Ophthalmology

PHILADELPHIA — Surgeons accustomed to using Wydase (hyaluronidase) to enhance the effect of anesthesia are now facing the fact that the drug will no longer be available through its manufacturer, Wyeth-Ayerst, based here.

In January, Wyeth-Ayerst announced it would not resume Wydase production. The drug has been in limited supply since Wyeth-Ayerst voluntarily closed its manufacturing facility to address quality assurance issues. The closure was temporary; the facility is open, but no Wydase is being made. Its current supply is in controlled inventory and is anticipated to last until April. Unless another drug manufacturer assumes production, Wydase will then be unavailable permanently.

Wyeth-Ayerst spokesperson Douglas Petkus said the company was shutting down production of the drug because Wyeth had re-evaluated its product portfolio and its priorities and would be moving on to other areas.

Mr. Petkus also said that Wyeth was working with physicians and the American Academy of Ophthalmology (AAO) to find other solutions for the Wydase shortage, but that Wyeth still had a supply until April. He said he knew of no emergency situations that had arisen.

According to Mr. Petkus, the patent protection on Wydase expired several years ago and any manufacturer who cared to would now have the legal right make the drug.

A timeline of events

In 1999, the Food and Drug Administration (FDA) inspected the plant producing Wydase and determined the 70-year old plant required major updating to bring it into regulatory compliance.

In February 2000, Wyeth-Ayerst voluntarily closed the plant and stopped manufacture of some products, including Wydase, while it addressed quality assurance problems. Wyeth-Ayerst placed Wydase in inventory control and has provided surgeons with supplies that reflect their previous demand patterns.

According to the AAO, Wyeth-Ayerst has tried to supply all existing customers, but it has not supplied any new customers in the past year.

In July 2000, the FDA and Wyeth-Ayerst entered into a consent decree to have evaluations performed by a third party and to have a schedule for addressing all improvements identified by the FDA.

In November 2000, Wyeth-Ayerst advised the AAO that its inventory of Wydase will be depleted in early 2001, and that it is expected to take from 6 to 24 months to resume production.

The AAO is attempting several solutions to the Wydase dilemma. These include finding another manufacturer to take over the production; identifying manufacturers overseas that might wish to begin production in the United States; and providing information to surgeons for alternatives to the use of Wydase in ophthalmic anesthesia, such as an increased use of topical anesthesia.

Hyaluronidase compounding

According to the AAO, with the decreased availability of Wydase some ophthalmologists are turning to local compounding pharmacies to obtain hyaluronidase as an alternative to Wydase.

The AAO has stated that unlike pharmaceutical manufacturers, compounding pharmacies do not come under the jurisdiction, scrutiny and regulation of the FDA when filling physician prescriptions for individual patients.

However, if a compounding pharmacy solicits prescriptions or fills orders for a drug without a physician’s prescription, the pharmacy is considered to be manufacturing the drug and would fall under the FDA purview and its manufacturing standards.

The AAO has stressed that it is important for surgeons to recognize that there are no uniform national standards for the production of drugs in compounding pharmacies. All pharmacies are regulated by their individual state pharmacy boards; some allow medications to be shipped from state to state.

The AAO has also said that there is no definitive way to ensure the quality of a drug until it is used; however, certain questions can be asked of the compounding pharmacy.

The AAO suggests, as a conservative measure, that hyaluronidase be used within 30 days after it is compounded.

While compounding pharmacies may use United States Pharmacopoeia (USP) grade base materials, the AAO says this is not a guarantee of the quality of the finished product. Compounding pharmacies may offer a “certificate of analysis,” but it may relate only to the USP composition of the basic chemical powder and have no relevance to the compounding done by the given pharmacy.

The AAO has received no reports of problems with hyaluronidase sold by compounding pharmacies.

Wydase solutions

When the AAO received notice in summer 2000 that Wydase would soon be in short supply, it formed a task force to evaluate the situation and procure possible solutions for surgeons accustomed to using Wydase. The task force offers many suggestions and insights in a round table published on the AAO Web site.

The task force panel consists of Robert J. Cionni, MD; David L. Guyton, MD; Michael J. Hawes, MD; H. Dunbar Hoskins Jr., MD; Samuel Masket, MD, chair of the task force; and Kenneth J. Rosenthal, MD.

In the round table, Dr. Hoskins noted that although Wydase is used most often in cataract surgery, it has applications in many other types of intraocular surgery as well; thus, many ophthalmic surgeons will be affected by tis withdrawal from the market. In 1999, Wydase was used in about 750,000 procedures, he said; used in local blocks, it allows the anesthesia to disseminate better and more rapidly.

“I’m now using Wydase in a significantly decreased concentration,” Dr. Cionni said. “In fact, I have reduced the concentration of Wydase to about a tenth of what I used before. I still obtain the desired akinesia but sometimes need to supplement with topical lidocaine or tetracaine to achieve a better anesthetic effect.”

Dr. Hawes said, “The absence of Wydase might also influence the type of block we give. For example, without Wydase I might be more inclined to use a regional block rather than a local injection in my oculoplastic surgery practice. Or I might be more likely to consider general anesthesia.”

Dr. Rosenthal said it is possible to give an anesthetic block without any Wydase, although this approach does pose certain problems. For example, surgeons might choose to use more volume of anesthetic in order to produce the same distribution effect, but they may get pockets of high concentration and intensity of the anesthetic.

There also is some debate over whether extraocular muscle palsies are linked to the injection of anesthetic without the use of Wydase. “It is my belief that the pooling of the drug could cause toxic levels of anesthetic to the extraocular muscles,” Dr. Rosenthal said.

Dr. Cionni said he uses topical Marcaine (bupivacaine HCl, Abbott) and/or lidocaine in about 85% to 90% of his cataract surgeries. He usually supplements that with about 0.2 cc of 1% nonpreserved lidocaine injected into the anterior chamber at the beginning of the procedure.

“However, in my experience, not every patient is a good candidate for topical anesthesia,” Dr. Cionni said. “Preoperatively, I examine patients with the indirect ophthalmoscope and hold their lids open gently. If they can look into the light, and tolerate it well without squeezing, then they’re good candidates for topical anesthesia. However, I believe that those patients who don’t tolerate this exam well should be blocked for their comfort — and for the surgeon to be able to safely perform the surgery.”

Dr. Masket said that there have been reports of postoperative double vision following local anesthetic blocks given without Wydase. While this is not common, he said, it is probably the chief complication that concerns the task force. Without Wydase, it takes much longer for the anesthetic to disseminate, and there also is a greater degree of orbital swelling.

To get around that complication, Dr. Guyton suggested that post-surgical strabismus may be avoided by giving the blocks via an alternative route. A sub-Tenon infusion rather than a retrobulbar or peribulbar injection provides blocks that can be just as good, he said.

“The anesthetic flows around the back of the globe, diffusing into the orbit slowly. There is essentially no chance of injecting the anesthetic into one of the extraocular muscles because this procedure uses a blunt cannula that cannot be pushed into the muscle,” Dr. Guyton said.

“With the sub-Tenon’s route, the surgeon can open the conjunctiva with a tiny incision, and after placing the blunt cannula directly into the retrobulbar space, he or she injects a small amount of anesthetic — accomplishing safe and adequate anesthesia absent Wydase,” Dr. Masket said.

For Your Information:

• Robert J. Cionni, MD, can be reached at 10494 Montgomery Rd., Cincinnati, OH 45242; (513) 984-5133; fax: (513) 984-4240; e-mail: rcjc97@aol.com.
• David L. Guyton, MD, can be reached at Wilmer 233, Johns Hopkins Hosp., 600 N. Wolfe St., Baltimore, MD 21287-9028; (410) 955-8314; fax: (410) 955-0809; e-mail: dguyton@jhmi.edu.
• Michael J. Hawes, MD, can be reached at #345, 850 East Harvard, Denver, CO 80210; (303) 698-2424; fax: (303) 698-2430; e-mail: mjhawes@aol.com.
• H. Dunbar Hoskins Jr., MD, can be reached at 655 Beach St., San Francisco, CA, 94109; (415) 561-8510; fax: (415) 561-8533; e-mail: dhoskins@aao.org.
• Samuel Masket, MD, can be reached at 7320 Woodlake Ave. Ste. 380, West Hills, CA 91307; (818) 348-6190; e-mail: avcmasket@aol.com.
• Douglas Petkus can be reached at Wyeth-Ayerst Laboratories, 555 Lancaster Avenue, St. Davids, PA 19087; (610) 902-7336; fax: (610) 964-5944.
• Kenneth J. Rosenthal, MD, can be reached at Waterview Bldg. Ste. 102, 310 E. Shore Rd., Great Neck, NY 11023; (516) 466-8989; fax: (516) 466-8962; e-mail: kenrosenthal@eyesurgery.com.

• Information on the American Academy of Ophthalmology Web site regarding Wydase can be found at www.eyenet.org/member/comm/wydase_a.html.