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Food and Drug Administration and Compliance Issues
Friday, August 14, 2020
FDA alerts health care professionals of risks associated with intraocular use of compounded moxifloxacin
August 12, 2020
Ophthalmologists frequently administer moxifloxacin and other anti-infective agents either topically or intraocularly to reduce the incidence of postoperative endophthalmitis. Endophthalmitis occurs at a low incidence following cataract surgery (estimated to be between 0.012% 1.3%).1 There are currently no FDA-approved drugs for endophthalmitis prophylaxis.
Outsourcing facilities have compounded moxifloxacin drug products from bulk drug substances and repackaged the FDA-approved topical moxifloxacin drugs. Traditional and hospital pharmacies (generally, those that operate under section 503A of the Federal Food, Drug, and Cosmetic Act), as well as individual ophthalmologists have used moxifloxacin ophthalmic solutions, approved for topical administration, as the starting material to prepare moxifloxacin drugs for use during intraocular procedures.
FDA received case reports of TASS (Toxic Anterior Segment Syndrome) following intraocular administration of compounded drugs using moxifloxacin as a bulk drug substance, as well as reports associated with the intraocular administration of repackaged and/or diluted FDA-approved moxifloxacin drugs. FDA searched the Adverse Event Reporting System (FAERS) database for all reports through December 19, 2019, and identified 29 cases that described TASS associated with intraocular administration of drugs containing moxifloxacin (16 compounded drugs using moxifloxacin as a bulk drug substance, 10 repackaged Moxeza, 2 unspecifieda Vigamox, and 1 unspecifieda Moxeza). The majority of cases (n = 19) reported use of moxifloxacin following cataract surgery and the remaining 10 did not specify the type of ophthalmic surgery.
Of the 29 TASS cases, five reported use of 0.5% moxifloxacin at a volume of 0.5 mL, one reported use of 0.1% moxifloxacin at a volume of 0.1 mL, and the remaining 23 did not report the volume used. Most cases were reported by a health care professional and did not report the use of concomitant intraocular drugs or drugs containing multiple active ingredients.
According to one facility that reported 10 of these cases, TASS developed within one week after intraocular administration of a compounded drug containing moxifloxacin. The report indicated a positive drug-event association, as the TASS events ceased following the discontinuation of the use of moxifloxacin at the facility. When the compounded moxifloxacin drug was reintroduced during subsequent surgical procedures, patients again presented with TASS. While it is not possible to determine if the TASS events were solely due to exposure to intraocular moxifloxacin, the occurrence of additional cases following re-introduction of compounded moxifloxacin use reduces the likelihood of other causes.
a Unspecified means the report did not specify whether the drug was either repackaged/diluted or administered without repackaging/dilution by the ophthalmologist during intraocular surgery.
Moxifloxacin topical ophthalmic solutions are FDA approved and marketed under the proprietary names Moxeza and Vigamox. Neither drug is approved for intraocular administration. FDA is aware of multiple literature reports that claim to support the use of intraocular moxifloxacin for the prophylaxis of endophthalmitis, and it is a common practice among ophthalmologists in association with cataract surgery. However, there are no adequate and well controlled studies that demonstrate moxifloxacin’s efficacy for treating endophthalmitis. There also are no adequate and well controlled studies that demonstrate that any anti-infective, topical or intraocular, is effective in reducing the incidence of endophthalmitis.
Moxifloxacin is an anti-infective, which, in a dose dependent manner, kills specific microorganisms. Moxifloxacin, in sufficient concentrations, may also contribute to cellular injury in the human body.2 The concentration that causes human harm is not precisely established, although multiple clinical studies support that intraocular use of moxifloxacin in volumes of 0.3mL or less with concentrations of 0.5% or less is unlikely to cause significant adverse events.3, 4, 5, 6, 7
In addition to selecting the proper concentration and volume, the safety of an intraocularly injected drug is also dependent on the content of the active and inactive ingredients in the formulation. There are two different topical moxifloxacin ophthalmic solutions approved for marketing, Vigamox (moxifloxacin ophthalmic solution) 0.5% and Moxeza (moxifloxacin ophthalmic solution) 0.5%. Although these two drugs contain the same active ingredient with the same concentration, they contain different inactive ingredients. Moxeza contains xanthan gum, which has been linked to causing TASS.8, 9 Intraocular injection of Moxeza, including diluted Moxeza, is likely to cause TASS. Moxeza carries a specific warning that it is for topical ophthalmic use only and should not be injected subconjunctivally or introduced directly into the anterior chamber of the eye. Moxeza should not be used, diluted, repackaged or compounded for intraocular injection.
FDA recommends that before health care professionals administer moxifloxacin intraocularly, they know its formulation. The agency also alerts compounders, ophthalmologists and other health care professionals of risks associated with the intraocular administration of moxifloxacin drugs that contain more than 0.3 mL of 0.5% moxifloxacin or that contain certain potentially harmful inactive ingredients, such as xanthan gum.8,9 Additionally, FDA cautions health care professionals to carefully consider the concentration and inactive ingredients of any moxifloxacin drug before intraocular administration.
Cao, H., Zhang, L., Li, L., Lo, S. (2013). Risk factors for acute endophthalmitis following cataract surgery: A systematic review and meta-analysis. PLoS ONE 8(8): e71731.
Miyake, H., Miyazaki, D., Shimizu, Y., et al. (2019). Toxicities of and inflammatory responses to moxifloxacin, cefuroxime, and vancomycin on retinal vascular cells. Sci Rep. 9:9745.
Arbisser, L.B. (2008). Safety of intracameral moxifloxacin for prophylaxis of endophthalmitis after cataract surgery. J Cataract Refract Surg. 34(7):1114-20.
Haripriya, A., Chang, D.F., Ravindran, R.D. (2017). Endophthalmitis reduction with intracameral moxifloxacin prophylaxis: Analysis of 600,000 surgeries. Ophthalmology. 124(6):768-775.
Chang, D.F., Prajna, N.V., Szczotka-Flynn, L.B. et al. (2020). Comparative corneal endothelial cell toxicity of differing intracameral moxifloxacin doses after phacoemulsification. J Cataract Refract Surg. 46(3):355-359.
Zhou, A.X., Messenger, W.B., Sargent, S., Ambati, B.K. (2016). Safety of undiluted intracameral moxifloxacin without postoperative topical antibiotics in cataract surgery. Int Ophthalmol. 36(4):493-8.
Lira, R.P.C., Lucena, N.P., Ferreira, K.S.A., dos Santos. B.M.A. (2017) Long-term safety of intracameral moxifloxacin after cataract surgery. J Cataract Refract Surg. 43(1):139-140.
Braga-Mele, R., Chang, D.F., Henderson, B.A., Mamalis, N., Talley-Rostov, A., Vasavada, A. (2014). Intracameral antibiotics: safety, efficacy, and preparation. J Cataract Refract Surg. 40:2134–2142.