Continuing Education Activity

Ranibizumab is a medication used in the management and treatment of neovascular age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, myopic choroidal neovascularization, and diabetic retinopathy. It is in the vascular endothelial growth factor (VEGF-A) inhibitors class of medications. This activity describes the indications, action, and contraindications for ranibizumab as a valuable agent in the treatment of ocular diseases with abnormal angiogenesis. This activity will also highlight the mechanism of action, adverse event profile, and other key factors (e.g., indications, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional professional team in the management neovascular age-related macular degeneration, macular edema, diabetic retinopathy, and related conditions.

Objectives:

• Identify the mechanism of action of ranibizumab.
• Describe the adverse effects and contraindications of ranibizumab.
• Review the appropriate monitoring and toxicity of ranibizumab.
• Outline interprofessional team strategies for improving care coordination and communication to advance ranibizumab and improve outcomes.

Indications

Ranibizumab is a humanized, recombinant monoclonal antibody fragment against vascular endothelial growth factor A (VEGF-A), and thus prevents choroidal neovascularization.[1][2] The vascular endothelial growth factor (VEGF) pathway has a key role in regulating angiogenesis, thus triggering signaling processes that promote tumor growth.[3][4][5] Increased levels of VEGF-A are present in vitreous and aqueous fluid of patients with proliferative diabetic retinopathy, diabetic macular edema, and glaucoma.[6] Additionally, VEGF pathway activation is associated with the rescue of retinal vasculature and prevents endothelial cell death in the case of hyperoxia-induced retinopathy of prematurity.[7]

Bevacizumab is another anti-VEGF agent that preceded ranibizumab. Bevacizumab is a full-length humanized monoclonal antibody that was first FDA approved in 2004 for the treatment of colon cancer. Due to its ability to inhibit neovascularization, bevacizumab was then used intravenously to treat neovascular age-related macular degeneration (NVAMD) as an off-label treatment.[8] At the time, the thinking was that bevacizumab was unable to effectively diffuse to the choroid (although this was later proven false).[8][9] Therefore, researchers first developed ranibizumab as a fragment of the monoclonal antibody against VEGF-A for the treatment of NVAMD, also known as “wet” age-related macular degeneration. NVAMD consists of 10% of AMD, which is one of the leading causes of vision loss among the elderly population.[8] Ranibizumab was first FDA-approved in 2006 for the treatment of NVAMD. Later, it was approved to treat the following conditions discussed below.

FDA-approved indications[10][11][12]:

• Neovascular (wet) age-related macular degeneration (NVAMD)
• Macular edema following retinal vein occlusion (RVO)
• Myopic choroidal neovascularization (mCNV)
• Diabetic macular edema (DME)
• Diabetic retinopathy (DR) with or without DME
• Retinal ischemia

In terms of a global health perspective, there is controversy regarding administering bevacizumab or ranibizumab since bevacizumab is significantly less costly. However, its use is treating NVAMD is off-label. Although both drugs have very similar effects on visual acuity in treating NVAMD, ranibizumab is more expensive than bevacizumab.[9][13]

Ranibizumab, combined with photodynamic therapy, to control abnormal growth of blood vessels in NVAMD is the gold-standard in many countries, however other treatment options with various VEGF inhibitors are also widely used.[14]

This medication is only available by prescription from a physician.

Mechanism of Action

Ranibizumab (molecular weight = 48 kD) is an affinity-matured, humanized immunoglobulin G1 monoclonal antibody fragment that binds to the receptor-binding site of active VEGF-A. Thus, ranibizumab inhibits the interaction of VEGF-A with its receptors on endothelial cells, preventing endothelial proliferation, vascular permeability, and neovascularization.[15] VEGF-A plays a significant role in vascular leak and angiogenesis in the development of NVAMD. Ranibizumab is an antigen-binding fragment (Fab) derived from bevacizumab and has a higher affinity to VEGF-A. Additionally, ranibizumab has one binding site for VEGF, allowing two molecules of ranibizumab to bind to one VEGF dimer. The small size of ranibizumab allows for enhanced diffusion into the retina and choroid.[2][16]

Administration

Ranibizumab administration is by intravitreal injection.[17][18]

• For NVAMD treatment therapy, 0.5 mg (0.05 mL) is recommended as an intravitreal injection once a month. 
• For macular edema treatment following RVO, 0.5 mg (0.05 mL) is recommended as an intravitreal injection once a month.
• For the treatment of DME and DR, 0.3 mg (0.03 mL) is recommended as an intravitreal injection once a month.
• For the treatment of mCNV, 0.5 mg (0.5 mL) is recommended as an intravitreal injection once a month for no more than three months.
• Acute treatment administration may be with variably prescribed injection protocols.

Adverse Effects

Adverse effects associated with ranibizumab use include conjunctival hemorrhage, eye pain, vitreous floaters, and a short-term and long-term increase in ocular pressure.[19][20][21] Adverse effects of intravitreal injections include endophthalmitis (incidence reported in the range 0.019 to 1.6%), retinal detachments (incidence reported in the range 0 to 0.67%), or hemorrhage, intraocular inflammation (incidence reported in the range 1.4 to 2.9%), and risk of thromboembolic events.[15][22][23] There are reports of a few cases of the development of significant sub-retinal hemorrhage when administering intravitreal ranibizumab.[24][25] The overall risk of systemic adverse effects of ranibizumab is low. However, these effects may increase in patients, especially in the elderly population.[22][26]

Contraindications

Contraindications include ocular or periocular infections and hypersensitivity.[22] Patients who have an ocular infection, who recently underwent ocular surgery, or have increased intraocular pressures should avoid ranibizumab use.

Monitoring

After ranibizumab administration, patient self-monitoring is essential to detect signs of infection, decreasing visual acuity, and pain. Patient self-monitoring with tools such as the Amsler grid may help monitor the reactivation of NVAMD.[27] Intravitreal injections can be associated with endophthalmitis, retinal detachment, and increases in intraocular pressures (IOP). The monitoring of IOPs should occur before and after the intravitreal injection of ranibizumab. Systemic exposure is low due to rapid elimination after passing through the vitreous.[28] Additionally, patients with macular ischemia should be carefully monitored when considering prolonged anti-VEGF therapy due to an already compromised blood supply.[29] For a 0.5 mg dose of ranibizumab, the half-life of the drug is around nine days.[2]

Toxicity

The maximum dose of ranibizumab is 0.5 mg single dose monocular, and intravitreal injection allows for the drug to penetrate all layers of the retina, minimizing systemic effects. When cultures of endothelial cells from human organ-cultured donor corneas received treatment with varying concentrations of ranibizumab, no cytotoxic effects of ranibizumab were observed.[30] There is no known antidote in case of an overdose of ranibizumab.

Enhancing Healthcare Team Outcomes

Ranibizumab is a recombinant, humanized monoclonal antibody fragment designed for intraocular use. Intravitreal injection is indicated for the treatment of neovascular age-related macular degeneration (AMD), macular edema (ME) following retinal vein occlusion (RVO), diabetic macular edema (DME), myopic choroidal neovascularization (mCNV), and diabetic retinopathy (DR).

Proper diagnosis and management of ocular diseases can majorly impact a patient's quality of life and can have long-term physical and mental health effects.

Healthcare practitioners, including pharmacists, should thoroughly counsel patients so that they can make informed decisions about their treatment with ranibizumab or other VEGF inhibitors. Managing the treatment of ocular diseases with abnormal angiogenesis, such as NVAMD and diabetic retinopathy, requires an interprofessional team of healthcare providers to ensure effective treatment and to prevent and monitor adverse effects. In addition to the prescribing of physicians and medication management of pharmacists, nursing plays a crucial role in monitoring and taking/updating the patient history, and reporting on therapy response and adverse events. Ranibizumab therapy requires the collaboration and communication of the entire interprofessional team to optimize therapeutic outcomes. [Level 5]

Patient education and self-monitoring are particularly important to detect signs of infection and a decrease in visual acuity. Intravitreal injections can be associated with endophthalmitis, retinal detachment, and increases in intraocular pressures (IOP). The intraocular pressures require monitoring before and after the intravitreal injection of ranibizumab by the ophthalmic nurse/ophthalmologist. Additionally, cost-effective treatment should be considered in the use of bevacizumab versus ranibizumab, as the outcomes of both treatments have demonstrated similar clinical results.[2][9][13]