Topical Ophthalmic Generics: They’re Back

Despite the problems with ophthalmic generics a decade ago, they are making their way back to the market.

Mitch Jackson, MD, Lake Villa, Ill.
6/11/2010

It has been a decade since generic diclofenac was voluntarily recalled from the market due to a significant increase in severe corneal events attributed to its use. At that time, it seemed unlikely that topical ophthalmic generics would return to the market. However, in 2009, the Food and Drug Administration approved generic ketorolac tromethamine ophthalmic solution 0.4% and 0.5%.


Unfortunately, the inherent problem with generic ophthalmic medications has not been resolved. While the active ingredients are required to be similar, the inactive ingredients may vary, and topical ophthalmic generics are not required by the FDA to be tested for bioequivalence or therapeutic equivalence. In other words, they do not have to demonstrate the same rate and extent of drug absorption, nor do they have to demonstrate the same pharmacologic effects.

 


Past Problems with Generics

Generic diclofenac was introduced in August 1998, and there was a significant increase in nonsteroidal anti-inflammatory drug-related severe corneal events after its introduction. Severity ranged from superficial punctate keratitis to full corneal melting. The generic was subsequently voluntarily recalled from the market in September 1999.

A 1991 study found that, while topical NSAIDs as a class may be associated with severe adverse events, AEs are more likely to occur at lower doses with generics.1


The study reviewed the records of 140 eyes in 129 patients. Cases of corneal or conjunctival pathology associated with NSAID use were classified as mild (n=51), moderate (n=55) and severe (n=34). More than half of the confirmed cases (53.8 percent) involved generic diclofenac. Cases associated with brand-name diclofenac (Voltaren) and ketorolac (Acular) were more likely to have received significantly higher doses of NSAIDs and were more likely to have ocular co-morbidity. Additionally, cases that did not occur during the perioperative period had significantly worse outcomes and significantly more ocular co-morbidities and received almost three times larger doses of NSAIDs.


In addition, in the late 1990s in Canada and the United States, some generic formulations of prednisolone acetate were reported to have "poorly suspended constituents," which can potentially seriously compromise the treatment of highly inflamed eyes.2

In 2000, five cases of corneal melting associated with the use of topical NSAIDs after ocular surgery were reported.3 In this small series, both generic and brand-name diclofenac were used. Two patients used brand-name Voltaren, and three patients used generic diclofenac. Because corneal melts can occur even with Voltaren, the author recommends that "the frequency of administration and duration of treatment should be minimized and as-needed use should be discouraged."

 


Cost

One of the reasons for the re-emergence of topical ophthalmic NSAID generics is the cost benefit. However, because only the active ingredients are similar, the cost benefits may not outweigh the risks. In reality, if generics cause significant visual problems, it is more expensive to treat the problems than it is to prescribe the brand-name drug. For example, a typical generic co-pay is $5 to $15, and a typical brand co-pay is $20 to $30 for tier 2 drugs and $30 to $40 for tier 3 drugs. The cost difference is not staggering, especially when patients are only on topical NSAIDs after cataract surgery for 30 days on average (a one-time prescription fill).


Generic glaucoma drugs are another concern. Patients with glaucoma are on medication for life, which can be costly. There are six different generic versions of dorzolamidetimolol. Glaucoma specialists are concerned because, if these drugs do not have the same pharmacologic effect as Cosopt, patients can potentially go blind. In other words, there can be a lot more morbidity as a result of a slightly less expensive drug.



The Pharmacy Connection

Because studies have raised doubts about the efficacy and side effect profile of generics, many ophthalmologists prescribe only brand-name drugs. Possibly the biggest concern of all is that ophthalmologists and their patients may not know that the pharmacist is substituting a generic. Each state has rules concerning generic substitutions, but substitution is not permitted in any state when "brand only," "dispense as written (DAW)," "no to generic substitute," or similar wording is indicated by the prescriber.

Some pharmacists receive incentives to convert prescriptions to generic, so it is important to write or check "brand only" on every prescription.

 

Future of NSAIDs

The newest NSAID in the marketplace is Acuvail 0.45%, which has several benefits over Acular. It does not contain BAK, edetate disodium and octoxynol-40. Therefore, it may have improved tolerability. Additionally, it contains a lower concentration of ketorolac, which may be safer. It has a pH of 6.8 and therefore has more un-ionized drug available for ocular absorption than Acular, which has a pH of 7.4. It contains CMC, which protects the ocular surface and helps improve comfort. The increased viscosity of CMC prolongs drug retention on the ocular surface. These formulation changes have enabled a twice-daily dosing regimen. A newer Xibrom once-a-day product will soon be available and is still pending FDA approval.


Topical NSAIDs reduce pain and inflammation after cataract surgery as labeled by the FDA and have been shown to reduce the incidence of cystoid macular edema postoperatively as shown in the ACME study.4However, be wary of generics, and make sure prescriptions indicate brand-name drugs only.

 

Dr. Jackson is medical director of Jackson Eye and a clinical assistant professor at the University of Chicago Hospitals. Contact him at mjlaserdoc@msn.com.

 

1. Congdon NG, Schein OD, von Kulajta P, Lubomski LH, Gilbert D, Katz J. Corneal complications associated with topical ophthalmic use of nonsteroidal anti-inflammatory drugs. J Cataract Refract Surg. 2001;27(4):622-631.

2. Fiscella RG, Gaynes BI, Jensen M. Equivalence of generic and brand-name ophthalmic products. Am J Health-Syst Pharm. 2001;58:616-617.

3. Lin JC. Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol.2000;118:1129-1132.

4. Wittpenn JR, Silverstein S, Heier J, Kenyon KR, Hunkeler JD, Earl M; Acular LS for Cystoid Macular Edema (ACME) Study Group. A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs steroid alone in low-risk cataract surgery patients. Am J Ophthalmol. 2008;146(4):554-560.