As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ranibizumab products may be misleading.
The pre-treatment incidence of immunoreactivity to ranibizumab was 0%-5% across treatment groups. After monthly dosing with ranibizumab for 6 to 24 months, antibodies to ranibizumab were detected in approximately 1%-9% of patients.
The clinical significance of immunoreactivity to ranibizumab products are unclear at this time. Among neovascular AMD patients with the highest levels of immunoreactivity, some were noted to have iritis or vitritis.
Intraocular inflammation was not observed in patients with RVO patients with the highest levels of immunoreactivity.
The following adverse reactions have been identified during postapproval use of ranibizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Ocular: Tear of retinal pigment epithelium among patients with neovascular AMD
Drug interaction studies have not been conducted with ranibizumab products.
Ranibizumab intravitreal injection has been used adjunctively with Photodynamic Therapy (PDT). Twelve of 105 (11%) patients with neovascular AMD developed serious intraocular inflammation; in 10 of the 12 patients, this occurred when ranibizumab was administered 7 days (± 2 days) after PDT.
There are no adequate and well-controlled studies of ranibizumab products administered in pregnant women.
Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses 13-times the predicted human exposure (based on maximal serum trough levels [Cmax ]) after a single eye treatment at the recommended clinical dose. No skeletal abnormalities were observed at serumtrough levels equivalent to the predicted human exposure after a single eye treatment at the recommended clinical dose [see Animal Data ].
Animal reproduction studies are not always predictive of human response, and it is not known whether ranibizumab products can cause fetal harm when administered to a pregnant woman. Based on the anti-VEGF mechanism of action for ranibizumab products [see Clinical Pharmacology (12.1) ], treatment with ranibizumab products may pose a risk to human embryofetal development.
BYOOVIZ should be given to a pregnant woman only if clearly needed.
An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received intravitreal injections of ranibizumab every 14 days starting on Day 20 of gestation, until Day 62 at doses of 0, 0.125, and 1 mg/eye. Skeletal abnormalities including incomplete and/or irregular ossification of bones in the skull, vertebral column, and hindlimbs and shortened supernumerary ribs were seen at a low incidence in fetuses from animals treated with 1 mg/eye of ranibizumab. The 1 mg/eye dose resulted in trough serum ranibizumab levels up to 13 times higher than predicted Cmax levels with single eye treatment in humans. No skeletal abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which resulted in trough exposures equivalent to single eye treatment in humans. No effect on the weight or structure of the placenta, maternal toxicity, or embryotoxicity was observed.
There are no data available on the presence of ranibizumab products in human milk, the effects of ranibizumab products on the breastfed infant or the effects of ranibizumab products on milk production/excretion.
Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when BYOOVIZ is administered to a nursing woman.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BYOOVIZ and any potential adverse effects on the breastfed child from BYOOVIZ.
No studies on the effects of ranibizumab products on fertility have been conducted and it is not known whether ranibizumab products can affect reproduction capacity. Based on the anti-VEGF mechanism of action for ranibizumab products, treatment with ranibizumab products may pose a risk to reproductive capacity.
The safety and effectiveness of ranibizumab products in pediatric patients have not been established.
In the clinical studies, approximately 76% (2449 of 3227) of patients randomized to treatment with ranibizumab were ≥ 65 years of age and approximately 51% (1644 of 3227) were ≥ 75 years of age [see Clinical Studies (14) ]. No notable differences in efficacy or safety were seen with increasing age in these studies. Age did not have a significant effect on systemic exposure.
More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been administered to patients. No additional unexpected adverse reactions were seen.
BYOOVIZ (ranibizumab-nuna) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab-nuna binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A). Ranibizumab-nuna, which lacks an Fc region, has a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product.
BYOOVIZ (ranibizumab-nuna) injection is a sterile, clear to slightly opalescent and colorless to pale yellow solution in a single-dose glass vial for intravitreal use. BYOOVIZ is supplied as a preservative-free, sterile solution in a single-dose container designed to deliver 0.05 mL of 10 mg/mL BYOOVIZ (0.5 mg dose vial) aqueous solution with 10 mM histidine HCl, 10% α,α-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5.
Ranibizumab products bind 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, and macular edema following RVO. The binding of ranibizumab products 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.
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, and macular edema following RVO. Leakage from choroidal neovascularization (CNV) as assessed by fluorescein angiography (FA) is associated with neovascular AMD and mCNV.
Neovascular (Wet) Age-Related Macular Degeneration
In Study AMD-3, CPT was assessed by time domain (TD)-OCT in 118 of 184 patients. TD-OCT measurements were collected at baseline, Months 1, 2, 3, 5, 8, and 12. In patients treated with ranibizumab, 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 (14.1) ].
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 ranibizumab injection through Month 24. CFT data did not provide information capable of predicting final visual acuity results [see Clinical Studies (14.1) ].
In patients treated with ranibizumab, 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.
Macular Edema Following Retinal Vein Occlusion
On average, CPT reductions were observed in Studies RVO-1 and RVO-2 beginning at Day 7 following the first ranibizumab injection through Month 6. CPT was not evaluated as a means to guide treatment decisions [see Clinical Studies (14.2) ].
Myopic Choroidal Neovascularization
On average CFT reductions were observed as early as Month 1, and were greater in the ranibizumab groups compared to PDT [see Clinical Studies (14.3) ].
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