Evaluating Generic Medications

When patients ask if a generic substitution is available for a glaucoma medication, they are assuming that medications are like other consumer goods—that the generic is equivalent to the branded product in efficacy, side-effect profile, drop size and ease of squeezing a single drop, but that it costs less. Yet even when a generic drug is bioequivalent to its branded version, the generic can make adherence more difficult.

Cost

Patients and physicians often assume that generics save money and help patients adhere to their drug regimens. Even price differences of less than $10 can affect adherence.¹ One study found that a seemingly trivial increase in prescription copayment (from $2 to $7 per month) significantly reduced adherence with gaps of up to 120 days in use of lipid-lowering medications, even for patients at high risk of disease.² When cost is a factor, patients split pills, use a once-daily medication every other day, or alternate between drugs for one condition one week and another condition the following week.¹

Availability of generic drugs may or may not improve adherence. Pricing can be confusing for patients with or without prescription drug coverage. Prices can vary from pharmacy to pharmacy within the same geographic region and from plan to plan within Medicare part D. Some plans carry no price difference between generic and branded products.

Complexity

Availability of generic drugs can make complex regimens even more complex. Glaucoma patients tend to be older, have visual impairments, and take multiple over-the-counter and systemic medications with various dosing schedules. The more medications and the more complex the dosing schedule, the more difficult adherence becomes.^3-7 Adherence becomes easier with visual clues, such as color or shape of the container. Patients often have trouble pronouncing or remembering the names of their medications, referring to prescriptions not by names, but by the shape of the bottle or color of the cap, to help them recall dosing instructions.

Generics can have bottle shapes different from the original medication, for example, a flat bottle for Xalatan versus a round bottle for generic latanoprost. The FDA does have a color code for glaucoma drug tops—prostaglandin analogues are teal, beta-blockers yellow, alpha-agonists purple, muscarinics green, and combination therapies blue—but manufacturers of generics are not bound by the color-coding scheme. In fact, the American Association of Eye and Ear Centers of Excellence opposes this scheme, arguing that it creates confusion within drug classes.⁸ Various top colors for the same type of product can lead to communication problems between the physician and patient when the ophthalmologist assumes the patient is taking a medication with a blue top, but the generic has a white top. The confusion can lead patients to take a medication either more or less often than prescribed.

Brand-Name Preference

Given a choice, patients and physicians say they prefer and would pay more for brand-name products, citing the security of knowing the product is consistent.^9-10 Many editorials have advised against interchanging branded and generic drugs and switching between one generic and another, even when evidence does not support the superiority of the brand-name drug.¹¹ Some neurologists write on their prescription forms that generics are acceptable but that once a patient starts a particular brand, he or she cannot switch the manufacturer of the product (personal communication Ron Lesser, MD, Dept. of Neurology, Johns Hopkins School of Medicine, May 2011). Researchers have found that switching from a brand-name antiepileptic to generic and from one generic to another can lead to higher utilization of all medications and risk of injury.^12-15

Patients worry about the similarity of a generic to the brand-name medication since the names and appearances are different. They may not realize that branded Xalatan and generic latanoprost are the same agent when the names, bottle shapes and cap colors are different. They may fear different side effects.¹⁶

Bioequivalence

The Food and Drug Administration requires bioequivalence between brand-name and generic versions of oral and intravenous medications, where blood levels can be measured. Bioequivalence is defined as “the absence of a significant difference in the rate and extent to which the active ingredient in pharmaceutical equivalents or alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”¹⁷

Peak concentration (Cmax) and area under the curve (AUC) for generics must be between 80% and 125% of the reference brand. Cmax and AUC are usually obtained in healthy younger individuals. These pharmacokinetic measures do not account for age, comorbid conditions, or the use of other medications. In healthy individuals on no other medications, Cmax varied by 15% to 25% in 11% of studies, and Cmax can vary at least 15% in 39% of cases and at least 25% in 3.7% of cases.¹⁸ In both neurology and cardiology, this variation can lead to an increased frequency of seizure disorders or arrhythmias when switching either from a branded to a generic product or from one manufacturer to another manufacturer of a generic of the same product.^19,20

Bioequivalence is more difficult to determine with ophthalmic solutions, where no simple blood test exists to measure how effectively a glaucoma medication has been absorbed by the eye. In addition, both the active and inactive ingredients in solutions should be equivalent, but the FDA does not ask for bioequivalence studies for suspensions and ointments.

This situation makes determining whether or not a patient is adhering to a drug regimen more difficult. Before the introduction of generic medications, if a patient’s IOP seemed less well-controlled than before, one might wonder whether the patient was taking the drug or having problems administering it.^21-22 The introduction of generics creates a new issue, making the treatment process more complex.

References

Lagnado L. The uncovered. Wall Street Journal. November 17, 1998:1.
Doshi JA, et al. Impact of prescription copayment increase on lipid-lowering medication adherence in veterans. Circulation. 2009;119:290-397.
Massof RW. A model of the prevalence and incidence of low vision and blindness among adults in the U.S. Optom Vis Sci. 2002;79:31‐38.
Covert D, Robin AL, Novack G. Systemic medications and glaucoma patients. Ophthalmology. 2005;120:1849.
Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg. 1995;26:233-236.
Robin AL, Novack GD, Covert DW, Crockett RS, Marcic TS. Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use. Am J Ophthalmol. 2007;144:533-540.
Robin AL, Covert D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? Ophthalmology. 2005;112:863-868.
The American Association of Eye and Ear Centers of Excellence. E-Petition. http://www.nyee.edu/lasa-e-petition.html?&large_print=1. Accessed June 14, 2011.
Jampel HD, Schwartz GF, Robin AL, Abrams DA, Johnson E, Miller RB. Patient preferences for eye drop characteristics: a willingness to pay analysis. Arch Ophthalmol. 2003;121:540-546.
Jampel HD, Parekh P, Johnson E, Robin AL, Miller RB. Preferences for eye drop characteristics among glaucoma specialists: A willingness-to-pay analysis. J Glaucoma. 2005;14:151-156.
Kesselheim AS, Misono AS, Lee JL, Stedman MR, Brookhart MA, Choudhry NK. JAMA. 2008;300(21):2514-2526.
Labiner DM, Paradis PE, Manjunath R, Duh MS, Lafeuille MH, Latremouille-Viau D, et al. Generic antiepileptic drug sand associated medical resource utilization inthe United States. Neurology. 2010;74:1566–1574.
Duh MS, Paradis PE, Latremouille-Viau D, Greenberg PE, Lee SP, Durkin MB, et al. The risks and costs of multiple generic substitution of topiramate. Neurology. 2009;72:2122–2129
LeLorier J, Duh MS, Paradis PE, Lefebvre P, Weiner J, Manjunath R, et al. Clinical consequences of generic substitution of lamotrigine for patients with epilepsy. Neurology. 2008;70:2179–2186.
Bazil CW. Epilepsy: generic substitution: are antiepileptic drugs different? Nat Rev Neurol. 2009;5:587–588.
Hakonsen H, Eilertsen M, Borge H, Toverud EL. Generic Substitution: an additional challenge for adherence in hypertensive patients? Curr Med Res Opin. 2010;25:2515-2521.
Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products. 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm070124.pdf. Accessed June 23, 2011.
Hurley D. Neurol Today. 2010;10:1.
Berg MJ, Gross RA, Tomaszewski KJ, Zingaro WM, Haskins LS. Generic substitution in the treatment of epilepsy: Case evidence of breakthrough seizures. Neurology. 2008;71:525-530.
Gagne JJ, Avorn J, Shrank WH, Schneeweiss S. Refilling and switching of antiepileptic drugs and seizure-related events. Clin Pharmacol Ther. 2010;88:347-353.
Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An objective evaluation of eye-drop instillation in glaucoma patients. Arch Ophthalmol. 2009;127:732-736.
Hennessy AL, Katz J, Covert D, Protzko C, Robin AL. Videotaped evaluation of eye drop instillation in glaucoma patients with visual impairment or moderate to severe visual field loss. Ophthalmology. 2010;117:2345-2352.