Ranibizumab

Comparative studies

In a phase I/II randomized controlled trial 64 patients received either ranibizumab 0.3 or 0.5 mg (n = 53) or usual care (n = 11) [ ]. The most commonly reported adverse event was sterile, painless, reversible inflammation, most often occurring the day after administration and resolving without treatment after 14 days. Minor scleral and conjunctival hemorrhage was the second most common adverse event. Three patients had a potentially sight-threatening adverse event; the first had a recurrent severe iridocyclitis, the second a culture-proven infectious endophthalmitis, and the third had a central retinal vein occlusion. Increases in intraocular pressure were transient and mostly mild and resolved without treatment. Vitreous hemorrhage occurred in five patients and a retinal tear in one. There was only one non-ocular adverse event judged to be due to ranibizumab, a metallic taste.

Adverse events have been reported in the 2-year results of a randomized, single-masked, controlled trial of ranibizumab 0.5 mg + verteporfin photodynamic therapy (n = 106) versus verteporfin photodynamic therapy alone (n = 56) in neovascular age-related macular degeneration (FOCUS study) [ ]. Serious ocular adverse events occurred more often in those who received ranibizumab + photodynamic therapy (17% versus 14%). This was due to endophthalmitis (2.9%, 3/105, versus 0%) and ocular inflammation (12%, 13/105, versus 0%). Serious systemic vascular events occurred more often with ranibizumab + photodynamic therapy (14/105, 13% versus 6/56, 11%). The authors reported that the cumulative rates of serious non-ocular adverse events were similar in the two groups at 2 years (17/56 versus 30/105). Of the serious non-ocular adverse vascular events, which might plausibly have been due to systemic VEGF inhibition, the cumulative rates were 6/56 (11%) versus 14/105 (13%). Hypertension among patients who were not hypertensive at study entry emerged as a serious adverse event in only one patient who received ranibizumab. The rates of non-ocular hemorrhage were balanced between the groups (4/56 versus 7/105) and none was reported as serious. Arterial thromboembolic events as defined using the Antiplatelet Trialists’ Collaboration (APTC) criteria (that is, vascular death or death from an unknown cause, non-fatal myocardial infarction, non-fatal ischemic or hemorrhagic stroke, or stroke of unknown cause) were slightly more common in those who received photodynamic therapy alone (4/56 versus 5/105).

Adverse reactions have been studied in 32 patients with exudative age-related macular degeneration who received standard fluence photodynamic therapy with verteporfin at baseline and months 3, 6, and 9 and ranibizumab 0.5 mg at baseline and months 1, 2, and 3 [ ]. The main adverse reactions outcome measure was severe loss of vision (a loss of best-corrected visual acuity of at least 30 letters). There was no severe loss of vision due to ocular inflammation or uveitis. One patient had moderate loss of vision (of at least 15 letters). Three patients had mild/moderate uveitis. There were two serious ocular adverse events (a retinal pigment epithelial tear and a moderate reduction in best-corrected visual acuity). There were no systemic adverse events.

In an open, prospective, uncontrolled study, 10 patients with macular edema due to central retinal vein occlusion were randomly assigned to ranibizumab 0.3 mg or 0.5 mg and adverse reactions were studied [ ]. There were no severe adverse events.

Ranibizumab has been studied in 4300 patients with choroidal neovascularization secondary to age-related macular degeneration [ ]. One group was randomized to ranibizumab 0.3 mg or 0.5 mg and the second group received open ranibizumab 0.5 mg. Some 82% of the first group and 50% of the second group completed the 12-month study. The average total numbers of ranibizumab injections were 4.9 and 3.6 respectively. The incidences of vascular and non-vascular deaths during the 12 months were 0.9% and 0.7% in those who took 0.3 mg, 0.8% and 1.5% in those who took 0.5 mg in the first group, and 0.7% and 0.9% in those who took 0.5 mg in the second group. The incidence of death due to unknown cause was 0.1% in all the groups. The numbers of vascular deaths and deaths due to unknown causes did not differ across the groups. Stroke rates were 0.7%, 1.2%, and 0.6% in the three groups. The rates of individual key ocular serious adverse events in the first group were less than 1%; two of those who took 0.3 mg and five of those who took 0.5 mg developed endophthalmitis or presumed endophthalmitis (i.e. ocular infection treated with antibiotics), and one subject in each dosage group had a serious cataract event. The rates of individual key ocular serious adverse events in the second group were less than 1%; one subject developed endophthalmitis, and one had a serious cataract event. The incidences of ocular inflammation, including iritis, uveitis, vitritis, and iridocyclitis, were 1.0% in those who took 0.3 mg, 1.5% in those who took 0.5 mg in the first group, and 0.5% in the second group. The overall incidences of cataract were 5.4%, 6.0%, and 2.8%. The rates of key non-ocular serious adverse events were similar across the two dosages in the first group, but non-vascular deaths, strokes, and hemorrhages were numerically higher in the 0.5 mg group. Eight subjects who took 0.3 mg and 15 who took 0.5 mg had a stroke during the 12 months. The incidences of myocardial infarctions and Antiplatelet Trialists’ Collaboration (APTC) 3 arterial thromboembolic events, which included vascular deaths and deaths of unknown cause, non-fatal myocardial infarctions, and non-fatal cardiovascular accidents, were similar across the two dosages. The rates of key non-ocular serious adverse events in the second group were generally lower than those in the first group, which may have been a result of under-reporting, because of the large number of subjects in the second group who withdrew. The incidence of non-ocular adverse events that were potentially related to VEGF inhibitors was low and comparable across all the groups. A prior stroke, a history of dysrhythmias, and a history of congestive heart failure were significant susceptibility factors for stroke. Although the numbers were small, there was a non-statistically significant trend toward a higher incidence of stroke in those in the first group who took 0.5 mg with a history of stroke. Seven of the 73 subjects with a history of stroke who took 0.5 mg had a stroke during the study compared with two of the 73 subjects with a history of stroke who took 0.3 mg. None of the subjects in the second group with a history of stroke had a stroke during the study. There were 82 deaths during the study (20, 29 and 33 subjects in the respective groups); the numbers of vascular deaths and deaths due to unknown causes did not differ across the groups.

In the ANCHOR study of ranibizumab 0.3 mg and 0.5 mg versus photodynamic therapy for neovascular age-related macular degeneration in 423 patients the adverse events were reported after 2 years [ ]. Overall, there was no imbalance among the three treatment groups in the rates of serious and non-serious ocular adverse events in the study eye. The percentages of patients with any serious ocular adverse event in the study eye were similar among those who received photodynamic therapy (7.7%), ranibizumab 0.3 mg (7.3%), and ranibizumab 0.5 mg (9.3%). “Presumed” endophthalmitis occurred in three of 277 patients (1.1%) in the pooled ranibizumab groups and in none in the photodynamic therapy group. Vitreous hemorrhage was reported in two of 277 patients (0.7%) in the former and none of 143 patients in the latter. Rhegmatogenous retinal detachment occurred in two (0.7%) and one patient (0.7%) respectively and the rates per ocular injection were two out of 5921 (0.03%) and two out of 2571 (0.07%). The percentage of patients who had any serious or non-serious intraocular inflammation in the study eye was higher in the ranibizumab groups (12% with 0.3 mg and 17% with 0.5 mg) than in the photodynamic therapy group (3.5%). As in all previous trials of ranibizumab, transient increases in intraocular pressure in the study eye were common in the hour after intravitreal injection. No cases of traumatic lens damage were reported. There was a trend to a higher rate of cataract in the study eye with ranibizumab (17% with 0.3 mg and 20% with 0.5 mg) compared with photodynamic therapy (11%); post hoc analysis showed that the difference between ranibizumab 0.5 mg and photodynamic therapy was statistically significant. Cataract surgery was performed during the 24 months in five of 137 patients (0.3 mg), five of 140 patients (0.5 mg), and one of 143 patients (photodynamic therapy). Overall, there was no imbalance among the three treatment groups in the rates of serious non-ocular adverse events, including those known to be potentially associated with systemic administration of VEGF inhibitors in patients with cancers. The rates of arterial thromboembolic events (defined using the Antiplatelet Trialists’ Collaboration criteria) were similar across the groups 4.4% (0.3 mg), and 5.0% (0.5 mg), and 4.2% (photodynamic therapy). Although the rate of arterial thromboembolic events with ranibizumab 0.5 mg (3.6%) was slightly higher than with ranibizumab 0.3 mg and photodynamic therapy (2.2% and 2.1% respectively) during the first treatment year, it was slightly lower than in the other two groups during the second year: 1.6% (2/128) compared with 2.4% (3/127) and 2.3% (3/128) respectively; none of these differences was statistically significant. There were no deaths from myocardial infarction or stroke during the study. Rates of non-fatal strokes were 2.2%, 0%, and 1.4% respectively. Hypertension was not more common with ranibizumab than photodynamic therapy. Non-ocular hemorrhages were more common with ranibizumab (8.8% with 0.3 mg, 9.3% with 0.5 mg, 4.9% with photodynamic therapy), although these differences were not statistically significant. The incidence of serious non-ocular hemorrhage was also slightly higher with ranibizumab (2.9% with 0.3 mg, 2.1% with 0.5 mg, and 0.7% with photodynamic therapy). Serious hemorrhages with ranibizumab included gastrointestinal hemorrhage (n = 4), traumatic subdural hematoma (n = 2), and duodenal ulcer hemorrhage (n = 1). The temporal pattern of these events in relation to ranibizumab dosing did not suggest a causal association. No ranibizumab-treated patient had proteinuria.

The risks of strokes and myocardial infarctions have been calculated in patients who received ranibizumab (0.3 or 0.5 mg intravitreally) for age related macular degeneration in three large randomized trials (MARINA, ANCHOR, and FOCUS) in a total of 859 subjects who were treated with monthly ranibizumab, and 434 subjects who were sham-treated [ ]. During the 2-year observation period, 19 of those who received ranibizumab (2.2%) had strokes and 16 (1.9%) had myocardial infarctions. Of the sham-treated subjects, three (0.7%) had strokes and 13 (3.0%) had myocardial infarctions. Intravitreal ranibizumab was associated with an increased risk of stroke (OR = 3.24; 95%CI = 0.96, 11), whereas there was no apparent association between intravitreal ranibizumab and myocardial infarction.

In a randomized controlled trial in patients with diabetic macular edema who were randomized to intravitreal ranibizumab 0.5 mg, focal or grid laser, and a combination of these interventions, there was one serious adverse event (a stroke in a high-risk patient), which was presumed to be unrelated to the use of ranibizumab because it occurred 6 weeks after the injection [ ]. There was no difference in blood pressure. Eight patients across the groups had vitreous hemorrhages, and in one patient it was combined with worsening of the macular edema, while in the others it was mild and had cleared at 6 months.

In a series of 943 eyes treated with intravitreal injection of triamcinolone acetonide 4 mg, ranibizumab 0.5 mg, bevacizumab 1.25 mg, or pegaptanib 0.3 mg, the most common ocular complication was subconjunctival hemorrhage, which was seen in 36% of cases [ ]. There was a temporary increase in intraocular pressure above 21 mmHg in 18 eyes (5%) after anti-VEGF agents and in 30 eyes (23%) after triamcinolone. Anterior uveitis developed in 16 cases (1.7%) with bevacizumab (five eyes) and ranibizumab (three eyes). Anterior–posterior inflammation occurred in eight eyes (0.8%), including four eyes (0.4%) with sterile endophthalmitis (three after bevacizumab and one after ranibizumab), and one eye (0.1%) with pseudoendophthalmitis after triamcinolone. There were three cases of suspected endophthalmitis (two after bevacizumab and one after triamcinolone, due to Staphylococcus epidermidis ). There was cataract formation or progression in 34 eyes. After triamcinolone there was progression of cataract in 23.4% of eyes (30 cases) during 2 years of follow-up and after anti-VEGF drugs there were two cases (0.6%) and two cases of iatrogenic cataract.

Placebo-controlled studies

In a multicenter, randomized, double-masked, sham injection-controlled trial in patients with predominantly or minimally classic or occult with no classic lesions due to age-related macular degeneration 184 patients were randomized to ranibizumab 0.3 or 0.5 mg or to sham treatment [ ]. Ranibizumab was given monthly for 3 months and then quarterly. Assessment of serious or non-serious non-ocular adverse events showed no overall difference between the groups. There were no deaths during the first year of treatment. Hypertension in subjects who were not hypertensive at baseline was reported as an adverse event in 8.1% of sham-treated subjects, 6.8% of those who received ranibizumab 0.3 mg, and 8.2% of those who received 0.5 mg. Routinely measured systolic and diastolic blood pressures were very similar among groups at baseline and at 12 months. Proteinuria was not reported during the first year. The rates of non-ocular hemorrhage were 2.4% and 6.6% with ranibizumab 0.3 mg and 0.5 mg respectively and 4.8% in the sham group. There was only one case of serious non-ocular hemorrhage (hemorrhage at the site of an intravenous catheter in a subject who received ranibizumab 0.5 mg). There were no cases of gastrointestinal perforation. There were no arterial thromboembolic events. The only serious or non-serious arterial thromboembolic event during the first year was ischemic cardiomyopathy in a sham-treated subject. Immunoreactivity to ranibizumab was assessed at screening and at month 12 or at early termination. During screening, one subject randomized to sham treatment tested positive, possibly because of pre-existing anti-Fab antibodies. None of those who received ranibizumab tested positive before study treatment, but two of those who received 0.5 mg group tested positive at month 12; neither of these two subjects had any severe or serious adverse events during the study.

Systematic reviews

The adverse events in three trials of ranibizumab have been summarized in a systematic review [ ]. Endophthalmitis occurred in 1.4% and 1.9% of patients receiving 0.5 mg ranibizumab in the ANCHOR and FOCUS trials respectively. The rate per injection was 0.05% in the MARINA trial.