Ranibizumab is a humanized, recombinant monoclonal antibody fragment against vascular endothelial growth factor A (VEGF-A), and thus prevents choroidal neovascularization. The vascular endothelial growth factor (VEGF) pathway has a key role in regulating angiogenesis, thus triggering signaling processes that promote tumor growth. Increased levels of VEGF-A are present in vitreous and aqueous fluid of patients with proliferative diabetic retinopathy, diabetic macular edema, and glaucoma. 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.
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. At the time, the thinking was that bevacizumab was unable to effectively diffuse to the choroid (although this was later proven false). Therefore, ranibizumab was first developed 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. Ranibizumab was first FDA-approved in 2006 for the treatment of NVAMD. Later, it was approved to treat the following conditions discussed below.
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.
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.
This medication is only available by prescription from a physician.
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. 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.
Adverse effects associated with ranibizumab use include conjunctival hemorrhage, eye pain, vitreous floaters, and a short-term and long-term increase in ocular pressure. 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. There are reports of a few cases of the development of significant sub-retinal hemorrhage when administering intravitreal ranibizumab. The overall risk of systemic adverse effects of ranibizumab is low. However, these effects may increase in patients, especially in the elderly population.
Contraindications include ocular or periocular infections and hypersensitivity. Patients who have an ocular infection, who recently underwent ocular surgery, or have increased intraocular pressures should avoid ranibizumab use.
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. Intravitreal injections can be associated with endophthalmitis, retinal detachment, and increases in intraocular pressures (IOP). 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. Additionally, patients with macular ischemia should be carefully monitored when considering prolonged anti-VEGF therapy due to an already compromised blood supply. For a 0.5 mg dose of ranibizumab, the half-life of the drug is around 9 days.
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 . There is no known antidote in case of an overdose of ranibizumab.
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 the pharmacists, should thoroughly counsel patients so that they can make informed decisions about their treatment with ranibizumab or other VEGF inhibitors. Managing 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.
|||Chong V, Ranibizumab for the treatment of wet AMD: a summary of real-world studies. Eye (London, England). 2016 Nov; [PubMed PMID: 27612184]|
|||Chen Y,Han F, Profile of ranibizumab: efficacy and safety for the treatment of wet age-related macular degeneration. Therapeutics and clinical risk management. 2012; [PubMed PMID: 22911433]|
|||Hicklin DJ,Ellis LM, Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005 Feb 10; [PubMed PMID: 15585754]|
|||Krispel C,Rodrigues M,Xin X,Sodhi A, Ranibizumab in diabetic macular edema. World journal of diabetes. 2013 Dec 15; [PubMed PMID: 24379922]|
|||Hsu JY,Wakelee HA, Monoclonal antibodies targeting vascular endothelial growth factor: current status and future challenges in cancer therapy. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2009; [PubMed PMID: 19754219]|
|||Lin RC,Rosenfeld PJ, Antiangiogenic therapy in neovascular age-related macular degeneration. International ophthalmology clinics. 2007 Winter; [PubMed PMID: 17237677]|
|||Alon T,Hemo I,Itin A,Pe'er J,Stone J,Keshet E, Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature medicine. 1995 Oct; [PubMed PMID: 7489357]|
|||Kim LA,D'Amore PA, A brief history of anti-VEGF for the treatment of ocular angiogenesis. The American journal of pathology. 2012 Aug; [PubMed PMID: 22749677]|
|||Martin DF,Maguire MG,Ying GS,Grunwald JE,Fine SL,Jaffe GJ, Ranibizumab and bevacizumab for neovascular age-related macular degeneration. The New England journal of medicine. 2011 May 19; [PubMed PMID: 21526923]|
|||Joachim SC,Renner M,Reinhard J,Theiss C,May C,Lohmann S,Reinehr S,Stute G,Faissner A,Marcus K,Dick HB, Protective effects on the retina after ranibizumab treatment in an ischemia model. PloS one. 2017; [PubMed PMID: 28800629]|
|||Nguyen QD,Brown DM,Marcus DM,Boyer DS,Patel S,Feiner L,Gibson A,Sy J,Rundle AC,Hopkins JJ,Rubio RG,Ehrlich JS, Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Apr; [PubMed PMID: 22330964]|
|||Evoy KE,Abel SR, Ranibizumab: the first vascular endothelial growth factor inhibitor approved for the treatment of diabetic macular edema. The Annals of pharmacotherapy. 2013 Jun; [PubMed PMID: 23656749]|
|||van Asten F,Michels CTJ,Hoyng CB,van der Wilt GJ,Klevering BJ,Rovers MM,Grutters JPC, The cost-effectiveness of bevacizumab, ranibizumab and aflibercept for the treatment of age-related macular degeneration-A cost-effectiveness analysis from a societal perspective. PloS one. 2018; [PubMed PMID: 29772018]|
|||Mohamad NA,Ramachandran V,Ismail P,Mohd Isa H,Chan YM,Ngah NF,Md Bakri N,Ching SM,Hoo FK,Wan Sulaiman WA, Prevalence and treatment patterns of ranibizumab and photodynamic therapy in a tertiary care setting in Malaysia. International journal of ophthalmology. 2017; [PubMed PMID: 29259909]|
|||Blick SK,Keating GM,Wagstaff AJ, Ranibizumab. Drugs. 2007; [PubMed PMID: 17521219]|
|||Papadopoulos N,Martin J,Ruan Q,Rafique A,Rosconi MP,Shi E,Pyles EA,Yancopoulos GD,Stahl N,Wiegand SJ, Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012 Jun; [PubMed PMID: 22302382]|
|||Dugel PU,Singh N,Francom S,Cantrell RA,Grzeschik SM,Fung AE, The Systemic Safety of Ranibizumab in Patients 85 Years and Older with Neovascular Age-Related Macular Degeneration. Ophthalmology. Retina. 2018 Jul; [PubMed PMID: 31047375]|
|||Stewart MW, A Review of Ranibizumab for the Treatment of Diabetic Retinopathy. Ophthalmology and therapy. 2017 Jun; [PubMed PMID: 28324452]|
|||Bressler SB,Almukhtar T,Bhorade A,Bressler NM,Glassman AR,Huang SS,Jampol LM,Kim JE,Melia M, Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment. JAMA ophthalmology. 2015 May; [PubMed PMID: 25719991]|
|||Wang W,Zhang X, Systemic adverse events after intravitreal bevacizumab versus ranibizumab for age-related macular degeneration: a meta-analysis. PloS one. 2014; [PubMed PMID: 25330364]|
|||Kampougeris G,Spyropoulos D,Mitropoulou A, Intraocular Pressure rise after Anti-VEGF Treatment: Prevalence, Possible Mechanisms and Correlations. Journal of current glaucoma practice. 2013 Jan-Apr; [PubMed PMID: 26997776]|
|||Falavarjani KG,Nguyen QD, Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (London, England). 2013 Jul; [PubMed PMID: 23722722]|
|||Fintak DR,Shah GK,Blinder KJ,Regillo CD,Pollack J,Heier JS,Hollands H,Sharma S, Incidence of endophthalmitis related to intravitreal injection of bevacizumab and ranibizumab. Retina (Philadelphia, Pa.). 2008 Nov-Dec; [PubMed PMID: 18827737]|
|||Karagiannis DA,Mitropoulos P,Ladas ID, Large subretinal haemorrhage following change from intravitreal bevacizumab to ranibizumab. Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2009; [PubMed PMID: 19390227]|
|||Modarres M,Naseripour M,Falavarjani KG,Nikeghbali A,Hashemi M,Parvaresh MM, Intravitreal injection of 2.5 mg versus 1.25 mg bevacizumab (Avastin) for treatment of CNV associated with AMD. Retina (Philadelphia, Pa.). 2009 Mar; [PubMed PMID: 19287288]|
|||Lim LS,Cheung CMG,Mitchell P,Wong TY, Emerging evidence concerning systemic safety of anti-VEGF agents--should ophthalmologists be concerned? American journal of ophthalmology. 2011 Sep; [PubMed PMID: 21855670]|
|||Holz FG,Bandello F,Gillies M,Mitchell P,Osborne A,Sheidow T,Souied E,Figueroa MS, Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme. The British journal of ophthalmology. 2013 Sep; [PubMed PMID: 23850682]|
|||Xu L,Lu T,Tuomi L,Jumbe N,Lu J,Eppler S,Kuebler P,Damico-Beyer LA,Joshi A, Pharmacokinetics of ranibizumab in patients with neovascular age-related macular degeneration: a population approach. Investigative ophthalmology [PubMed PMID: 23361508]|
|||Manousaridis K,Talks J, Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease? The British journal of ophthalmology. 2012 Feb; [PubMed PMID: 22250209]|
|||Merz PR,Röckel N,Ballikaya S,Auffarth GU,Schmack I, Effects of ranibizumab (Lucentis®) and bevacizumab (Avastin®) on human corneal endothelial cells. BMC ophthalmology. 2018 Dec 11; [PubMed PMID: 30537942]|