Oral MS medication may increase risk of macular edema in some patients

Patients should undergo ophthalmic examinations before initiating treatment and for 3 or 4 months thereafter, specialist says.

The first U.S. Food and Drug Administration-approved oral medication for multiple sclerosis poses a potential risk of macular edema, particularly in patients with a history of uveitis, according to a neuro-ophthalmologist.

MS patients who receive Gilenya (fingolimod, Novartis) should undergo baseline and follow-up examinations 3 to 4 months after initiation of treatment, Robert C. Sergott, MD, said at the Wills Eye Institute Alumni Conference in Philadelphia.

“The macular edema issue is one that we as ophthalmologists are very familiar with and most neurologists are not familiar with,” he said. “It’s our obligation then to help them take care of these patients because we have an intersection of MS with a medication that can cause visual loss.”

Fingolimod was originally approved for transplantation-related indications. The active ingredient is believed to thwart lymphocyte migration.

“It sequesters T-cells in lymph nodes,” Dr. Sergott said. “By modulating the sphingosine-1-phosphate receptor, fingolimod keeps the lymphocytes within lymph nodes so that they cannot enter the central nervous system.”

Fingolimod was approved in Canada in March and was recently approved in Europe, Dr. Sergott said.

Clinical trials

Data on ocular complications were culled from two phase 3 FDA clinical trials to assess the efficacy and safety of fingolimod. A 2-year trial compared fingolimod with placebo; a 1-year trial compared fingolimod with interferon beta-1a, Dr. Sergott said.

Investigators were required to report patients’ medical histories, visual acuity and findings from dilated ophthalmoscopy, optical coherence tomography or fluorescein angiography. Patients underwent ophthalmic examinations at 1, 3, 6, 12 and 18 months. OCT examination was not mandatory.

Although not currently required, spectral-domain OCT may prove to be an optimal method of following retinal changes in patients treated with fingolimod, he said.

“It’s changing not only the way we practice in retinal disease and glaucoma but also for neuro-ophthalmology and for monitoring toxicities,” Dr. Sergott said.

Fingolimod was administered in 0.25-mg and 1.25-mg doses. Two patients who received 1.25-mg doses of fingolimod died; one patient had herpes zoster encephalitis and one patient had herpes simplex encephalitis. No deaths or signal for increased risk of viral infections was found in the 0.5-mg trial.

Although not required, antibody titers to varicella zoster should be measured before therapy, Dr. Sergott said. If the antibody levels are low or absent, then the patients should be vaccinated for varicella zoster. After vaccination, antibody levels should be rechecked to ensure that the patient has immune protection.

Fingolimod reduced the MS relapse rate and increased the percentage of patients without an MS relapse in both studies. The differences were statistically significant (P < .001).

In the 2-year trial, macular edema occurred in 0.4% of patients treated with fingolimod 0.25 mg and 0.1% of patients who received the placebo. Of four patients diagnosed with macular edema, three were symptomatic.

Patients with a history of uveitis had a 20% rate of macular edema; patients without a history had a rate of about 0.5%, Dr. Sergott said.

Warnings, recommendations

The FDA requires the manufacturer to include warnings and precautions on labeling of fingolimod. Monitoring is required for cardiac patients. It has not been tested in patients with pre-existing arrhythmia.

Warnings also address infection. Clinical trial data showed a 20% to 50% dose-dependent reduction in peripheral lymphocyte counts. Restoration of peripheral lymphocyte counts may take up to 2 months after discontinuation of fingolimod, Dr. Sergott said.

Relapses of MS should be treated with corticosteroids only after possible viral infections have been excluded as a cause of the infections. In addition, bronchitis and, to a lesser degree, pneumonia were more common in patients treated with fingolimod during the clinical trial.

Patients should undergo ophthalmic examination 3 or 4 months after initiation of fingolimod therapy; patients with diabetes mellitus or a history of uveitis may need more frequent examinations, he said.

Visual acuity should be monitored at baseline and during routine exams, Dr. Sergott said.

Physicians should use their judgment in deciding whether or not to continue fingolimod treatment in patients with macular edema, Dr. Sergott said.

“Continuation in patients with macular edema has not been evaluated,” he said. “The decision whether or not to discontinue should be assessed from a benefit-risk profile.”

Patients with diabetes mellitus and a history of uveitis are likely to be at elevated risk for macular edema, Dr. Sergott said.

“They will have to be examined on a case-by-case basis,” he said. “This is new information. It will be part of your practice as comprehensive ophthalmologists in knowing the guidelines for the treatment and follow-up of these patients taking fingolimod for relapsing-remitting MS.” – by Matt Hasson

• Robert C. Sergott, MD, can be reached at Wills Eye Institute, 840 Walnut St., 9th Floor, Philadelphia, PA 19107; 215-928-3130; fax: 215-592-1923; email: rcs220@comcast.net.
• Disclosure: Dr. Sergott reported financial relationships with Novartis and Biogen Idec.