FDA Seeks Halt to Marketing of Ophthalmic Salts and Papain Drugs

Posted Sep 23, 2008.By Alicia Ault

The Food and Drug Administration said on Sept. 23 that it intends to take enforcement action against the manufacturers of certain ophthalmic balanced salt solutions and topical drugs containing papain if they do not seek and receive formal agency approval to market the products.

The announcement is part of the agency's ongoing initiative to remove unapproved prescription drugs from the market, which began in June 2006. The FDA estimates that 2% of prescriptions are filled with unapproved products. In the last 2 years, FDA has removed about 400 unapproved products from the market, said Michael Levy, director of the Division of New Drugs and Labeling Compliance at FDA's Center for Drug Evaluation and Research, in a briefing with reporters.

The agency is going after these two types of products because of they have been associated with a large number of adverse events, said Deborah M. Autor, director of the Office of Compliance at CDER in the briefing.

In the case of balanced salt solutions (BSS), there are two approved alternatives currently on the market that are manufactured by Alcon inc., and Akorn Inc. Three companies are making unapproved versions: B. Braun, Baxter, and Hospira Inc., Ms. Autor said.

Topical papain, which is used to debride wounds, has not been shown to be effective in any rigorous scientific study, she said.

The companies that make unapproved versions of papain and BSS "have bypassed the requirements of the law and put consumers at risk," said Ms. Autor. Without formal approval, there is no way to gauge the potency, safety, or effectiveness of these products, she said.

Manufacturers of unapproved BSS and unapproved papain must stop making them by Nov. 24, and must stop distribution of the products by Jan. 21, 2009.

BSS is used to irrigate the eye during surgery. In 2007, 3.2 million units of BSS were sold, 1% of which were unapproved, said Ms. Autor. Since FDA first began tracking adverse events for all drugs in 1969, there have been more than 300 reports associated with BSS, said Dr. Charles Lee, a medical officer in FDA's Division of New Drugs. Reports included infections and corneal clouding. One product was contaminated with endotoxins and produced a large number of adverse events, said Dr. Lee. There are 16 cases of blindness in the database, he said.

One rationale for not allowing unapproved versions of products is that FDA oversight of the manufacturing of approved ophthalmic BSS products helps to ensure that they are properly made, which reduces the risk of contamination and associated injuries, according to an announcement on the FDA Web site.

However, there is no way to determine how many adverse events were associated with approved and unapproved versions, said Dr. Lee.

Papain is used to debride diabetic ulcers, pressure ulcers, varicose ulcers and traumatic infected wounds. According to the FDA, there are at least a dozen manufacturers and trade names that include Accuzyme, Allanfil, Allanzyme, Ethezyme, Gladase, Kovia, Panafil, Pap Urea and Ziox. Approximately $50 million worth of papain - about 1.3 million units - is sold annually, said Ms. Autor.

There have been 37 adverse events reported with papain, including hypersensitivity reactions, said Dr. Lee. Although that might seem like a small number, there were four cases of anaphylaxis, he said. And, he pointed out, adverse events are notoriously underreported to the FDA.

Papain is derived from papaya. Patients who are allergic to the fruit or to latex are at heightened risk for reactions to products that contain papain-, the FDA said in a statement.

The agency published its intentions on papain products and BSS in the Sept. 23 Federal Register.