Update: July 5, 2018
On July 28, 2017, FDA alerted health care professionals of adverse event reports concerning at least 43 patients who were administered intravitreal (eye) injections of a drug containing triamcinolone acetonide (steroid) and moxifloxacin (anti-infective) compounded by Guardian Pharmacy Services in Dallas, Texas. The patients reportedly experienced various symptoms, including vision impairment, poor night vision, loss of color perception, and significant reductions in best-corrected visual acuity and visual fields. As part of its investigation into these adverse events, FDA collected and tested samples of Guardian’s product to identify and quantify the substances contained therein. FDA also prepared and tested in-house samples to assess the impact of autoclaving and sonication, which were used by Guardian during its compounding process, on the stability of the drug product. Below is a description of the test results and the agency’s analysis of those results.
Sample Collection and Identity and Concentration Testing of Guardian’s Samples
In May 2017, FDA collected from the PRG Dallas Ambulatory Surgery Center in Dallas, Texas, 1 vial of Guardian’s triamcinolone-moxifloxacin product with a beyond use date of February 3, 2017. In December 2017, FDA collected from the Texas State Department of Health seven vials of Guardian’s product with a beyond use date of November 10, 2016. In March 2018, two additional vials of Guardian’s product were shipped from the Texas State Department of Health to FDA.
FDA tested these samples to identify the substances in Guardian’s product and their amounts. In addition to the triamcinolone and moxifloxacin declared on the label, Guardian’s product contained pluronic F127, which is also known as poloxamer 407. Poloxamer 407 is a hydrophilic non-ionic surfactant that is sometimes used in pharmaceuticals as a solubilizing and stabilizing agent. The amount of poloxamer 407 in Guardian’s product was 12% weight by volume (g/100 mL).
FDA identified two other substances that are commonly used as preservatives in the following specified concentrations: methylparaben (0.317 mg/mL) and propylparaben (0.175 mg/mL). Guardian’s product is labeled “PF,” or preservative-free.
FDA also identified 2,2’-methylenebis(6-tert-butyl-4-methylphenol) at a concentration of 0.0361 mg/mL. This substance is commonly used in rubber products, such as rubber septa used in vial closures.
FDA further identified the following substances in the specified concentrations: formaldehyde (0.70 mM), acetaldehyde (0.63 mM), formate (0.49 mM), and acetone (0.06mM). Formaldehyde, acetaldehyde, and formate are likely degradants of poloxamer 407, and acetone is a degradant of triamcinolone acetonide.
In-House Sample Preparation and Testing the Impact of Sonication and Autoclaving
FDA prepared in-house samples of triamcinolone acetonide (15 mg/mL) and moxifloxacin (1 mg/mL) with concentrations of poloxamer 407 varying from 0.5% to 15% (g/100 mL). FDA visually inspected the samples and observed phase separation and gelation in samples with concentrations of poloxamer 407 at and above 5% (g/100 mL) after autoclaving. FDA also observed that storing the samples at 4 degrees Celsius for a week caused loss of viscosity and precipitation of triamcinolone acetonide that was difficult to re-suspend.
The in-house samples were tested to evaluate the impact of autoclaving, sonication for one hour, and sonication for an additional hour on the stability of the ingredients. The results showed that poloxamer 407 degraded upon autoclaving or sonication, and the triamcinolone acetonide and moxifloxacin degraded upon autoclaving or two hours of sonication. The poloxamer degradants identified in the freshly prepared in-house samples (formaldehyde, acetaldehyde, and formate) were the same poloxamer degradants identified in the expired samples of Guardian’s product.
FDA’s investigation revealed a high percentage of poloxamer 407 and the presence of potential process degradation products in Guardian’s product. The amount of poloxamer 407 in Guardian’s product is much greater than the amount of poloxamers in FDA-approved ophthalmic products, and the poloxamer 407 degrades upon autoclaving or sonication. Poloxamers, including poloxamer 407, are used as surfactants to increase the solubility of topical ophthalmic solutions. Poloxamer 407 is an ingredient in FDA-approved topical ophthalmic products such as AzaSite (azithromycin ophthalmic solution), Besivance (besifloxacin ophthalmic suspension), and Neomycin and Polymyxin B Sulfates and Gramicidin Ophthalmic Solution USP. The maximum concentration of poloxamers in the FDA-approved topical ophthalmic solutions and suspensions is 0.1-0.2% (g/100 mL), which is significantly less than the 12% (g/100 mL) in Guardian’s intravitreal product. Poloxamer 407 is not used in any FDA-approved product intended for intravitreal injection, although other poloxamers have been used in intraocularly administered FDA-approved products. FDA is not aware of any drug product containing poloxamer 407 that has been shown to be safe when administered intravitreally to humans.
At least 43 patients reportedly experienced ocular adverse events after receiving eye injections of Guardian’s compounded triamcinolone-moxifloxacin product during cataract surgery. FDA identified multiple substances in Guardian’s product, including poloxamer 407 and poloxamer 407 degradants. FDA prepared in-house samples of Guardian’s product and found that autoclaving and sonication caused the poloxamer 407 to degrade. The amount of poloxamer 407 in Guardian’s product (12%, g/100 mL) is much greater than the maximum amount of poloxamers in FDA-approved ophthalmic products for topical administration (0.1-0.2%, g/100 mL), and the safety profile of drug products intended for intravitreal injection containing poloxamer 407 is unknown.
Compounding pharmacies should determine, based on the route of administration and the organ or tissue involved, whether the excipients are safe in the amount that will be present in the administered dose. One way to accomplish this is to use an excipient in an amount where scientific data support its safety, such as data supporting FDA approval of a comparable drug product with a similar concentration of the excipient. Compounding pharmacies also should consider whether the compounding process will generate degradants of such ingredients. Because compounded products are not evaluated by FDA for safety, effectiveness, or quality, health care professionals should consult the compounding pharmacy about the safety information related to the excipients in the compounded products they plan to inject into their patients.
FDA encourages consumers, patients, and health care professionals to report adverse events or quality problems experienced with the use of compounded drug products to FDA’s MedWatch Adverse Event Reporting program:
- Complete and submit the report online at www.fda.gov/medwatch/report.htm; or
- Download and complete the form, then submit it via fax at 1-800-FDA-0178.
Please note: Guardian Pharmacy Services is located at 7920 Elmbrook Drive, Suite 108C, Dallas, Texas.