The advantage of generic drugs is that they can reduce prescription costs to patients (and Medicare carriers) by perhaps 25% or more compared with brand-name drugs. Thats usually fine as long as the generic drug is as safe and effective as its brand-name progenitor.
Yet recent problems with generic ophthalmic products have demonstrated that some of these products may not be truly equivalent to the branded product. Generic drugs may have differences in inactive ingredients and, in some cases, in safety and efficacy. Here, Ill explain how ophthalmic generic drugs, in particular, may differ from branded products, and provide a few historic examples.
Why Generics Can Differ
In 1984 the Drug Price Competition and Patent Term Restoration Act restored the use of the abbreviated new drug approval application (ANDA). This law sped up the time that would normally be required to bring a generic drug to market and helped to reduce the costs of developing generic drugs.
Look closely. A generic may have different inactive ingredients than the original brand-name medication.
This law also allowed that generic medications may have certain differences from the branded product.1 These differences included variations in route of administration, dosage form or strength, some minor labeling changes, and changes in active ingredients for a combination product containing at least two active ingredients.1
The law also said that the bioequivalence of the generic drug must be demonstrated compared to the parent or branded compound. Bioavailabilitythe rate and extent to which a drug is absorbed or is otherwise available to the treatment site in the bodymust be similar when administered at the same dosage and under analogous conditions. Most bioavailability studies of systemic generic products measure only the concentrations of the drug in blood or body fluids rather than the amount of drug available at the site of action.
For a systemic medication, the bioavailability can be assessed by drawing a blood level and determining if a therapeutic concentration of medication is absorbed into the systemic circulation within a timely manner. For an ophthalmic medication, however, the amount of the drug that is bioavailable to the eye is difficult to assess.
Ophthalmic Bioavailability When Inactive Ingredients May Not Be
To gauge bioavailability, researchers often test ophthalmic medications on animals. But results may be limited in relation to human absorption. Animal testing cannot easily determine how pH changes or viscosity differences of an ophthalmic product may affect a human eye. Likewise, animal results cannot be used to assess comfort, blurry vision, stinging, etc. An animal model also makes it difficult to assess drug pharmacokinetics and bioequivalence under various ocular pathologic conditions, such as dry eye, and corneal inflammatory and infectious disease, which may be critical to the effectiveness of the product.
Branded ophthalmic products must undergo human phase III trials. The branded medication is studied in patients with a specific disease state and in the proper dosing for that disease.
The FDA does not hold generic drugs to the same requirements, however. Ophthalmic generic products often lack true bioequivalence testing. And, there can be differences between the branded and generic products in various inactive ingredients, which may have some effect on the efficacy and safety of the generic product. Nevertheless, the Medical Letter on Drugs and Therapeutics concluded that FDA-approved systemic generic drugs are bioequivalent to brand-name products and that inequivalence has not been reported.2
Manufacturers of generic ophthalmic products must list the inactive ingredients (excipients) as exceptions or nonexceptions compared with its brand-name counterpart. Exception excipients can differ from the branded product (i.e., reference-listed drug, or RLD), while non-exception excipients may not. In ophthalmic products, preservatives, pH adjusters, antioxidants, thickening agents, buffers and agents to adjust tonicity are all considered exception excipients. Labeling on the box must identify them, and they must be qualitatively and quantitatively similar to the brand.
Generally with ophthalmic products, if the excipient has demonstrated prior safe use in any ophthalmic product, then the FDA often considers it an acceptable modification of an existing brand product excipient. However, various combinations of these acceptable substitutable excipients may present unforeseen problems under various ocular pathologic conditions and when combined with active ingredients (e.g., generic diclofenac).
Other considerations prior to generic substitution should include particle size and suspension properties. These are critical for proper dispersion of the active ingredient on the ocular surface. Formulation of generic agents, in terms of inactive ingredients and preservatives in different vehicles, deserves further human testing before general release. Various gel-based vehicles and other extended-release formulations have different properties and bioavailability characteristics. The FDA would be prudent to require the manufacturer to perform further testing for true generic equivalency.R.G.F.
Some systemic medications have a very narrow therapeutic index. In other words, the amount of medication in the dosage form must vary little from the stated strength to produce a certain pharmacologic effect. Too much variance either way may produce an underdose or overdose. This has led manufacturers of some systemic generic drugs to increase their quality control to produce products that are acceptable as generic substitutes, even for medications with narrow therapeutic indexes.
Generic Lapses Use Precaution with Generics
This is not always the case with ophthalmic products. Some examples of generic products that have not lived up to their branded counterparts include:
Prednisolone acetate. The branded product of prednisolone acetate 1% (Pred Forte, Allergan) has been an industry standard for anti-inflammatory potency. Eye doctors consider it one of the most potent topical corticosteroids.
The generic version has not fared as well. Problems with generic suspensions of prednisolone acetate have been reported in both the United States and Canada.3 The generic formulation has exhibited caking of the drug and inadequate suspension of the product constituents.3 Inadequately formulated products may have poorly suspended constituents and may compromise the treatment of inflamed eyes. Complaints of precipitated product clogging of the dropper tip have been filed, and two lots of generic prednisolone acetate were recalled due to precipitation of the active ingredient.3-4
Diclofenac sodium. Another example of inequivalence involved a 1% diclofenac sodium ophthalmic solution, which became available in the United States in August 1998. Although corneal complications have rarely been reported with use of the branded product (Voltaren, Novartis Ophthalmics), the release of a generic diclofenac was instrumental in bringing to light the real potential concerns for generic product substitution. Patients who received generic diclofenac for prevention and treatment of inflammation after cataract extraction faced serious, sight-threatening side effects. Members of the American Society of Cataract and Refractive Surgery (ASCRS) reported at least 200 cases of corneal toxicity ranging from superficial punctate keratopathy to full corneal melt associated with, in most cases, generic diclofenac.5-6 The generic diclofenac sodium was voluntarily recalled in September 1999.
A recent paper reviewed the safety of topical nonsteroidal anti-inflammatory drugs.7 The serious corneal complications were predominantly associated with the generic diclofenac and ranged from indolent corneal ulceration to full-thickness corneal melts. Possible explanations included corneal epithelial hypoxia, corneal matrix metalloproteinase interactions and direct toxicity due to cytotoxic excipients such as solubilizers, surfactants and preservatives found in the NSAID products.
Although topical NSAIDs are generally safe, use them cautiously with agents that are known to produce corneal epithelial toxicity (e.g., gentamicin), which may allow for increased corneal penetration. The concomitant use of NSAIDs and topical corticosteroids with pre-existing corneal inflammation is a risk factor for corneal erosions and melts. Exercise caution in the prolonged use of this combination.
Timolol gel. A timolol gel-forming solution was released as the generic equivalent of Timoptic-XE (Merck), but whether it is a therapeutic equivalent remains in question. The generic product received an AB rating from the FDA in the absence of head-to-head study data against the branded gel product, even though these products are suspended in different extended-release gel vehicles.
There are a few things you can do to evaluate and validate a generic product.
Consider the manufacturer. Many branded companies also have their own generic companies. These companies often run many of the generic products off the same line as the brand products (such as Allergan and Pacific Pharma). If the branded product is acceptable, the generic product will probably be a reasonable substitution. There are also a few companies that have excellent track records with their generic products and have been in business for many years. They produce reliable and often pharmaceutically acceptable generic products.
Contact managed-care plans. In critical instances in which you deem substitution of a generic product unacceptable, you may contact the patients managed-care plan and apply for a prior approval. You may have to document why the specific requested product has important therapeutic advantages over the generic alternative. You may also check the may not substitute box, or write out may not substitute and write the brand name on the prescription. However, some state laws vary on the specific wording concerning generic substitution.
Report problems with generic products. Although clinicians agree that some generic ophthalmic products sting more or cause more ocular irritation, these are not often reported to the FDA or submitted as case reports. More obvious side effects such as suspension caking or severe corneal complications with generic products are often reported and are considered clinically significant. Anecdotal reports have limited impact on the prescribing clinician, and unless there is a visually significant side effect, generic inequivalence is difficult to demonstrate. To report problems, go to the FDA Web site (www.FDA.gov), scroll down to the FDA Activities section and click on MedWatch Safety Information/Adverse Event Reporting.R.G.F.
The FDA divides medications with therapeutic equivalents into three categories: A, B or AB. Medications with A ratings are considered equivalent and can be substituted when filling prescriptions as the generic equivalent. B-rated drugs have not demonstrated evidence of bioequivalence and should not be substituted for the branded product. AB-rated products have undergone some in vitro or in vivo testing, and may have actual or probable bioequivalence. Retention time on the ocular surface may differ among the AB products, as may inactive ingredients and preservative concentrations.8
Many clinicians were concerned that although the generic timolol gel received an AB rating, its performance is unknown because it is in a different vehicle and there are no study data available to compare it directly against the branded drug.
Even if generic ophthalmic drugs produce minor ocular complaints, it may be easy to overlook the true effect of these products on patient compliance, efficacy and potential side effects. Given the potential for serious ocular side effects, however, I suggest that you prescribe newly released generic ophthalmic products cautiously until safety and efficacy can truly be demonstrated.
Mr. Fiscella is the assistant director of clinical servicesambulatory care, a clinical associate professor for the department of pharmacy practice, and a clinical research associate in the department of ophthalmology at the University of Illinois at Chicago. He is a speaker and researcher for Allergan, Merck and Pharmacia.
1. Cantor LB. Ophthalmic generic drug approval process: implications for efficacy and safety. J Glaucoma 1997 Oct;6(5):344-9.
2. Generic drugs. Med Lett Drugs Ther 1999 May 21; 41(1053):47-8.
3. Fiscella RG, Jensen M, Van Dyck G. Generic prednisolone suspension substitution. Arch Ophthalmol 1998 May;116(5):703.
4. Recent FDA recalls. ASHP News 1999;32(9):5.
5. Flach A. Topically applied nonsteroidal anti-inflammatory drugs and corneal problems: an interim review and comment. Ophthalmology 2000 July; 107(7):1224-6.
6. Lin JC, Rapuano CJ, Laibson PR, et al. Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol 2000 Aug; 118(8):1129-32.
7. Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use. A safety review. Drug Saf 2002;25(4):233-50.
8. Meseguer G, Buri P, Plazonnet B, et al. Gamma scintigraphic comparison of eyedrops containing pilocarpine in healthy volunteers. J Ocul Pharm Ther 1996 Winter;12(4):481-8.
