Ranibizumab Injection

Ranibizumab is used to treat wet age-related macular degeneration (AMD; an ongoing disease of the eye that causes loss of the ability to see straight ahead and may make it more difficult to read, drive, or perform other daily activities). It is also used to treat macular edema after retinal vein occlusion (an eye disease caused by blockage of blood flow from the eye that leads to blurry vision and vision loss), diabetic macular edema (an eye disease caused by diabetes that can lead to vision loss), and diabetic retinopathy (damage to the eyes caused by diabetes). Ranibizumab is in a class of medications called vascular endothelial growth factor A (VEGF-A) antagonists. It works by stopping abnormal blood vessel growth and leakage in the eye(s) that may cause vision loss.

• Lucentis^®

LUCENTIS is indicated for the treatment of patients with:

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

Macular Edema Following Retinal Vein Occlusion (RVO)

Diabetic Macular Edema (DME)

Diabetic Retinopathy (Non Proliferative Diabetic Retinopathy (NPDR), Proliferative Diabetic Retinopathy (PDR)) in patients with Diabetic Macular Edema (DME)

Myopic Choroidal Neovascularization (mCNV)

Included as part of the PRECAUTIONS section.

Mechanism Of Action

Ranibizumab binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. VEGF-A has been shown to cause neovascularization and leakage in models of ocular angiogenesis and vascular occlusion and is thought to contribute to pathophysiology of neovascular AMD, mCNV, DR, DME and macular edema following RVO. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

Pharmacodynamics

Increased retinal thickness (i.e., center point thickness (CPT) or central foveal thickness (CFT)), as assessed by optical coherence tomography (OCT) is associated with neovascular AMD, mCNV, macular edema following RVO, and DME. Leakage from choroidal neovascularization (CNV) as assessed by fluorescein angiography (FA) is associated with neovascular AMD and mCNV. Microvascular retinal changes and neovascularization, as assessed by color fundus photography, are associated with diabetic retinopathy.

In Study AMD-3, CPT was assessed by time domain (TD)-OCT in 118 of 184 patients. TDOCT measurements were collected at baseline, Months 1, 2, 3, 5, 8, and 12. In patients treated with LUCENTIS, CPT decreased, on average, more than in the sham group from baseline through Month 12. CPT decreased by Month 1 and decreased further at Month 3, on average. In this study, CPT data did not provide information useful in influencing treatment decisions [see Clinical Studies].

In Study AMD-4, CFT was assessed by spectral domain (SD)-OCT in all patients; on average, CFT reductions were observed beginning at Day 7 following the first LUCENTIS injection through Month 24. CFT data did not provide information capable of predicting final visual acuity results [see Clinical Studies].

In patients treated with LUCENTIS, the area of CNV leakage, on average, decreased by Month 3 as assessed by FA. The area of CNV leakage for an individual patient was not correlated with visual acuity.

On average, CPT reductions were observed in Studies RVO-1 and RVO-2 beginning at Day 7 following the first LUCENTIS injection through Month 6. CPT was not evaluated as a means to guide treatment decisions [see Clinical Studies].

On average, CPT reductions were observed in Studies D-1 and D-2 beginning at Day 7 following the first LUCENTIS injection through Month 36. CPT data did not provide information useful in influencing treatment decisions [see Clinical Studies].

Improvements from baseline in DR severity as assessed on fundus photography were observed in Studies D-1 and D-2 at Month 3 (first scheduled DR photographic assessment after randomization) through Month 36 [see Clinical Studies].

On average CFT reductions were observed as early as Month 1, and were greater in the LUCENTIS groups compared to vPDT [see Clinical Studies].

Pharmacokinetics

In patients with neovascular AMD, following monthly intravitreal administration of 0.5 mg LUCENTIS, mean (±SD) maximum ranibizumab serum concentrations were 1.7 (± 1.1) ng/mL. These concentrations were below the concentration range of ranibizumab (11 to 27 ng/mL) that was necessary to inhibit the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay (based on human umbilical vein endothelial cells (HUVEC)). No significant change from baseline was observed in the mean plasma VEGF concentrations following three monthly 0.5 mg intravitreal injections. The maximum observed serum concentration was dose proportional over the dose range of 0.05 to 2 mg/eye. Serum ranibizumab concentrations in RVO and DME and DR patients were similar to those observed in neovascular AMD patients.

Based on a population pharmacokinetic analysis of patients with neovascular AMD, maximum serum concentrations are predicted to be reached at approximately 1 day after monthly intravitreal administration of LUCENTIS 0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the estimated average vitreous elimination half-life was approximately 9 days. Steady-state minimum concentration is predicted to be 0.22 ng/mL with a monthly dosing regimen. In humans, serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal concentrations.

In pharmacokinetic covariate analyses, 48% (520/1091) of patients had renal impairment (35% mild, 11% moderate, and 2% severe). Because the increases in plasma ranibizumab exposures in these patients are not considered clinically significant, no dosage adjustment is needed based on renal impairment status.

Clinical Studies

Unless otherwise noted, visual acuity was measured at a distance of 4 meters.

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The safety and efficacy of LUCENTIS were assessed in three randomized, double-masked, sham-or active-controlled studies in patients with neovascular AMD. A total of 1323 patients (LUCENTIS 879, control 444) were enrolled in the three studies.

In Study AMD-1, patients with minimally classic or occult (without classic) CNV lesions received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections. Data are available through Month 24. Patients treated with LUCENTIS in Study AMD-1 received a mean of 22 total treatments out of a possible 24 from Day 0 to Month 24.

In Study AMD-2, patients with predominantly classic CNV lesions received one of the following: 1) monthly LUCENTIS 0.3 mg intravitreal injections and sham PDT; 2) monthly LUCENTIS 0.5 mg intravitreal injections and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Sham PDT (or active verteporfin PDT) was given with the initial LUCENTIS (or sham) intravitreal injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of leakage. Data are available through Month 24. Patients treated with LUCENTIS in Study AMD-2 received a mean of 21 total treatments out of a possible 24 from Day 0 through Month 24.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all LUCENTIS-treated patients (approximately 95%) maintained their visual acuity. Among LUCENTIS-treated patients, 31% to 37% experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months. The size of the lesion did not significantly affect the results. Detailed results are shown in Table 3, Table 4, and Figure 1 below.

Table 3 : Visual Acuity Outcomes at Month 12 and Month 24 in Study AMD-1

Table 4 : Visual Acuity Outcomes at Month 12 and Month 24 in Study AMD-2

Figure 1: Mean Change in Visual Acuity from Baseline to Month 24 in Study AMD-1 and Study AMD-2

Visual acuity was measured at a distance of 2 meters

Patients in the group treated with LUCENTIS had minimal observable CNV lesion growth, on average. At Month 12, the mean change in the total area of the CNV lesion was 0.1-0.3 disc areas (DA) for LUCENTIS versus 2.3-2.6 DA for the control arms. At Month 24, the mean change in the total area of the CNV lesion was 0.3-0.4 DA for LUCENTIS versus 2.9-3.1 DA for the control arms.

Study AMD-3 was a randomized, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of LUCENTIS in patients with neovascular AMD (with or without a classic CNV component). Data are available through Month 12. Patients received LUCENTIS 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 for 9 months. A total of 184 patients were enrolled in this study (LUCENTIS 0.3 mg, 60; LUCENTIS 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study. Patients treated with LUCENTIS in Study AMD-3 received a mean of 6 total treatments out of a possible 6 from Day 0 through Month 12.

In Study AMD-3, the primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline (see Figure 2). After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every 3 months with LUCENTIS lost visual acuity, returning to baseline at Month 12. In Study AMD-3, almost all LUCENTIS-treated patients (90%) lost fewer than 15 letters of visual acuity at Month 12.

Figure 2 : Mean Change in Visual Acuity from Baseline to Month 12 in Study AMD-3

Study AMD-4 was a randomized, double-masked, active treatment-controlled, two-year study designed to assess the safety and efficacy of LUCENTIS 0.5 mg administered monthly or less frequently than monthly in patients with neovascular AMD. Patients randomized to the LUCENTIS 0.5 mg less frequent dosing arm received 3 monthly doses followed by monthly assessments where patients were eligible to receive LUCENTIS injections guided by pre- specified re-treatment criteria. A total of 550 patients were enrolled in the two 0.5 mg treatment groups with 467 (85%) completing through Month 24. Data are available through Month 24. Clinical results at Month 24 remain similar to that observed at Month 12.

From Month 3 through Month 24, visual acuity decreased by 0.3 letters in the 0.5 mg less frequent dosing arm and increased by 0.7 letters in the 0.5 mg monthly arm (see Figure 3). Over this 21 month period, patients in the 0.5 mg less frequent dosing and the 0.5 mg monthly arms averaged 10.3 and 18.5 injections, respectively. The distribution of injections received in the less frequent dosing arm is shown in Figure 4.

Figure 3 : Mean Change in Visual Acuity from Baseline to Month 24 in Study AMD-4

Figure 4: Distribution of Injections from Month 3 to Month 24 in the Less Frequent Dosing Arm in Study AMD-4

Macular Edema Following Retinal Vein Occlusion (RVO)

The safety and efficacy of LUCENTIS were assessed in two randomized, double-masked, 1-year studies in patients with macular edema following RVO. Sham controlled data are available through Month 6. Patient age ranged from 20 to 91 years, with a mean age of 67 years. A total of 789 patients (LUCENTIS 0.3 mg, 266 patients; LUCENTIS 0.5 mg, 261 patients; sham, 262 patients) were enrolled, with 739 (94%) patients completing through Month 6. All patients completing Month 6 were eligible to receive LUCENTIS injections guided by pre-specified re-treatment criteria until the end of the studies at Month 12.

In Study RVO-1, patients with macular edema following branch or hemi-RVO, received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 6month treatment period. Macular focal/grid laser treatment was given to 26 of 131 (20%) patients treated with 0.5 mg LUCENTIS and 71 of 132 (54%) patients treated with sham.

In Study RVO-2, patients with macular edema following central RVO received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months.

At Month 6, after monthly treatment with 0.5 mg LUCENTIS, the following clinical results were observed:

Table 5 : Visual Acuity Outcomes at Month 6 in Study RVO-1 and Study RVO-2

Figure 5: Mean Change in Visual Acuity from Baselineto Month 6 in Study RVO-1 and Study RVO-2

p < 0.01 for all time points

Diabetic Macular Edema (DME)

Efficacy and safety data of LUCENTIS are derived from studies D-1 and D-2 (See Section on Diabetic Retinopathy below). All enrolled patients had DR and DME at baseline.

The safety and efficacy of LUCENTIS were assessed in two randomized, double-masked, 3-year studies. The studies were sham-controlled through Month 24. Patient age ranged from 21 to 91 years, with a mean age of 62 years. A total of 759 patients (LUCENTIS 0.3 mg, 250 patients; LUCENTIS 0.5 mg, 252 patients; sham, 257 patients) were enrolled, with 582 (77%) completing through Month 36.

In Studies D-1 and D-2, patients received monthly LUCENTIS 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections during the 24-month controlled treatment period. From Months 25 through 36, patients who previously received sham were eligible to receive monthly LUCENTIS 0.5 mg and patients originally randomized to monthly LUCENTIS 0.3 mg or 0.5 mg continued to receive their assigned dose. All patients were eligible for macular focal/grid laser treatment beginning at Month 3 of the 24-month treatment period or panretinal photocoagulation (PRP) as needed. Through Month 24, macular focal/grid laser treatment was administered in 94 of 250 (38%) patients treated with LUCENTIS 0.3 mg and 185 of 257 (72%) patients treated with sham; PRP was administered in 2 of 250 (1%) patients treated with LUCENTIS 0.3 mg and 30 of 257 (12%) patients treated with sham.

Compared to monthly LUCENTIS 0.3 mg, no additional benefit was observed with monthly treatment with LUCENTIS 0.5 mg. At Month 24, after monthly treatment with LUCENTIS 0.3 mg, the following clinical results were observed:

Table 6 : Visual Acuity Outcomes at Month 24 in Study D-1 and D-2

Figure 6: Mean Change in Visual Acuity from Baseline to Month 36 in Study D-1 and Study D-2

p < 0.01 for all time points comparing LUCENTIS 0.3 mg to sham through Month 24

VA outcomes observed at Month 24 in patients treated with LUCENTIS 0.3 mg were maintained with continued treatment through Month 36 in both DME studies. Patients in the sham arms who received LUCENTIS 0.5 mg beginning at Month 25 achieved lesser VA gains compared to patients who began treatment with LUCENTIS at the beginning of the studies.

In Studies D-1 and D-2, patients received monthly injections of LUCENTIS for 12 or 36 months, after which 500 patients opted to continue in the long-term follow-up study. Of 298 patients who had at least 12 months of follow-up from Month 36, 58 (19.5%) patients maintained vision with no further therapy. The remaining 202 patients were followed for less than 12 months.

Diabetic Retinopathy In Patients With Diabetic Macular Edema (DME)

Efficacy and safety data of LUCENTIS are derived from studies D-1 and D-2 [see Clinical Studies]. All enrolled patients had DR and DME at baseline.

Of the 759 patients enrolled, 746 patients had a baseline assessment of fundus photography. Patients had baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Retinopathy Severity Scores (ETDRS-RSS) ranging from 10 to 75. At baseline, 62% of patients had non-proliferative diabetic retinopathy (NPDR) (ETDRS-RSS less than 60) and 31% had PDR (ETDRS-RSS greater than or equal to 60). The ETDRS-RSS could not be graded in 5% of patients at baseline, and 2% of patients had absent or questionable DR at baseline. Approximately 20% of the overall population had prior PRP.

After monthly treatment with LUCENTIS 0.3 mg, the following clinical results were observed (Table 7; Figure 7):

Table 7 : ≥ 3-step and ≥ 2-step improvement at Month 24 in Study D-1 and Study D-2

At Month 24, DR improvement by ≥ 3-steps in ETDRS-RSS from baseline in subgroups examined (e.g., age, gender, race, baseline visual acuity, baseline HbA1c, prior DME therapy at baseline, baseline DR severity (NPDR, PDR)) were generally consistent with the results in the overall population.

The difference in the proportion of patients treated with LUCENTIS 0.3 mg compared to sham who achieved DR improvement based on the ETDRS-RSS was observed as early as Month 3 for ≥ 2-step improvement or at Month 12 for ≥ 3-step improvement.

Figure 7 : Proportion of Patients with ≥ 3-Step and ≥ 2-Step Improvement from Baseline in ETDRSDiabetic Retinopathy Severity Level over Time in Study D-1 and Study D-2

Myopic Choroidal Neovascularization (mCNV)

The efficacy and safety data of LUCENTIS were assessed in a randomized, double-masked, active-controlled 3-month study in patients with mCNV. Patients age ranged from 18 to 87 years, with a mean age of 55 years. A total of 276 patients (222 patients in the LUCENTIS treated Groups I and II; 55 patients in the active control verteporfin photodynamic therapy (vPDT) group) were enrolled. Patients randomized to the LUCENTIS groups received injections guided by pre-specified re-treatment criteria. The retreatment criteria in Group I were vision stability guided, with the BCVA at the current visit being assessed for changes compared with the two preceding monthly BCVA values. The retreatment criteria in Group II were disease activity guided, based on BCVA decrease from the previous visit that was attributable to intra-or sub-retinal fluid or active leakage secondary to mCNV as assessed by OCT and/or FA compared to the previous monthly visit.

Visual gains for the two LUCENTIS 0.5 mg treatment arms were superior to the active control arm. The mean change in BCVA from baseline at Month 3 was: +12.1 letters for Group I, +12.5 letters for Group II and +1.4 letters for the vPDT group. (Figure 8; Table 8). Efficacy was comparable between Group I and Group II.

Table 8 : Mean Change in Visual Acuity and Proportion of patients who gained ≥ 15 letters from Baseline at Month 3

Figure 8 : Mean Change in Visual Acuity from Baseline to Month 3 in mCNV Study

The proportion of patients who gained ≥ 15 letters (ETDRS) by Month 3 was 37.1% and 40.5% for LUCENTIS Groups I and II, respectively and 14.5% for the vPDT group. The mean number of injections between baseline and Month 3 was 2.5 and 1.8 for Groups I and II, respectively. 41% of patients received 1, 2 or 3 injections between baseline and Month 3 with no injections afterwards.

Advise patients that in the days following LUCENTIS administration, patients are at risk of developing endophthalmitis. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise the patient to seek immediate care from an ophthalmologist [see WARNINGS AND PRECAUTIONS].

Your doctor or pharmacist can provide more information about ranibizumab ophthalmic.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 2.02. Revision date: 8/28/2012.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

• Macular Degeneration