Preserved Kenalog linked to cases of sterile endophthalmitis

No similar problems have been reported with compounded, nonpreserved triamcinolone acetate, an investigator reports.

NAPLES, Fla. — Several cases of sterile endophthalmitis have been associated with intravitreal injection of a preserved triamcinolone acetate formulation within the past 4 months, according to a surgeon speaking here.

Alexander M. Eaton

Alexander M. Eaton, MD, reported on these cases at the Florida Society of Ophthalmology annual meeting. He discussed several cases from his own experience, as well as from surgeons throughout the United States. All have been associated with intravitreal injection of preserved Kenalog (triamcinolone acetate, Bristol-Myers Squibb), which is an off-label use of the drug. No similar problems have been reported with unpreserved triamcinolone from compounding pharmacies, he said.

“While we don’t know the exact cause right now, I think it is something that seems to be a widespread problem and one that early recognition of is important,” Dr. Eaton said in an interview conducted with Ocular Surgery News at the meeting. “Hopefully with recognition and taking appropriate measures, one can prevent it in the future. In the meantime, we’re continuing to try to figure out what exactly happened and what the reason for it was.”

Initial suspicion

Dr. Eaton became suspicious of the drug might be the cause after four patients at his practice, the Retina Health Center in Fort Myers, Fla., returned with signs of inflammation after intravitreal injection of Kenalog for a variety of indications.

Dr. Eaton said he was not suspicious after the first patient. Studies such as the VISION (VEGF Inhibition Study in Ocular Neovascularization) study of Macugen (pegaptanib sodium, OSI/Pfizer) indicate that endophthalmitis can occur after about one in every 1,000 cases of intravitreal injection.

“It had been a long time since I had one previously, so I didn’t think much about it,” he told OSN.

When a second patient presented with inflammation, Dr. Eaton said, he thought the situation was unusual, and he went back to confirm that correct preparation and injection techniques had been used. After the third case, he bought a new lot of Kenalog.

“After the fourth case, I knew something just was not right,” he explained to OSN. “That’s when I decided that there had to be something that was wrong, and I stopped using intravitreal injections.”

Dr. Eaton explained in his presentation that all of the patients had decreased vision, but none reported any pain. They typically presented between 24 and 72 hours after injection, he said.

He added that patients did not come from any one age group, that both men and women were affected, and that the underlying pathologies varied.

Examining earlier records, Dr. Eaton found that only one patient had developed endophthalmitis out of 662 patients he injected with the drug from 2003 to 2005, an incidence rate of 0.15%.

Since May, Dr. Eaton said he has seen four cases of sterile endophthalmitis among 29 patients he has treated with intravitreal Kenalog injections, an incidence of 14%.

Since those four cases presented, three have recovered their vision, with the quickest recovery being 6 weeks, he said. Unfortunately, he said, one patient experienced a retinal detachment, and her visual prognosis is still unsure.

“Clearly this recent trend is a change,” Dr. Eaton said in his presentation. “This patient shows the importance of identifying this problem and the need for prevention.”

Additional cases

Dr. Eaton contacted other retina specialists in his region to inquire about their recent experiences with preserved triamcinolone acetate. He said a number of surgeons at Bascom Palmer Eye Institute in Miami, as well as surgeons in other Florida centers and at Duke, told him they had experienced similar problems.

“That made me realize that this was not a problem that was isolated to my office,” he told OSN. “There had to be a more generalized problem with the medication.”

He noted that, during this time, no similar problems were reported with intravitreal injections of other medications, including Macugen, Avastin (bevacizumab, Genentech) or Lucentis (ranibizumab, Genentech).

Dr. Eaton theorized that the problem might be limited to certain lot numbers of Kenalog shipping to the Southeast United States or to heat in their geographic area, until he heard from a colleague in California who had the same experience.

“That showed that it’s a more global problem,” Dr. Eaton told OSN. “It was quite clear to me that we had a problem.”

Philip J. Rosenfeld

Philip J. Rosenfeld, MD, PhD, who also attended the meeting here in Naples, Fla., spoke of his experiences at Bascom Palmer, where one of his recent patients also developed sterile endophthalmitis after an intravitreal triamcinolone injection.

“I’ve been injecting Kenalog since 2001, and never had a case until recently. Just within the past month, I had my first case, but a tap and inject was not performed since the eye had the characteristic appearance of a pseudoendophthalmitis rather than a true endophthalmitis. The patient did well over the next few days and the pseudo-endophthalmitis resolved. “It seems as though something has changed since we went through a period of several years without seeing any pseudo-endophthalmitis and now there are reports popping up once again.”

Although he said there do not seem to be any long-term sequelae, he said the patients who had experienced sterile endophthalmitis were under observation.

“We’ve just been watching these cases, but it’s been disturbing,” Dr. Rosenfeld said.

Taking action

Dr. Eaton took his concerns to the Centers for Disease Control and Prevention, the Food and Drug Administration and Bristol-Myers Squibb.

In working with the CDC, Dr. Eaton said a vial of Kenalog from his original lot was tested for endotoxins because the presentation of this endophthalmitis was similar to the presentation in recently reported cases of toxic anterior segment syndrome. The test came back negative for 2 endotoxin units per milliliter.

The FDA requires no more than 0.5 endotoxin units per milliliter for the production of Kenalog, he said, but the particulate matter of triamcinolone acetate made it difficult to test to that level.

The FDA provided this written statement to OSN: “The use of Kenalog intravitreally is not a labeled use of triamcinolone, and the FDA does not advocate its use in this manner. The FDA does encourage Bristol-Myers Squibb and any other interested manufacturer to reformulate triamcinolone without a preservative and to study it for those indications which ophthalmologists think may be of benefit to patients.”

Bristol-Myers Squibb provided the following statement to OSN: “Bristol Myers Squibb is aware of reported cases of sterile endophthalmitis being seen with the use of Kenalog associated with intravitreal injections. It is important to note intravitreal use of Kenalog is an unlabeled route of administration. We are currently taking active steps to address the concerns of physicians.”

Dr. Eaton said the company told him there has not been any change in its manufacturing of Kenalog. They requested more information on his cases, he said, which he plans to provide.

Short-term solution

Until more information about the situation is available, Dr. Eaton advised retinal specialists to consider using preservative-free triamcinolone.

“The good news is that we do have, it appears, a short-term solution in using nonpreserved Kenalog,” Dr. Eaton said in his presentation.

Dr. Eaton advised other ophthalmologists to order unpreserved triamcinolone acetate from a compounding pharmacy with which they are comfortable.

“My recommendation would be to switch before they have a problem,” he said. “The problem may come to an end at any point because we don’t know what changed, and since we don’t know what changed, nothing is saying it can’t change back.”

The preservative of benzyl alcohol is the suspected source of the problem, he said. The FDA acknowledged the same in an e-mail to OSN.

“The exact cause of the sterile endophthalmitis is not known, but assumed to be due to the benzyl alcohol,” an FDA representative said. “Benzyl alcohol is well known to be injurious to the eye.”

Dr. Rosenfeld, however, cited recent studies in which researchers have shown triamcinolone to be more toxic to retinal tissue than the vehicle.

For more information:

• Alexander M. Eaton, MD, can be reached at 1567 Hayley Lane, Fort Myers, FL 33907; 239-337-3337; e-mail: ame@retinahealthcenter.com.
• Philip J. Rosenfeld, MD, PhD, can be reached at Bascom Palmer Eye Institute, University of Miami School of Medicine, 900 NW 17th St., Miami, FL 33163; 305-326-6148; fax: 305-326-6417. e-mail: prosenfeld@med.miami.edu.

• Bristol-Myers Squibb, maker of Kenalog, can be reached at 345 Park Ave., New York, NY 10154-0037; 212-546-4000; Web site: www.bms.com.

• Katrina Altersitz is an OSN Staff Writer who covers all aspects of ophthalmology.