Ameliv

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMELIVU (AMELIVU)

Composition:

Active substance: ranibizumab;

One vial contains 2.3 mg of ranibizumab in 0.23 ml of solution (10 mg/ml);

Excipients: α,α-trehalose dihydrate; histidine hydrochloride monohydrate; histidine;
polysorbate 20; water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear aqueous solution, colorless to pale yellow.

Pharmacotherapeutic group. Agents used in ocular vascular diseases. Anti-neovascular agents. Ranibizumab.

ATC code S01LA04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action

Ranibizumab is a recombinant humanized monoclonal antibody fragment directed against human vascular endothelial growth factor A (VEGF-A). It has high affinity for VEGF-A isoforms (e.g., VEGF110, VEGF121, and VEGF165), thereby preventing VEGF-A binding to its receptors VEGFR-1 and VEGFR-2. Binding of VEGF-A to its receptors leads to endothelial cell proliferation and neovascularization, as well as excessive vascular permeability, which is believed to contribute to the development of neovascular age-related macular degeneration (AMD), pathological myopia (PM), and choroidal neovascularization (CNV), or vision impairment due to diabetic macular edema (DME) or macular edema following retinal vein occlusion (RVO).

Clinical Efficacy and Safety

Treatment of Exudative AMD

The clinical safety and efficacy of ranibizumab were evaluated in three randomized, double-masked, placebo- or active-controlled trials involving patients with neovascular AMD over 24 months. Overall, 1323 patients (879 in the active and 444 in the control groups) participated in these studies.

In study FVF2598g (MARINA), 716 patients with minimally classic or occult non-classic forms of the disease were randomized in a 1:1:1 ratio to receive monthly injections of ranibizumab 0.3 mg, ranibizumab 0.5 mg, or placebo.

In study FVF2587g (ANCHOR), 423 patients with predominantly classic CNV were randomized in a 1:1:1 ratio to receive monthly injections of ranibizumab 0.3 mg, ranibizumab 0.5 mg, or verteporfin photodynamic therapy (vPDT) (at baseline and every 3 months thereafter if fluorescein angiography indicated persistence or recurrence of vascular leakage).

Results from both studies indicate that continued treatment with ranibizumab may also improve outcomes in patients who lost ≥15 letters of best-corrected visual acuity (BCVA) during the first year of treatment.

Statistically significant improvement in patient-reported visual function, as assessed by the National Eye Institute Visual Function Questionnaire (NEI VFQ-25), was observed with ranibizumab treatment compared to the control group in both the MARINA and ANCHOR studies.

In study FVF3192g (PIER), 184 patients with all forms of neovascular AMD were randomized in a 1:1:1 ratio to receive monthly injections of ranibizumab 0.3 mg, ranibizumab 0.5 mg, or placebo for 3 consecutive months, followed by dosing every 3 months. Starting at month 14, patients receiving placebo could switch to ranibizumab treatment, and from month 19, more frequent dosing was allowed. Patients receiving ranibizumab in the PIER study received an average of 10 injections.

After initial improvement in visual acuity (following monthly dosing), patients receiving ranibizumab every 3 months, on average, lost visual acuity, returning to baseline levels by month 12. This effect was maintained in the majority of patients receiving ranibizumab (82%) up to month 24. Limited data from the placebo group, who later received ranibizumab, suggest that early initiation of treatment may provide better preservation of visual acuity.

Based on two post-marketing studies (MONT BLANC, BPD952A2308 and DENALI, BPD952A2309), the efficacy of ranibizumab was confirmed, but they did not demonstrate additional benefit of combining verteporfin (Visudyne PDT) with ranibizumab compared to ranibizumab monotherapy.

Treatment of Vision Impairment due to CNV Secondary to Pathological Myopia (PM)

The clinical safety and efficacy of ranibizumab in patients with vision impairment due to CNV secondary to PM were evaluated based on data collected over 12 months in a randomized, double-masked, sham-controlled study F2301 (RADIANCE). In this study, 277 patients were randomized in a 2:2:1 ratio into the following groups:

• Group I (ranibizumab 0.5 mg, dosing regimen based on "visual stability" criteria defined as no change in BCVA compared to the results of two previous monthly assessments).
• Group II (ranibizumab 0.5 mg, dosing regimen based on "disease activity" criteria defined as vision impairment associated with presence of intra- or subretinal fluid or active leakage due to CNV lesion, assessed by optical coherence tomography and/or fluorescein angiography).
• Group III (vPDT, patients were allowed to receive ranibizumab treatment starting from month 3).

In Group II, where the recommended dose was used (see section "Dosage and Administration" for details), 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. 62.9% of patients in Group II did not require injections during the subsequent 6-month study period.

Visual improvement was accompanied by a reduction in central subfield retinal thickness (CSRT).

Patients reported benefits of treatment in the ranibizumab groups compared to vPDT (p-value < 0.05), including in the overall score and several subscales (general vision, near vision, psychological well-being, and dependency) in the NEI VFQ-25 questionnaire.

Treatment of Vision Impairment due to CNV (excluding that secondary to PM and exudative AMD)

The clinical safety and efficacy of ranibizumab in patients with vision impairment due to CNV were evaluated based on data collected over 12 months in a randomized, double-masked, placebo-controlled study G2301 (MINERVA). In this study, 178 adult patients were randomized in a 2:1 ratio to receive:

• Ranibizumab 0.5 mg at baseline followed by an individualized dosing regimen based on disease activity assessed by visual acuity and/or anatomical parameters (e.g., VA loss, presence of intra/subretinal fluid, hemorrhage, or blood leakage);
• Sham injection at baseline followed by an individualized treatment regimen based on disease activity.

From month 2 onwards, all patients received open-label ranibizumab treatment as needed.

Visual improvement was accompanied by a reduction in CSRT over the 12-month period.

The mean number of injections received over 12 months was 5.8 in the ranibizumab treatment group compared to 5.4 in the placebo group, which received ranibizumab starting from month 2. In the placebo group, 7 out of 59 patients did not receive ranibizumab in the affected eye over the 12-month period.

At month 2, a sustained treatment effect was observed when comparing the ranibizumab treatment group with the placebo control group, both in the overall population and in subgroups of patients with different etiologies at baseline.

In the core study G2301 (MINERVA), five adolescents aged 12 to 17 years with vision impairment due to CNV received open-label ranibizumab 0.5 mg at baseline and subsequently on an individualized regimen as for adult patients. Improvement in BCVA from baseline to month 12 was achieved in all five patients, ranging from 5 to 38 letters (mean 16.6 letters). Visual improvement was accompanied by stabilization or reduction in CSRT over the 12-month period. The mean number of ranibizumab injections administered to the study eye over 12 months was 3 (range 2 to 5). Overall, ranibizumab treatment was well tolerated.

Treatment of Vision Impairment in Diabetic Macular Edema (DME)

The efficacy and safety of ranibizumab were evaluated in three randomized, controlled trials lasting at least 12 months. Overall, 868 patients (708 in the active and 160 in the control groups) were enrolled.

In phase II study D2201 (RESOLVE), 151 patients received ranibizumab (6 mg/mL, n = 51; 10 mg/mL, n = 51) or placebo (n = 49) as monthly intravitreal injections. The mean change in BCVA from month 1 to month 12 compared to baseline was +7.8 (±7.72) letters in the combined ranibizumab group (n = 102) versus -0.1 (±9.77) letters in the placebo group. The mean change in BCVA at month 12 from baseline was 10.3 (±9.1) letters versus -1.4 (±14.2) letters, respectively (p < 0.0001 for treatment difference).

In phase III study D2301 (RESTORE), 345 patients were randomized in a 1:1:1 ratio to receive ranibizumab 0.5 mg monotherapy with sham laser photocoagulation, combination therapy with ranibizumab 0.5 mg and laser photocoagulation, or placebo injection with laser photocoagulation. 240 patients who previously completed the 12-month RESTORE study were enrolled in a 24-month open-label extension study (RESTORE extension study). Patients received ranibizumab 0.5 mg pro re nata (PRN – as needed) in the same study eye as in the main study (D2301 RESTORE).

The effect was consistent across most subgroups at month 12. However, in patients with baseline BCVA > 73 letters and macular edema with central subfield thickness < 300 µm, no benefit was observed with ranibizumab therapy compared to laser photocoagulation.

Statistically significant improvement in patient-reported visual function across most visual function domains was observed with ranibizumab treatment (with or without laser photocoagulation) compared to the control group according to the NEI VFQ-25 questionnaire. No differences between treatments were observed for other domains of this questionnaire.

The safety profile of ranibizumab observed during the 24-month extension study was consistent with the known safety profile of ranibizumab.

In phase IIIb study D2304 (RETAIN), 372 patients were randomized in a 1:1:1 ratio to receive:

• Ranibizumab 0.5 mg with concomitant laser photocoagulation using a "treat-and-extend" (TE) regimen.
• Ranibizumab 0.5 mg monotherapy using a TE regimen.
• Ranibizumab 0.5 mg monotherapy using a PRN regimen.

Ranibizumab was administered monthly in all groups until BCVA was stable for at least three consecutive monthly assessments. Under the TE regimen, ranibizumab was administered at intervals of 2–3 months. In all groups, monthly therapy was restarted after a decrease in BCVA due to DME progression and continued until BCVA stabilization was re-established.

After the first three injections, the number of scheduled treatment visits was 13 and 20 for the TE and PRN regimens, respectively. With both TE regimens, BCVA was maintained in over 70% of patients with a mean visit frequency of ≥2 months.

In the DME studies, improvement in BCVA was accompanied by a reduction in mean CSRT over time in all treatment groups.

Treatment of Proliferative Diabetic Retinopathy (PDR)

The clinical safety and efficacy of ranibizumab in patients with PDR were evaluated in Protocol S, a study comparing intravitreal injections of ranibizumab 0.5 mg with panretinal photocoagulation (PRP). The primary endpoint was mean change in visual acuity at year 2. Additionally, the progression of diabetic retinopathy (DR) severity was assessed using fundus photographs and the Diabetic Retinopathy Severity Scale (DRSS).

Protocol S was a multicenter, randomized, active-controlled, parallel-group phase III study comparing the efficacy of intravitreal ranibizumab 0.5 mg with standard PRP treatment. A total of 305 patients (394 eyes) with PDR with or without DME at baseline participated. 191 eyes (48.5%) were randomized to receive ranibizumab 0.5 mg and 203 eyes (51.5%) to PRP. DME was diagnosed at baseline in 88 eyes (22.3%): 42 (22.0%) and 46 (22.7%) eyes in the ranibizumab and PRP groups, respectively.

In this study, the mean change in visual acuity over 2 years was +2.7 letters in the ranibizumab group compared to -0.7 letters in the PRP group. The difference in least squares means was 3.5 letters (95% CI: [0.2–6.7]).

During the first year, ≥2-step improvement on the DRSS was observed in 41.8% of eyes in the ranibizumab group (n = 189) compared to 14.6% of eyes in the PRP group (n = 199). The estimated treatment difference between ranibizumab and laser photocoagulation was 27.4% (95% CI: [18.9; 35.9]).

During the first year in Protocol S, ≥2-step improvement on the DRSS was sustained in eyes without DME (39.9%) and with DME at baseline (48.8%) in the ranibizumab group.

Based on 2-year data from Protocol S, ≥2-step improvement on the DRSS from baseline was observed in 42.3% (n = 80) of eyes in the ranibizumab group compared to 23.1% (n = 46) of eyes in the PRP group. In the ranibizumab group, ≥2-step improvement on the DRSS from baseline was observed in 58.5% (n = 24) of eyes with baseline DME and 37.8% (n = 56) of eyes without DME.

DRSS was also assessed in three separate phase III DME studies with active control (ranibizumab 0.5 mg PRN vs. PRP), including a total of 875 patients, approximately 75% of whom were of Asian origin. In a meta-analysis of these studies, ≥2-step improvement on the DRSS was observed in 48.4% of 315 patients with baseline moderate to severe non-proliferative diabetic retinopathy (NPDR) or worse in the ranibizumab subgroup (n = 192) compared to 14.6% in the laser photocoagulation group (n = 123) over 12 months. The estimated treatment difference between ranibizumab and laser photocoagulation was 29.9% (95% CI: [20.0; 39.7]). Among 405 patients with baseline mild or moderate NPDR, ≥2-step improvement on the DRSS was observed in 1.4% and 0.9% in the ranibizumab and laser photocoagulation groups, respectively.

Treatment of Vision Impairment due to Macular Edema Secondary to Retinal Vein Occlusion (RVO)

The clinical safety and efficacy of ranibizumab in patients with vision impairment due to macular edema secondary to RVO were evaluated in randomized, double-masked, controlled studies BRAVO and CRUISE in patients with branch retinal vein occlusion (BRVO) (n = 397) and central retinal vein occlusion (CRVO) (n = 392), respectively. In both studies, patients received ranibizumab 0.3 mg or 0.5 mg, or placebo. After 6 months, placebo control patients were switched to ranibizumab 0.5 mg.

In both studies, visual improvement was accompanied by sustained and significant reduction in macular edema, measured by CSRT.

In patients with CRVO (CRUISE and the extension study HORIZON): control group patients who received placebo for the first 6 months and were subsequently switched to ranibizumab treatment achieved a BCVA improvement of ~6 letters by month 24, which did not reach the level observed in those who received ranibizumab from the start of the study (~12 letters).

Statistically significant improvement in patient-reported outcomes in near and distance vision subscales was observed with ranibizumab treatment compared to the control group in the NEI VFQ-25 questionnaire.

Long-term (24 months) clinical safety and efficacy of ranibizumab in patients with vision impairment due to macular edema secondary to RVO were evaluated in studies BRIGHTER (BRVO) and CRYSTAL (CRVO). In both studies, patients received PRN dosing of ranibizumab 0.5 mg based on individual stability criteria. BRIGHTER was a randomized, active-controlled, three-arm study comparing ranibizumab 0.5 mg monotherapy or in combination with adjuvant laser photocoagulation versus laser photocoagulation alone. After 6 months, patients in the laser photocoagulation group could receive ranibizumab 0.5 mg. CRYSTAL was a non-comparative study of ranibizumab 0.5 mg monotherapy.

In study BRIGHTER, ranibizumab 0.5 mg with adjuvant laser therapy demonstrated non-inferior efficacy compared to ranibizumab monotherapy from baseline to month 24 (95% CI: -2.8; 1.4).

In both studies, rapid and statistically significant reduction in CSRT from baseline was observed at month 1. This effect was maintained up to month 24.

The treatment effect of ranibizumab was similar regardless of the presence of retinal ischemia. In study BRIGHTER, in patients with (n = 46) or without (n = 133) ischemia receiving ranibizumab monotherapy, the mean change from baseline was +15.3 and +15.6 letters, respectively, at month 24. In study CRYSTAL, in patients with (n = 53) or without (n = 300) ischemia receiving ranibizumab monotherapy, the mean change from baseline was +15.0 and +11.5 letters, respectively.

During studies BRIGHTER and CRYSTAL, visual improvement over time was observed in all patients receiving ranibizumab 0.5 mg monotherapy, regardless of disease duration. In patients with disease duration < 3 months, visual acuity improvement was 13.3 and 10.0 letters at month 1 and 17.7 and 13.2 letters at month 24 in studies BRIGHTER and CRYSTAL, respectively. Corresponding visual acuity improvement in patients with disease duration > 12 months was 8.6 and 8.4 letters in the respective studies. Early initiation of treatment upon diagnosis should be considered.

The long-term safety profile of ranibizumab observed in the 24-month studies was consistent with the known safety profile of ranibizumab.

Paediatric Population

The European Medicines Agency has deferred the obligation to submit the results of ranibizumab studies in all paediatric subgroups for neovascular AMD, vision impairment due to DME, vision impairment due to macular edema secondary to RVO, vision impairment due to CNV, and diabetic retinopathy (see section "Dosage and Administration" for information on use in children).

Pharmacokinetics.

After intravitreal administration of ranibizumab (monthly) in patients with neovascular AMD, serum concentrations of ranibizumab were generally low, with maximum concentrations (Cmax) typically below the concentration required to inhibit 50% of vascular endothelial growth factor (VEGF) biological activity (11–27 ng/mL based on in vitro cell proliferation assay). Cmax was dose-proportional in the dose range of 0.05–1.0 mg per eye. Serum concentrations in some patients with DME suggest that slightly higher systemic exposure cannot be excluded compared to that observed in patients with neovascular AMD. Serum concentrations of ranibizumab in patients with RVO were similar to or slightly higher than those observed in patients with neovascular AMD.

Based on population pharmacokinetic data and elimination of ranibizumab from serum in patients with neovascular AMD receiving ranibizumab 0.5 mg, the mean half-life of ranibizumab in the vitreous humor is approximately 9 days. After intravitreal administration of ranibizumab 0.5 mg per eye (monthly), Cmax in serum occurs approximately 1 day after administration and typically ranges from 0.79–2.90 ng/mL, with Cmin ranging from 0.07–0.49 ng/mL. Systemic exposure to ranibizumab is approximately 90,000 times lower than in the vitreous humor.

Patients with Renal Impairment

Formal pharmacokinetic studies of ranibizumab in patients with renal impairment have not been conducted. In pharmacokinetic studies in a group of patients with neovascular AMD, 68% (136 out of 200) had renal impairment (46.5% mild [50–80 mL/min], 20% moderate [30–50 mL/min], and 1.5% severe [<30 mL/min]). In the RVO group, 48.2% (253 out of 525) had renal impairment (36.4% mild, 9.5% moderate, and 2.3% severe). Systemic clearance was slightly lower but clinically insignificant.

Patients with Hepatic Impairment

Formal pharmacokinetic studies of ranibizumab in patients with hepatic impairment have not been conducted.

Clinical characteristics.

Indications.

• Neovascular (exudative) age-related macular degeneration (AMD).
• Visual impairment due to diabetic macular edema (DME).
• Proliferative diabetic retinopathy (PDR).
• Visual impairment due to macular edema secondary to retinal vein occlusion (branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO)).
• Visual impairment due to choroidal neovascularization (CNV).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Active or suspected ocular or periocular infection.
• Active severe intraocular inflammation.

Interaction with other medicinal products and other forms of interaction.

Formal interaction studies have not been conducted.

Information regarding concomitant use of verteporfin photodynamic therapy (vPDT) and ranibizumab in exudative AMD and myopic choroidal neovascularization (mCNV) can be found in the section "Pharmacodynamics".

Information regarding concomitant use of laser photocoagulation and ranibizumab in DME and BRVO is provided in the section "Dosage and administration" and in the "Pharmacodynamics" subsection.

In clinical trials of treatment for visual impairment due to DME, the outcome in terms of visual acuity or central retinal thickness (CRT) in patients receiving ranibizumab treatment was not influenced by concomitant treatment with thiazolidinediones.

Special precautions for use.

Traceability

In order to improve the traceability of biological medicinal products, it is necessary to clearly record the name and batch number of the medicinal product being administered.

Reactions associated with intravitreal injection

Intravitreal injections, including ranibizumab injections, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear, and iatrogenic traumatic cataract (see section "Adverse reactions"). Ranibizumab injection should always be performed under appropriate aseptic conditions. In addition, patients should be monitored for one week after injection to allow timely treatment in case of infectious complications. Patients should be informed of the need to immediately report any symptoms suggestive of endophthalmitis or other aforementioned conditions.

Elevated intraocular pressure (IOP)

Transient elevation of IOP has been observed within 60 minutes following ranibizumab injection. Persistent elevation of IOP has also been reported (see section "Adverse reactions"). IOP and optic nerve head perfusion should be monitored and managed appropriately.

Patients should be informed about the symptoms of these potential adverse reactions and advised to promptly notify their physician if any signs occur, including eye pain or increased discomfort, increased eye redness, blurred or decreased vision, increased floaters in the visual field, or increased sensitivity to light (see section "Adverse reactions").

Bilateral therapy

Limited data on bilateral administration of ranibizumab (including administration on the same day) indicate no increased risk of systemic adverse events compared to unilateral administration.

Immunogenicity

There is a risk of immunogenicity with ranibizumab. Since patients with DME may have increased systemic exposure, these patients may have an elevated risk of hypersensitivity reactions.

Patients should also be warned to report any symptoms suggestive of intraocular inflammation, which may be a clinical sign of intraocular antibody formation.

Concomitant use with other VEGF inhibitors (vascular endothelial growth factor)

Ranibizumab should not be used concomitantly with other VEGF inhibitors (when administered systemically or into the eye).

Discontinuation of ranibizumab treatment

Ranibizumab administration may be discontinued and not resumed earlier than the next scheduled dose in the following cases:

• Decrease in best-corrected visual acuity (BCVA) of ≥ 30 letters compared to the most recent visual acuity measurement;
• Intraocular pressure ≥ 30 mm Hg;
• Retinal tear;
• Subretinal hemorrhage reaching the center of the fovea or if the hemorrhage size is ≥ 50% of the total lesion area;
• Planned or performed ocular surgery within 28 days before or after injection.

Rupture of retinal pigment epithelium

Risk factors associated with the development of retinal pigment epithelium tears following VEGF inhibitor treatment for exudative AMD and potentially other forms of CNV include large and/or high pigment epithelium detachment. Caution should be exercised at the start of ranibizumab therapy in patients with risk factors for retinal pigment epithelium tears.

Rhegmatogenous retinal detachment or macular holes

Treatment should be discontinued in patients with rhegmatogenous retinal detachment or with macular holes of grade 3–4.

Patient groups with limited experience of drug use

There is limited experience in treating DME patients due to type 1 diabetes. The use of ranibizumab has not been studied in patients who have previously received intravitreal injections, patients with active systemic infections, or patients with concomitant ophthalmic conditions such as retinal detachment or macular holes. There is also no experience with ranibizumab treatment in diabetic patients with glycated hemoglobin (HbA1c) levels above 108 mmol/mol (12%) or in patients with uncontrolled hypertension. Physicians should consider this information when treating such patients.

There are insufficient data to conclude on the efficacy of ranibizumab in BRVO patients with irreversible visual function loss due to ischemia.

Limited data are available on the effect of ranibizumab in PCV patients who did not respond to prior verteporfin photodynamic therapy (vPDT). Although sustained effects were observed in patients with subfoveal and juxtafoveal lesions, data on the effect of ranibizumab in PCV patients with extrafoveal lesions are insufficient.

Systemic effects after intravitreal administration

Systemic adverse events, including extraocular hemorrhage and arterial thromboembolic events, have occasionally been observed after intravitreal injections of VEGF inhibitors.

There are limited data on the safety of treatment in patients with DME, macular edema due to BRVO, and CNV secondary to PCV, as well as in patients with a history of stroke or transient ischemic attacks. Caution should be exercised when treating such patients (see section "Adverse reactions").

Use during pregnancy or breastfeeding.

Women of reproductive potential/contraception in women

Women of reproductive potential should use effective contraception during treatment.

Pregnancy

Clinical data on the effects of ranibizumab during pregnancy are lacking. Studies in cynomolgus monkeys do not indicate a direct or indirect adverse effect on pregnancy or embryonic/fetal development. Systemic exposure to ranibizumab after intravitreal administration is low; however, due to its mechanism of action, ranibizumab should be considered potentially teratogenic and embryotoxic/fetotoxic. Therefore, ranibizumab is not recommended during pregnancy unless the expected benefit to the woman outweighs the potential risk to the fetus. Women planning pregnancy who have received ranibizumab are advised to wait at least 3 months between the last dose and conception.

Breastfeeding

It is unknown whether ranibizumab is excreted in human breast milk. Therefore, breastfeeding is not recommended during treatment with this medicinal product.

Fertility

Data on the effect on fertility are lacking.

Effect on ability to drive and use machines.

Treatment with this medicinal product may cause temporary visual disturbances, which may affect the ability to drive or operate machinery (see section "Adverse reactions"). Patients experiencing such symptoms should refrain from driving or operating machinery until these transient symptoms resolve.

Method of Administration and Dosage

For intravitreal use only. Administration of the medicinal product AMELIVU must be performed only by a qualified ophthalmologist experienced in intravitreal injections.

Dosage

The recommended dose of AMELIVU is 0.5 mg administered as a single intravitreal injection. This dose corresponds to an injection volume of 0.05 mL. The interval between two consecutive doses administered into the same eye should be at least 4 weeks.

Treatment should be initiated with one injection per month and continued until maximum visual acuity is achieved and/or signs of disease activity have resolved, i.e., absence of changes in visual acuity and other signs and symptoms of the disease despite continued treatment. Patients with neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), or branch retinal vein occlusion (BRVO) may initially require 3 or more consecutive monthly injections.

Thus, the frequency of monitoring and intervals between drug administrations should be determined by the physician based on disease activity, assessed by visual acuity and/or anatomical parameters.

If, in the physician’s opinion, visual acuity and anatomical parameters indicate lack of benefit from continued treatment, administration of AMELIVU should be discontinued.

Monitoring of disease activity may include clinical examination, functional tests, or imaging techniques (e.g., optical coherence tomography or fluorescein angiography).

If patients are treated according to a "treat-and-extend" regimen after achieving maximum visual acuity and/or absence of disease activity, the intervals between drug administrations may be gradually extended until recurrence of disease activity or vision loss. Intervals between injections may be extended by no more than 2 weeks at a time in cases of neovascular AMD and by no more than 1 month at a time in cases of DME. For PDR and BRVO, intervals between injections may also be gradually extended; however, available data are insufficient to define the optimal duration of these intervals. In case of recurrence of disease activity, the intervals between injections should be appropriately shortened.

Treatment of vision impairment due to choroidal neovascularization (CNV) should be individualized for each patient based on disease activity. Some patients may require only one injection during the first 12 months; others may require more frequent administration, including monthly injections. If treatment is initiated for CNV secondary to pathological myopia (PM), most patients may require only one or two injections during the first year (see section "Pharmacodynamics").

Use of ranibizumab and laser photocoagulation in DME and macular edema secondary to branch retinal vein occlusion (BRVO)

There is limited experience with administering ranibizumab concurrently with laser photocoagulation (see section "Pharmacodynamics"). When used on the same day, ranibizumab should be administered at least 30 minutes after laser photocoagulation. Ranibizumab may be used in patients who have previously undergone laser photocoagulation.

Use of ranibizumab and photodynamic therapy (PDT) with verteporfin in CNV secondary to PM

Data on concomitant use of ranibizumab and verteporfin are not available.

Special Patient Groups

Patients with hepatic impairment

The use of ranibizumab in patients with hepatic impairment has not been studied. However, this patient group does not require special consideration.

Patients with renal impairment

Dose adjustment is not required in patients with renal impairment (see section "Pharmacokinetics").

Elderly patients

Dose adjustment is not required in elderly patients. Experience in patients aged 75 years and older with DME is limited.

Administration Method

Since the volume in the vial (0.23 mL) exceeds the recommended dose (0.05 mL), a portion of the volume in the vial should be discarded prior to administration.

Before administration, AMELIVU should be visually inspected for the presence of particulate matter and discoloration.

The administration procedure should be performed under aseptic conditions, including surgical hand disinfection, use of sterile gloves, sterile drapes, sterile eyelid speculum (or equivalent device), and sterile instruments for paracentesis (if necessary). The patient’s medical history should be carefully reviewed for hypersensitivity reactions prior to intravitreal injection (see section "Special Precautions"). Prior to injection, appropriate anesthesia and a broad-spectrum bactericidal agent for skin disinfection around the eye, eyelids, and ocular surface should be selected according to local practice.

The injection needle should be inserted 3.5–4.0 mm posterior to the limbus into the vitreous cavity, avoiding the horizontal meridian and directing the needle toward the center of the globe. Then, 0.05 mL of the solution should be injected; the scleral puncture site should be changed with each subsequent injection.

The vial is intended for single use only. After injection, any unused portion of the medicinal product should be discarded. Do not use the vial if its packaging shows signs of damage or compromised integrity. If the package seal is broken, sterility cannot be guaranteed.

The following single-use medical devices should be used for preparation and intravitreal administration:

• 5 µm filter needle (18G);
• Injection needle (30G × ½");
• Sterile 1 mL syringe with 0.05 mL graduations.

These medical devices are not included in this package.

Detailed instructions for preparation of AMELIVU for intravitreal administration are provided below.

The following instructions should be followed for preparation of AMELIVU for intravitreal administration.

After injection, do not recap the needle and do not detach it from the syringe. The used syringe with the needle should be disposed of in a sharps container or according to the requirements of current legislation.

Children.

The safety and efficacy of ranibizumab in children and adolescents (under 18 years of age) have not been established. Available data on the use of ranibizumab in adolescents aged 12 to 17 years with vision impairment due to nAMD are described in the section "Pharmacodynamics"; however, dosing recommendations are lacking.

Overdose.

Cases of accidental overdose were reported during clinical trials of exudative AMD and in the post-marketing period. Adverse reactions most frequently associated with overdose include increased intraocular pressure, transient blindness, decreased visual acuity, corneal edema, corneal pain, and eye pain. In case of overdose, intraocular pressure should be monitored and, if necessary, appropriate treatment should be initiated, as deemed necessary by the physician.

Adverse Reactions

Most of the adverse reactions reported during the use of ranibizumab are related to the intravitreal injection procedure.

The most common adverse reactions associated with the administration procedure of ranibizumab included: eye pain, ocular hyperemia, increased intraocular pressure, vitritis, vitreous detachment, retinal hemorrhage, vision impairment, floaters in the vitreous body, conjunctival hemorrhage, eye irritation, foreign body sensation in the eye, increased lacrimation, blepharitis, dry eye, and eye pruritus.

The most frequently reported non-ocular adverse reactions were headache, nasopharyngitis, and arthralgia.

Less common but more serious adverse reactions included endophthalmitis, blindness, retinal detachment, retinal tear, and iatrogenic traumatic cataract (see section "Special Warnings and Precautions for Use").

Adverse reactions observed after administration of ranibizumab in clinical trials are listed in the table below.

Adverse reactions# are categorized by system organ class and frequency of occurrence according to the following classification: 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), frequency not known (frequency cannot be estimated from the available data). Within each group, adverse reactions are listed in order of decreasing severity.

Adverse reactions associated with the drug class

In Phase III studies of neovascular AMD, the overall incidence of non-ocular hemorrhage, an adverse event potentially associated with systemic VEGF (vascular endothelial growth factor) inhibitors, was slightly higher in patients receiving ranibizumab. However, no consistent pattern across different types of hemorrhages was observed. There is a theoretical risk of arterial thromboembolic events following intravitreal administration of VEGF inhibitors. In clinical trials of ranibizumab in patients with AMD, DME, PDR, RVO, and CRVO, the incidence of arterial thromboembolic events was low, and no significant differences were observed between ranibizumab-treated and control treatment groups.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life.

30 months.

Storage conditions.

Store in a refrigerator (at 2 to 8 °C) in the original packaging to protect from light. Do not freeze.

Keep out of reach and sight of children.

Prior to use, an unopened vial may be stored at temperatures not exceeding 30 °C for up to 1 month.

Incompatibilities.

Since compatibility studies of this medicinal product have not been conducted, this product must not be mixed with other medicinal products.

Packaging.

Type I borosilicate glass vial with a rubber stopper and aluminum cap with flip-off seal; 1 vial per standard export pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Samsung Bioepis NL B.V.

Manufacturer’s address.

Olof Palmestraat 10, Delft, 2616 LR, Netherlands.

Marketing Authorization Holder.

SAMSUNG BIOEPIS CO., LTD.

Address of the Marketing Authorization Holder.

76, Sondogjuk-ro, Yeonsu-gu, Incheon, Republic of Korea.