evaluated that response to treatment was not sufficiently achieved. Laser photocoagulation rescue treatment was allowed from Month 3 in both treatment arms. The study was comprised of 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 outcomes from the confirmatory part of the study (2/3 of the patients) are summarised in Table 5 and Figure 3. (See Table 5 and Figure 3.)

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Patients treated with ranibizumab experienced a continuous reduction in central retina thickness (CRT). At month 12, the mean CRT change from baseline was -194 micrometers for ranibizumab versus -48 micrometers 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 D2304 (RETAIN): In the phase IIIb study D2304 (RETAIN), 372 patients with visual impairment due to DME were randomized to receive either intravitreal injection of ranibizumab 0.5 mg with concomitant laser photocoagulation on a treat-and-extend (TE) regimen (n=121), 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 TE regimen, ranibizumab was then administered, at scheduled treatment at intervals of 2-3 months. On PRN regimen, BCVA was assessed monthly and ranibizumab was 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 the number of scheduled treatment visits required by the TE regimen was 40% lower than the number of monthly visits required by the PRN regimen. With both regimens, more than 70% of patients were able to maintain their BCVA with a visit frequency of ≥ 2 months.
Key outcome measures are summarized in Table 6. (See Table 6.)

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In DME studies, the improvement in BCVA was accompanied by a reduction over time in mean CRT in all the treatment groups.
There was no difference in the BCVA or CRT outcomes of patients in RETAIN study who received or did not receive concomitant thiazolidinediones.
Study D2303 (REVEAL): The study D2303 (REVEAL), was a 12 month, randomized, 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 edema were randomized 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.
Treatment of visual impairment due to macular edema secondary to RVO: Study FVF4165g (BRAVO) and study FVF4166g (CRUISE): The clinical safety and efficacy of ranibizumab in patients with visual impairment due to macular edema secondary to RVO have been assessed in the randomized, 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 outcomes from BRAVO and CRUISE are summarized in Tables 7 and 8, and Figures 4 and 5. (See Table 7, Figure 4 and Table 8, Figure 5.)

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In both studies, the improvement of vision was accompanied by a continuous decrease in the macular edema 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 ranibizumab 0.5 mg and the control group was assessed at Month 6 with p-values of 0.02 to 0.0002.
Study E2401 (CRYSTAL) and study E2402 (BRIGHTER): The long term (24 month) clinical safety and efficacy of ranibizumab in patients with visual impairment due to macular edema secondary to RVO were assessed in the BRIGHTER and CRYSTAL studies, which recruited subjects with BRVO (n=455) and CRVO (n=357), respectively. In both studies, subjects received a 0.5 mg ranibizumab PRN dosing regimen driven by individualized stabilization criteria. BRIGHTER was a 3-arm, randomized, active-controlled study that compared 0.5 mg ranibizumab given as monotherapy or in combination with adjunctive laser photocoagulation, to laser photocoagulation alone. After 6 months, subjects in the laser monotherapy arm could receive 0.5 mg ranibizumab. CRYSTAL was a single-arm study with 0.5 mg ranibizumab monotherapy.
Key outcome measures from BRIGHTER and CRYSTAL are shown in Table 9 and Figures 6 and 7. (See Table 9 and Figures 6 and 7.)

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In BRIGHTER, 0.5 mg ranibizumab with adjunctive laser therapy demonstrated non-inferiority to ranibizumab monotherapy from baseline to Month 24 as assessed by the mean average change in BCVA. There was no difference between the two groups in the number of ranibizumab injections administered over this period.
In both studies, a rapid and significant decrease from baseline in central retinal subfield thickness was observed at Month 1. This effect was maintained up to Month 24.
The beneficial effect of ranibizumab treatment was similar irrespective of the presence of retinal ischemia. In BRIGHTER, patients with retinal ischemia present (N=87) or absent (N=35) and treated with ranibizumab monotherapy had a mean change from baseline of +15.4 and +12.9 letters respectively, at Month 24. In CRYSTAL, patients with retinal ischemia present (N=107) or absent (N=109), treated with ranibizumab monotherapy had a mean change from baseline of +11.1 and +12.9 letters, respectively.
The beneficial effect in terms of visual improvement was observed in all patients treated with 0.5 mg ranibizumab monotherapy regardless of their disease duration in both BRIGHTER and CRYSTAL. In patients with <3 months disease duration an increase in visual acuity of 13.3 and 10.0 letters was seen at Month 1; and 17.7 and 13.2 letters at Month 24 in BRIGHTER and CRYSTAL, respectively. Treatment initiation at the time of diagnosis should be considered.
The long term safety profile of ranibizumab observed in these 24-month studies is consistent with the known ranibizumab safety profile.
Treatment of visual impairment due to CNV: Study G2301 (MINERVA): The clinical safety and efficacy of ranibizumab in patients with visual impairment due to CNV secondary to etiologies other than nAMD and PM have been assessed based on the 12-month data of the randomized, double-masked, sham controlled pivotal study G2301 (MINERVA). 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 randomized 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 10 and 11 and Figure 8. (See Tables 10 and Figure 8.)

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When comparing ranibizumab versus sham control at Month 2, a consistent treatment effect both overall and across baseline etiology subgroups was observed. (See Table 11.)

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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.
A trend in patient-reported benefits, as measured by the NEI VFQ-25 composite score, was observed from baseline to Month 2 for patients receiving ranibizumab treatment versus the sham control group. This trend was maintained to Month 12.
Pediatric 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 Dosage & Administration, Pediatric patients).
Treatment of visual impairment due to CNV secondary to PM: Study F2301 (RADIANCE): The clinical safety and efficacy of ranibizumab 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 0.5 mg ranibizumab given as an intravitreal injection in comparison to verteporfin PDT (vPDT, Visudyne photodynamic therapy).
The 277 patients were randomised to one of the following arms: 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 OCT and/or 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 DOSAGE & 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 summarized in Table 12 and Figure 9. (See Table 12 and Figure 9.)

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The improvement of vision was accompanied by a reduction in central retinal thickness.
Patient-reported benefits were observed with 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.
Paediatric population: The safety and efficacy of ranibizumab have not yet been studied in paediatric patients.
Pharmacokinetics (PK): Absorption: Following monthly intravitreal administration of ranibizumab to patients with neovascular AMD, serum concentrations of ranibizumab were generally low, with maximum levels (Cmax) generally below the ranibizumab concentration necessary to inhibit the biological activity of VEGF by 50% (11 to 27 ng/mL, as assessed in an in vitro cellular proliferation assay). Cmax was dose proportional over the dose range of 0.05 to 1.0 mg/eye. Upon monthly intravitreal administration of ranibizumab 0.5 mg/eye, serum ranibizumab Cmax, attained approximately 1 day after dosing, is predicted to generally range between 0.79 and 2.90 ng/mL, and Cmin is predicted to generally range between 0.07 and 0.49 ng/mL. Serum ranibizumab concentrations in DME and 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.
Special populations: Renal impairment: No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in patients with renal impairment. In a population pharmacokinetic analysis of neovascular AMD patients, 68% (136 of 200) 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 ranibizumab in patients with hepatic impairment.
Toxicology: Non-Clinical Safety Data: Bilateral intravitreal administration of ranibizumab to cynomolgus monkeys at doses between 0.25 mg/eye and 2.0 mg/eye once every 2 weeks for up to 26 weeks resulted in dose-dependent ocular effects.
Intraocularly, there were dose-dependent increases in anterior chamber flare and cells with a peak 2 days after injection. The severity of the inflammatory response generally diminished with subsequent injections or during recovery. In the posterior segment, there were vitreal cell infiltration and floaters, which also tended to be dose-dependent and generally persisted to the end of the treatment period. In the 26-week study, the severity of the vitreous inflammation increased with the number of injections. However, evidence of reversibility was observed after recovery. The nature and timing of the posterior segment inflammation is suggestive of an immune-mediated antibody response, which may be clinically irrelevant. Cataract formation was observed in some animals after a relatively long period of intense inflammation, suggesting that the lens changes were secondary to severe inflammation. A transient increase in post-dose intraocular pressure was observed following intravitreal injections, irrespective of dose.
Microscopic ocular changes were related to inflammation and did not indicate degenerative processes. Granulomatous inflammatory changes were noted in the optic disc of some eyes. These posterior segment changes diminished, and in some instances resolved, during the recovery period. Following intravitreal administration, no signs of systemic toxicity were detected. Serum and vitreous antibodies to ranibizumab were found in a subset of treated animals.
No carcinogenicity and mutagenicity data are available.
In pregnant monkeys, IVT ranibizumab treatment did not elicit developmental toxicity or teratogenicity, and had no effect on weight or structure of the placenta, although, based on its pharmacological effect ranibizumab should be regarded as potentially teratogenic and embryo-foetotoxic.
However due to restrictions dictated by the intravitreal route of administration the feasible doses used in this study did not reach maternal toxicity but only a multiple with respect to human systemic exposure. The absence of ranibizumab-mediated effects on the embryo-foetal development is plausibly related mainly to the inability of the Fab fragment to cross the placenta.
Nevertheless, a case was described with high maternal ranibizumab serum levels and presence of ranibizumab in foetal serum, suggesting that 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. 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 (see recommendations in WOMEN OF CHILD-BEARING POTENTIAL, PREGNANCY AND BREAST-FEEDING AND FERTILITY under Use in Pregnancy & Lactation).
Indications/Uses
Accentrix is indicated for: the treatment of neovascular (wet) age-related macular degeneration (AMD), the treatment of visual impairment due to diabetic macular oedema (DME), the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (RVO), the treatment of visual impairment due to choroidal neovascularization (CNV).
Dosage/Direction for Use
Dosage: 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.
Accentrix must be administered by a qualified ophthalmologist experienced in intravitreal injections.
The recommended dose for Accentrix 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.
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 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, Accentrix should be discontinued.
Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography).
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.
The treatment of visual impairment due to CNV should be determined individually per patient based on disease activity. Some patients may only need one injection during the first 12 months; others may need more frequent treatment, including a monthly injection. For CNV secondary to pathologic myopia (PM), many patients may only need one or two injections during the first year (see PHARMACOLOGY under Actions).
Ranibizumab and laser photocoagulation in DME and in macular oedema secondary to BRVO: There is some experience of Ranibizumab administered concomitantly with laser photocoagulation (see Pharmacology: PHARMACODYNAMICS under Actions). When given on the same day, Ranibizumab should be administered at least 30 minutes after laser photocoagulation. Ranibizumab can be administered in patients who have received previous laser photocoagulation.
Ranibizumab and Visudyne photodynamic therapy in CNV secondary to PM: There is no experience of concomitant administration of Ranibizumab and Visudyne.
Special populations: Hepatic impairment: Ranibizumab 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 Pharmacology: PHARMACOKINETICS under Actions).
Pediatric population: The safety and efficacy of ranibizumab in children and adolescents below 18 years of age have not been established. Available data in adolescent patients aged 12 to 17 years with visual impairment due to CNV are described in Pharmacology: Pharmacodynamics: CLINICAL STUDIES under Actions.
Elderly: No dose adjustment is required in the elderly. There is limited experience in patients older than 75 years with DME.
Method of administration: Single-use vial for intravitreal use only.
Accentrix should be inspected visually for particulate matter and discoloration prior to administration.
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 PRECAUTIONS). Adequate anaesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid and ocular surface should be administered prior to the injection, in accordance with local practice.
For information on preparation of Accentrix, see INSTRUCTIONS FOR USE AND HANDLING under Cautions for Usage.
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; a different scleral site should be used for subsequent injections.
Overdosage
Cases of accidental overdose (injection of volumes greater than the recommended 0.05 mL ranibizumab) have been reported from the clinical studies in wet AMD and post-marketing data. Adverse reactions most frequently associated with these reported cases were increased intraocular pressure 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) ranibizumab dose.
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.
Special Precautions
Intravitreal injection-related reactions: Intravitreous injections, including those with Ranibizumab, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract (see ADVERSE REACTIONS). Proper aseptic injection techniques must always be used when administering Accentrix. 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 previously mentioned events without delay.
Intraocular pressure increases: Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of ranibizumab. Sustained IOP increases have also been identified (see ADVERSE REACTIONS). Both intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately.
Bilateral treatment: Limited data on bilateral use of ranibizumab (including same-day administration) do not suggest an increased risk of systemic adverse events compared with unilateral treatment.
Immunogenicity: There is a potential for immunogenicity with ranibizumab. 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.
Concomitant use of other anti-VEGF (vascular endothelial growth factor): Ranibizumab should not be administered concurrently with other anti-VEGF medicinal products (systemic or ocular).
Withholding Accentrix: 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 ≥30 letters compared with the last assessment of visual acuity; an intraocular pressure of ≥30 mmHg; a retinal break; a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50%, of the total lesion area; performed or planned intraocular surgery within the previous or next 28 days.
Retinal pigment epithelia tear: 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 Accentrix therapy, caution should be used in patients with these risk factors for retinal pigment epithelial tears.
Rhegmatogenous retinal detachment or macular holes: Treatment should be discontinued in subjects with rhegmatogenous retinal detachment or stage 3 or 4 macular holes.
Population with limited data: There is only limited experience in the treatment of subjects with DME due to type I diabetes. Ranibizumab 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 ranibizumab in diabetic patients with an HbA1c over 12% and uncontrolled hypertension. This lack of information should be considered by the physician when treating such patients.
There are insufficient data to conclude on the effect of ranibizumab in patients with RVO presenting irreversible ischaemic visual function loss.
In patients with PM, there are limited data on the effect of ranibizumab in patients who have previously undergone unsuccessful verteporfin photodynamic therapy (vPDT) treatment. Also, while a consistent effect was observed in subjects with subfoveal and juxtafoveal lesions, there are insufficient data to conclude on the effect of ranibizumab in PM subjects with extrafoveal lesions.
Systemic effects following intravitreal use: Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGT inhibitors.
There are limited data on safety in the treatment of DME, macular oedema due to RVO and CNV secondary to PM patients with prior history of stroke or transient ischaemic attacks. Caution should be exercised when treating such patients (see ADVERSE REACTIONS).
Driving and using machines: The Accentrix treatment procedure may induce temporary visual disturbances, which may affect the ability to drive or use machines (see ADVERSE REACTIONS). Patients who experience these signs must not drive or use machines until these temporary visual disturbances subside.
Use In Pregnancy & Lactation
Women of child-bearing potential: Women of child-bearing 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 Pharmacology: Toxicology: NON-CLINICAL SAFETY DATA under Actions). 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-/fetotoxic. 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 not known whether ranibizumab is excreted in human milk. As a precautionary measure, breast-feeding is not recommended during the use of ranibizumab.
Fertility: There is no fertility data available.
Adverse Reactions
Summary of the safety profile: Wet AMD population: A total of 1,315 patients constituted the safety population in the three controlled phase III studies for wet AMD (FVF2598g (MARINA), FVF2587 (ANCHOR) and FVF3192g (PIER)) with 24 months exposure to ranibizumab 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 PRECAUTIONS).
Other serious ocular events observed among ranibizumab-treated patients included intraocular inflammation and increased intraocular pressure (see PRECAUTIONS).
The adverse events listed below in Table 13 occurred at a higher rate (at least 2 percentage points) in patients receiving treatment with ranibizumab 0.5 mg than in those receiving control treatment (sham injection, as defined in PHARMACOLOGY: PHARMACODYNAMICS under Actions or verteporfin photodynamic therapy (PDT)) in the pooled data of the three controlled wet AMD studies. These were therefore considered potential adverse drug reactions. The safety data described as follows 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 ranibizumab.
DME population: The safety of ranibizumab 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 Pharmacology: Pharmacodynamics: CLINICAL STUDIES under Actions). The event of urinary tract infection, in the common frequency category, met the adverse reaction criteria for the Table 13 as follows; 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 ranibizumab 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 edema secondary to BRVO and CRVO, respectively (see Pharmacology: Pharmacodynamics: CLINICAL STUDIES under Actions). 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.
PM population: The safety of ranibizumab 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 Pharmacology: Pharmacodynamics: CLINICAL STUDIES under Actions). Ocular and non-ocular events in this trial were reported with a frequency and severity similar to those seen in the wet AMD trials.
Tabulated summary of adverse drug reactions from clinical trials: The adverse drug reactions from clinical trials (Table 13) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions 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 III): 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). (See Table 13.)

Click on icon to see table/diagram/image

A meta-analysis of pooled safety data from completed, randomized, 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 patient years) compared to control (0.27/100 patient years). The relationship to ranibizumab remains unknown.
Drug Interactions
No formal interaction studies have been performed.
For the adjunctive use of verteporfin photodynamic therapy (PDT) and ranibizumab in wet AMD, and PM, see Pharmacology: Pharmacodynamics: CLINICAL STUDIES under Actions.
For the adjunctive use of laser photocoagulation and ranibizumab in DME and BRVO, see Pharmacology: Pharmacodynamics: CLINICAL STUDIES under Actions and DOSAGE & ADMINISTRATION.
In clinical studies for the treatment of visual impairment due to DME, the outcome with regard to visual acuity or central retinal subfield thickness (CSFT) in patients treated with ranibizumab was not affected by concomitant treatment with thiazolidinediones.
Caution For Usage
Instructions for Use and Handling: Vials are for single use only (see DOSAGE & ADMINISTRATION). After injection any unused product must be discarded.
The vial is sterile. 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 discolored, cloudy, or contains particulates.
For preparation and intravitreal injection, the following single-use medical devices are needed: a 5 micrometer filter needle (18G); a 1 mL sterile syringe; an injection needle (30G x 1/2 inch).
These medical devices are not supplied in the Accentrix pack that contains only the vial.
To prepare Accentrix for intravitreal administration, please adhere to the following instructions: 1. Before withdrawal, the outer part of the rubber stopper of the vial should be disinfected.
2. Attach a 5 micrometer filter needle (18G) to a 1 mL syringe using 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) to 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 off the used syringe together with the needle in a sharps disposal container or in accordance with local requirements.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Storage
Store in a refrigerator (2°C to 8°C).
Do not freeze. Keep the vial in the outer carton in order to protect from light.
ATC Classification
S01LA04 - ranibizumab ; Belongs to the class antineovasculatisation agents. Used in the management of neovascular macular degeneration.
Presentation/Packing
Soln for inj (sterile, clear, colorless to pale yellow and preservative-free aqueous solution in a vial) 10 mg/mL x 0.23 mL x 1's.
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