The use of topical and oral medications in the treatment of ocular disease is a hard-won privilege optometrists have enjoyed for over a quarter century. With this privilege comes the responsibility of insuring our patients receive the proper medications for their condition. As the costs of prescription medications spiral upward, our patients often request generic alternatives to brand name medications. And, as eye care practitioners, we must be prepared to discuss the pros and cons of ophthalmic generics with all our patients.
There can be no doubt about the acceptance and use of generic medications in the United States. In fact, the U.S. has one of the highest levels of generic drug use relative to total prescription volume among developed nations.1 The U.S. Food and Drug Administration (FDA) estimates that seven out of 10 prescriptions written in the country is for a generic medication.2 More than three-fourths of the drugs listed in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book) include generics. Under both Medicare and state Medicaid drug plans, generics are substituted for their brand name counterparts approximately 80% of the time if a generic version is available.3
To best serve our patients, we must know the answers to the following questions: Are generic agents as effective as their brand name counterparts? Are there any potentially negative outcomes associated with generic medications? And, are our patients really saving by using generic medications?
Safety and Efficacy Profile
While generic medications may offer patients some cost savings, many questions have been raised regarding the efficacy and safety of these agents. Here’s how a generic medication makes its way onto the market: When the patent on a drug expires, typically after 20 years, the FDA authorizes the production of that medication’s generic counterpart if bioequivalence can be demonstrated—that is, if the generic version releases its active ingredient (e.g., the drug) into the bloodstream at essentially the same speed and in the same amount as the original drug.4 In general, the FDA approval process for generic medications is less rigorous than for that of a new drug. Manufacturers of generic medications are not required to include data establishing the safety and effectiveness of the active drug component because the assumption is that it was previously determined with the branded medication.
How a generic is packaged can also affect the patient’s use of the medication. Trademark laws prevent generic medications from looking identical to their brand name product counterparts.5 This may be confusing for the elderly and for visually impaired patients. The eye drop size delivered from the bottle and the amount of product in the bottle itself may also vary in generic products, which may cause patients to deplete their medication before the refill date.6,7
Systemic vs. Ocular Generics
It is important to recognize the difference between systemic and ophthalmic drugs. Manufacturers can perform bioequivalence studies comparing the absorption, efficacy and elimination of a systemic generic drug much more easily against its branded version. For systemic medications, this proof is typically obtained by measuring blood plasma levels of the drug following administration. The concentrations of the drug must be within 85% to 125% of that measured for the branded drug during clinical trials.8 Ophthalmic drugs, however, cannot be compared in this manner. The only federal regulation for generic ophthalmic medications requires the generic must contain the same concentration of active ingredient as the brand name product, as well as the dosage, form and route of administration.
Unlike systemic generic products, ophthalmic generics are not required to demonstrate therapeutic equivalence to the branded medication.6 There is little reassurance of these generic products’ safety and efficacy until the doctor has gained clinical experience with the generic medication. Absent bioequivalence studies, the clinician is left to assume the generic works equally as well as the branded medication. This lack of therapeutic bioequivalence testing is a primary concern regarding ophthalmic generic products.9 Without published head-to-head clinical trials comparing topical ophthalmic generic drugs to their brand name counterparts, it is impossible to determine whether ophthalmic generics are truly equivalent.
While the active ingredient and concentration must be equal in generic and brand name drugs, excipient or inactive ingredients such as preservatives, pH adjusters, antioxidants, thickening agents, buffers and other inactive ingredients are allowed to vary under FDA guidance. But in ocular medications, changes in inactive compounds may alter the drug’s effectiveness and comfort. They can affect the drug’s bioavailability by interfering with its solubility and ocular penetration.
Differences in preservatives, pH and tonicity may impact drop comfort, which may lead to patient noncompliance. Changes in the product’s composition may ultimately affect the drug’s effectiveness, potentially leading to adverse events. Several such events have been noted in the past: A generic formulation of the ophthalmic steroid prednisolone acetate 1% was reported to not suspend properly and required vigorous shaking of the bottle to suspend the contents.10,11 Several lots were recalled due to the precipitation of the steroid. A more serious problem occurred with the generic topical non-steroidal anti-inflammatory drug diclofenac sodium. There were rare case reports of complications with the brand name product, which was developed using different preservatives and excipient ingredients within a year of the release of the generic formulation. There was an increased incidence of severe adverse events, including corneal melting—some so severe, the patients required corneal transplants.12-14 A generic formulation of latanoprost manufactured in India, formulated at a higher pH than its branded product, was found to be less effective at lowering intraocular pressure than the branded version.15 A generic version of latanoprost may become available in the U.S. this year.
Generic glaucoma medications are a particular concern. Patients are using glaucoma medications for life, and this presents a huge cost issue. Some glaucoma specialists are concerned that if generic glaucoma medications do not have the same therapeutic effect as their branded versions, patients could lose vision. There could be significantly more ocular morbidity from a less expensive drug.16
At least four pharmaceutical manufacturers are currently producing generic versions of the fixed combination dorzolamide–timolol.17 A review of the available formulations of fixed combination dorzolamide–timolol, including the concentration of the two active ingredients, the preservative and its concentration and inactive ingredients, revealed that there are no significant differences in these parameters.18 But anecdotally, patients have reported differences in side effects among the various generic products; still, no controlled trials documenting these observations have been published. In another study conducted overseas, the concentration of generic ciprofloxacin was found to be under-potent in 20% of the bottles sold.19
Another difficulty in assessing the safety of a generic ophthalmic medication is that many of these reports are anecdotal in nature.20 While we all have our reasons to prefer one medication to another for a particular condition, it is difficult to scientifically determine whether generic medications are less effective than their brand name counterparts. In fact, a study published in the Journal of the American Medical Association reviewed 38 published clinical trials comparing brand name cardiovascular medications against generic substitutes and found no difference between brand name medicines and the generic versions.21
Cost is the driving force affecting patients’ and providers’ choice of a generic over a brand name drug, especially in today’s struggling economy. Yet generic medications are not always less expensive than their brand name versions.
When the manufacturer has a six-month period where it may exclusively produce a generic drug (sole-source generic drugs), the medication’s cost to the patient may be only 15% to 20% less than the branded form of the drug.20 Generics prices usually do not start to significantly fall until multiple manufacturers bring generics to the free market. At this point, the individual states set the maximum allowable cost for the generic medication, allowing the drug manufacturers to compete solely on price.22
In managed-care formularies, sole-source generics are often offered as second-tier options.20 For example, a typical generic copay is $5 to $15 vs. a $20 to $30 copay for tier-two drugs and $30 to $40 for tier-three drugs.16 An IMS National Prescription Audit shows that a typical formulary now charges $6 for generic medications, $29 for preferred branded drugs and $40 or more for non-preferred branded drugs.23 While many pharmacies now offer $4 prescriptions, the drugs available at that price often do not represent the ophthalmic stand of care. Generic gentamycin is a good example. While an eye care provider may use this medication in a case of bacterial conjunctivitis, gentamycin use as a prophylactic following intraocular surgery would not be appropriate because fourth-generation fluoroquinolones are the accepted standard of care for surgical prophylaxis. When multiple generic formulations are available and used interchangeably, the doctor cannot be confident the patient is on a stable therapeutic regimen.
Out of Your Hands?
Perhaps the largest concern is that the doctor and the patient may not know when a brand name medication is being substituted for a generic by the pharmacy. Today, every state has enacted generic drug substitution laws, expanding the scope of pharmacy practice to allow pharmacists to substitute a generically equivalent drug for the prescribed drug, subject to certain requirements and restrictions.24 Drug product selection laws concerning substituting generic medications vary significantly among the states, and substitution is usually not permitted in any state when notations such as “brand necessary,” “do not substitute,” “dispense as written” are written on the prescription.24 While not an FDA requirement, it is a generally held opinion that a pharmacy should dispense a generic in lieu of the branded medication if that is the only option allowed by the patient’s prescription drug plan and only after the substitution is discussed with the patient.20 But many patients simply cannot afford the higher copay for the brand name medication.
Until more peer-reviewed, published studies are available, our challenge as eye care providers is to be cognizant of the unknowns regarding ophthalmic generic medications. We must consider these unknowns when discussing ophthalmic generics with our patients, making patients aware that these medications may not be as therapeutically effective as the brand name drugs and may have different effects and side effects. For these reasons, the patient on a generic medication—or one who is changing between generic medications—should be re-evaluated often to ensure the medication is performing as expected and there are no untoward side effects.
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