By the Food and Drug Administration’s definition, a “generic drug is identical—or bioequivalent—to a brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use.” As we see in ophthalmic clinical practice, this is not always the case, especially with respect to nonsteroidal anti-inflammatory drugs (NSAIDs). Although generic drugs are chemically identical to their branded counterparts, they are typically sold at a comparatively substantial discount.1 For the manufacturer to obtain market approval from the FDA, it must submit an abbreviated new drug application for a generic product. The approval process for a generic drug is less rigorous than that for a new one, as it is assumed that safety and efficacy have been determined by the trials for the branded agent. On June 23, 2001, the Supreme Court ruled in a 5-4 decision that the manufacturers of generic drugs cannot be sued for failing to warn consumers of the possible side effects of their products, as long as they use the same warnings that are used on the brandname drug equivalent. Generic drug companies are not required to update their warning labels when significant new risks emerge, therefore, they do not share the same level of responsibility as the makers of brand-name agents. This ruling further potentiates the possibility for inconsistency in therapeutic quality and the potential for adverse events.

Equivalency

For pharmacists, generic drugs are more appealing, because the profit margin and bonus structure are greater with these products. For our patients, the generic drug is more appealing due to its lower cost. The oath that we physicians take, however, requires that we warn patients of the increased risks or lessened effects that we are aware of for any ophthalmic agent, be it branded or generic. In fact, I (JLG) require surgical patients to sign an informed consent when they choose generic ophthalmic drugs. This consent serves not only to educate patients about the differences between branded and generic products, but it also puts the medicolegal responsibility for the choice on them.

When the FDA approves a systemic generic medication, bioequivalence is demonstrated by administering the drug and then obtaining blood plasma levels showing concentrations between 85% and 125% of those measured during the clinical trials of a branded drug.² This measuring method is not feasible for ophthalmic medications. The only federal regulations for ophthalmic drugs are that the same concentration of the active ingredient is present and that the dosage and the route of administration are the same. Showing therapeutic equivalence is not required.³ Ocular medications’ effectiveness and tolerance may be altered by the inactive components. Preservatives, pH, and other inactive ingredients all play a part in bioavailability.

Steroids

Branded prednisolone acetate contains minute particles in the suspension. In the late 1990s, reports emerged stating that the generic version did not suspend properly.⁴ The Wittpenn study of the 1990s showed that patients who received generic prednisolone had significantly higher rates of punctate keratopathy and complained of burning and stinging with generic prednisolone.⁵ More shaking was required to suspend the drops, and the medication caked and plugged the bottle’s tip.^2,4 This raised the question of what amount of the active drug was being delivered. When two branded agents were compared with a generic, the results showed that the smaller, more uniform particles present in the brand-name product remained in the suspension longer rather than settling to the bottom of the bottle.² This homogeneity, therefore, increases consistent ocular bioavailability.

Glaucoma Medications

Variance in pH levels affects the absorption and effectiveness of glaucoma medications. A comparison study from India of generic latanoprost versus brand-name Xalatan (Pfizer, Inc.) used among patients with primary open-angle glaucoma or ocular hypertension showed that the generic version was less effective at lowering intraocular pressure than its brand-name counterpart.6 Generic latanoprost ophthalmic solution manufactured in India had a higher pH than the brand-name drug. The obvious concern is that patients risk losing their eyesight if the therapeutic effect is compromised by the generic formulation. In our clinic, we have noted that the use of generic latanoprost results in intraocular pressures that are generally the same or higher than those associated with Xalatan. Any variability could be related to the fact that there are multiple manufacturers of the generic product, and the patient may get one made by a different company with each refill.

Antibiotics

Inconsistencies between brand-name and generic antibiotics with regard to the active agent’s concentration have also been reported.

John Wittpenn, MD, had generic gentamicin analyzed after using the drug in a series of patients with conjunctivitis. ⁵ All of the patients initially improved, but then worsened, showing symptoms consistent with conjunctival burns. He found the tonicity to be more than 700 mOsm/L, resulting in the osmotic depletion of fluid in patients’ conjunctival epithelial cells.⁵

A 2005 study showed that approximately 20% of generic ciprofloxacin drops purchased over the counter in India were not sufficiently potent.⁷ Because these concentrations are lower than the standard advised ranges, these drops pose a threat to the clinical outcome for patients, and, ultimately, could accelerate resistance to the active ingredient.

NSAIDs

At least 200 cases of corneal toxicity ranging from superficial punctate keratopathy to full corneal melting were reported by members of the American Society of Cararact and Refractive Surgery through a member survey in 1999.⁹ Responses were received from 1,033 physicians with 106 physicians reporting adverse events. On August 11, 1999, the American Society of Cataract and Refractive Surgery/American Society of Ophthalmic Administrators sent a letter to nonmembers suggesting generic diclofenac, and possibly brand-name Voltaren (Alcon Laboratories, Inc.), as the cause. On August 20, 1999, the distribution of Falcon Pharmaceutical’s version of generic diclofenac was halted, and on September 24th, 1999, the generic was voluntarily recalled by Alcon Laboratories, Inc., the parent company of Falcon Pharmaceutical.⁹

Personal Experience

In our clinic in 1999, it was not uncommon to hear patients complain of transient burning, stinging, and conjunctival hyperemia with branded diclofenac and ketorolac. Our NSAID of choice had been branded diclofenac (Voltaren), but we had seen no cases of persistent epithelial defects or corneal melting. Once the generic diclofenac was introduced to our area, we had eight eyes develop corneal melts. Of these, two required pericardial grafts (Figure 1), one required suturing (Figure 2), and one required a penetrating keratoplasty (Figure 3). The other four healed without surgical intervention once the generic diclofenac was stopped. In my (JLG) conversation with Drs. Robert E. Fenzl and James P. Gills, we were able to isolate Falcon Pharmaceutical’s generic diclofenac as the causative agent. After the previously mentioned recall, the incidence rate of nonhealing epithelial defects decreased to a nationally reported rate of 0.07%.¹⁰

Conclusions

With resistance to rising costs in health care, generics are here to stay. Although many systemic generics may be bioequivalent, the absorption and efficacy of generic formulations of ophthalmics is dependent on inactive ingredients, pH, the size of particles in suspension, and the concentration of active ingredients. With less FDA oversight of generic drug approvals, we may not know what drug the patient will receive when we allow generic substitutions. Unfortunately, to prescribe brand-name products we frequently have to communicate with the pharmacy, the patient, and the insurance company. If we do not get approval for the brand-name agent, the patient may be unhappy at having to pay out of pocket. We need to make sure our patients understand that purchasing brand-name drugs may save them both time and money in the long run because the therapeutic effects are more predictable. Patients who develop corneal issues due to their use of generic NSAIDs can end up spending large sums treating their condition and suffer significant morbidity. In trying to provide the best care for our patients, the use of generic ophthalmics of variable quality and consistency may prove to be a risky compromise between lower costs and safety.

Johnny L. Gayton, MD, is in private practice with EyeSight Associates in Warner Robins, Georgia. He is a member of the speakers’ bureau for Alcon Laboratories, Inc., and Ista Pharmaceuticals, Inc. Dr. Gayton may be reached at (478) 923-5872; jlgayton@aol.com.

Riley N. Sanders, BS, is a technician at EyeSight Associates in Warner Robins, Georgia, and a first-year medical student at Ross University, Roseau, Commonwealth of Dominica, West Indies. He may be reached at rileysanders@students.rossu.edu

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