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cover story The High Cost of Saving Money: Risks Associated With Generic Drugs Generic ophthalmic medications are appealing as cheaper alternatives to brand name drugs up front, but the risk of inconsistent formulations and different inactive ingredients can lead to more costly side effects in the long run. By Johnny L. Gayton, MD, and Riley N. Sanders, BS B y 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 38 Advanced ocular care March/april 2012 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 cover story (All photographs by Val Sanders, CRA, COT, Eyesight Associates, Warner Robins, GA) A B Figure 1. A peripheral corneal melt (A). It was confirmed that this patient had used generic diclofenac in place of the prescribed brand-name Voltaren. The same eye with a pericardial graft repair (B). 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 conjunc- tivitis.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, A B Figure 2. A corneal melt with a positive Seidel test result (A, B). This patient’s eye was repaired with suturing at the corneal-scleral junction. March/april 2012 Advanced ocular care 39 cover story these drops pose a threat to the clinical outcome for patients, and, ultimately, could accelerate resistance to the active ingredient. sion, 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 substiNSAID s tutions. Unfortunately, to prescribe At least 200 cases of corneal toxicbrand-name products we frequently ity ranging from superficial punctate have to communicate with the pharkeratopathy to full corneal melting were macy, the patient, and the insurance reported by members of the American company. If we do not get approval Society of Cararact and Refractive for the brand-name agent, the patient Surgery through a member survey in may be unhappy at having to pay out 1999.9 Responses were received from of pocket. We need to make sure our 1,033 physicians with 106 physicians patients understand that purchasing reporting adverse events. On August 11, brand-name drugs may save them 1999, the American Society of Cataract Figure 3. Corneal melt believed to both time and money in the long be caused by generic diclofenac, and Refractive Surgery/American run because the therapeutic effects Society of Ophthalmic Administrators which progressed to perforation and are more predictable. Patients who required a penetrating keratoplasty. develop corneal issues due to their use sent a letter to nonmembers suggesting generic diclofenac, and possibly of generic NSAIDs can end up spendbrand-name Voltaren (Alcon Laboratories, Inc.), as the ing large sums treating their condition and suffer significause. On August 20, 1999, the distribution of Falcon cant morbidity. In trying to provide the best care for our Pharmaceutical’s version of generic diclofenac was patients, the use of generic ophthalmics of variable qualhalted, and on September 24th, 1999, the generic was ity and consistency may prove to be a risky compromise voluntarily recalled by Alcon Laboratories, Inc., the parbetween lower costs and safety. n ent company of Falcon Pharmaceutical.9 Johnny L. Gayton, MD, is in private practice with EyeSight Associates in Warner Robins, Personal Experience Georgia. He is a member of the speakers’ In our clinic in 1999, it was not uncommon to hear bureau for Alcon Laboratories, Inc., and Ista patients complain of transient burning, stinging, and Pharmaceuticals, Inc. Dr. Gayton may be conjunctival hyperemia with branded diclofenac and reached at (478) 923-5872; [email protected]. ketorolac. Our NSAID of choice had been branded diclofRiley N. Sanders, BS, is a technician at EyeSight Associates enac (Voltaren), but we had seen no cases of persistent in Warner Robins, Georgia, and a first-year medical student epithelial defects or corneal melting. Once the generic at Ross University, Roseau, Commonwealth of Dominica, diclofenac was introduced to our area, we had eight eyes West Indies. He may be reached at develop corneal melts. Of these, two required pericardial [email protected] grafts (Figure 1), one required suturing (Figure 2), and one required a penetrating keratoplasty (Figure 3). The other US Food and Drug Administration. Generic Drugs: Questions and Answers. http://www.fda.gov/Drugs/Resources four healed without surgical intervention once the generic 1.ForYou/Consumers/QuestionsAnswers/ucm100100.htm 2. Roberts CW, Nelson PL. Comparative analysis of prednisolone acetate suspensions. J Ocul Pharmacol Ther. diclofenac was stopped. In my (JLG) conversation with 2007;23(2):182-187. Drs. Robert E. Fenzl and James P. Gills, we were able to 3. Cantor LB. Generic ophthalmic medications: as good as a Xerox? http://www.medscape.org/viewarticle/583866. 4. Fiscella RG, Jensen M, Van Dyck G. Generic prednisolone suspension substitution. Arch Ophthalmolisolate Falcon Pharmaceutical’s generic diclofenac as the causative agent. After the previously mentioned recall, the ogy.1998;116(5):703. 5. Wittpenn J. Lack of testing for generic ophthalmic drugs seen as problematic by some experts. May 25, 2011. Ocular Surgery News. http://www.osnsupersite.com/view.aspx?rid=83790. incidence rate of nonhealing epithelial defects decreased 6. Fiscella RG. Weighing the choice between generic and branded drugs. Insert to: Cataract & Refractive Surgery Today. to a nationally reported rate of 0.07%.10 2010;10(6):6-8. 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 suspen40 Advanced ocular care March/april 2012 7. Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension. Indian J Ophthalmol. 2007:55:127-131. 8. Weir R, Zaidi F, Charteris D, et al. Variability in the content of Indian generic ciprofloxacin eye drops. Br J Ophthalmol. 2005;89(9):1094-1096. 9. Flach A. Topically applied nonsteroidal anti-inflammatory drugs and corneal problems: an interim review and comment. Ophthalmology. 2000;107(7):1224-1226. 10. Rowsey JJ. Increased incidence of corneal melt postcataract extraction after the introduction of generic diclofenac sodium. Presented at: The ASCRS Symposium on Cataract, IOL and Refractive Surgery Congress. May 21, 2000. Boston, MA.