EFFICACY IN OTHER RETINAL DISEASES

Preliminary results from clinical trials of ranibizumab in ocular neovascular diseases other than AMD have been promising. Interim results from the RESOLVE phase I/II trial (n = 150) of ranibizumab in diabetic macular edema show that patients who received ranibizumab (0.3 or 0.5 mg) achieved, on average, a decrease in macular thickness and an increase in VA; this was in contrast to sham-treated patients in whom there was a slight increase in macular thickness and a decrease in VA (Novartis; data on file). Phase III trials of ranibizumab as monotherapy (RISE/RIDE) or as adjunctive therapy, when added to laser photocoagulation (RESTORE), for diabetic macular edema are currently in progress. Furthermore, phase III trials of ranibizumab in CRVO and branch retinal vein occlusion (BRVO) are under way (BRAVO and CRUISE).

CONTRAINDICATIONS

Ranibizumab is contraindicated in patients with ocular or periocular infections. Ranibizumab is also contraindicated in patients with known hypersensitivity to ranibizumab or any of the known excipients in the drug formulation. Hypersensitivity reactions may manifest as severe intraocular inflammation.26

OCULAR COMPLICATIONS AND TOXICITY

There is now a significant body of evidence from preand postlicensing trials to show that ranibizumab is generally safe and well tolerated.7,18,21 The most frequently reported ocular AEs in the three trials, occurring more often in ranibizumab treatment groups compared with control groups, are conjunctival hemorrhage (43–77%), eye pain (17–37%), vitreous floaters (3–32%), and increased intraocular pressure (8–25%).26

The incidence of serious ocular AEs is low (<1.5% of patients): in the MARINA and ANCHOR trials, the most common were endophthalmitis (0–1.4%) and uveitis (0–1.3%). Other serious ocular AEs reported were retinal detachment, retinal tear, retinal hemorrhage, and vitreous hemorrhage. In the PIER trial, there were no serious ocular AEs.21,22

(ATEs). Given the average age of patients requiring treatment for AMD, it is important that their treatment does not significantly increase the risk of these events. In phase III trials of ranibizumab, the incidence of Antiplatelet Trialists Collaboration27 ATEs and hypertension was low. Over the 24-month trial period, the rate of ATEs in the ranibizumab 0.5-mg treatment group of the ANCHOR, MARINA, and PIER trials was 5.0%, 4.6%, and 0%, respectively, compared with 4.2%, 3.8%, and 0% in the control arms.7,18,21

Interim analysis of safety data from a further phase III trial, SAILOR (n = 2378), which is designed to investigate further the safety of a quarterly monitoring regimen and ranibizumab injections based on VA (>5-letter loss from the previous highest VA score during the first 3 months) or OCT (>100 m increase in CRT from the previous lowest measurement), indicates that there is a higher incidence of stroke in patients with pre-existing risk factors, particularly a previous history of stroke (data on file). The incidence of stroke continues to be monitored in phase IV trials; however, the risk should be taken into account, particularly in patients with a history of stroke.

The most frequently occurring nonocular AEs, for which the incidence is greater than in the control groups, are nasopharyngitis (5–25%), headache (2–15%), and upper respiratory tract infection (4–12%).26

DRUG INTERACTIONS

Drug interaction studies have not been conducted with ranibizumab. Combined therapy with ranibizumab and verteporfin PDT has been investigated in patients with predominantly classic CNV secondary to AMD. At 12 months, combination therapy resulted in a greater proportion of patients losing fewer than 15 letters than with PDT alone (90.5% and 67.9%, respectively).28 This VA benefit persisted at 24 months; on average, patients receiving ranibizumab plus PDT exhibited less lesion growth and greater reduction of CNV leakage, and required fewer PDT treatments than patients receiving PDT alone.29 Ranibizumab treatment did increase the incidence of serious ocular inflammation and endophthalmitis; however, affected patients, on average, still experienced a

VA gain.28–30

The clinical data support the use of a 3-month loading phase of consecutive monthly injections. For optimal outcomes, this should be followed by continued monthly injections or, if this is not possible, monthly monitoring and treatment as required.

Overall, ranibizumab has been well tolerated in the clinical trials completed to date, with a low incidence of ocular and systemic serious AEs. The safety profile continues to be monitored in postmarketing trials.

In conclusion, ranibizumab has demonstrated significant benefits to patients with neovascular AMD, not only in terms of VA gains but also in terms of improved quality of life. As such, it represents a valuable therapeutic option for ophthalmologists treating neovascular AMD.

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