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BY MARK J. GALLARDO, MD; RICHARD G. FISCELLA, RPH, MPH; AND JESS T. WHITSON, MD, FACS
Primary open-angle glaucoma is a multifactorial optic neuropathy with characteristic changes to the optic disc and visual field loss. Althoughmechanisms other than elevated IOP may con- tribute to the underlying pathophysiology of glaucoma, reducing IOP remains the cornerstone of therapy. Re-cent clinical studies have shown that decreasing IOP can delay, or in some cases prevent, glaucomatous After the diagnosis of glaucoma, the clinician must tailor an appropriate therapeutic regimen to the indi- Act benefited the generic industry by allowing generic vidual patient’s needs. Intervention typically begins with drugs to forego expensive and time-consuming clinical topical medical therapy supplemented, if necessary, by trials. The FDA has attempted to increase these agents’ laser or incisional surgery to achieve an adequate reduc- availability further by implementing initiatives to tion in IOP. Currently, there are five classes of medica- streamline the application process for generics. In June tions used to lower IOP: beta-adrenergic antagonists; 2003, the FDA launched the initiative, “Improving Ac- alpha-2 adrenergic agonists; carbonic anh Bugs,” to expedite the time necessary
itors (CAIs); prostaglandin analogs; and cholinergic ago- nists. Each class comprises a number of different prod- When the patent for a brand-name drug expires, ucts offered by various pharmaceutical companies. competing pharmaceutical companies may issue an Patients’ adherence to therapy is an important con- Abbreviated New Drug Application to the FDA for ap- cern, and increasing drug costs can be a factor.3 In all proval of their generic agent. The innovating company fields of medicine, generic medications have become of the brand-name drug typically holds the patent for more widely used because they cost patients less,4 and 20 years following its issuance. When a generic drug is recent years have brought the development of several submitted for approval, the applicant must provide evi- generic ocular hypotensive agents for the treatment of dence of the bioequivalence of the product. For sys- glaucoma (Table 1). Although generics are only available temic medications, this proof is typically obtained by in certain classes (beta-adrenergic antagonists, alpha-2 measuring plasma levels of the drug following adminis- adrenergic agonists, cholinergic agonists, and systemic tration. The concentrations of the drug must be within CAIs), additional agents should become available in the a certain range (85% to 125%) of that measured for the future as the patents of branded drugs expire. The branded drug during clinical trials. In addition to bio- question for clinicians, then, is how equivalent are equivalence, generics must have the same active in- generics to their brand-name counterparts.
gredients, dosage, route of administration, labeledstrength, and labeling as the brand-name drug. The F DA A P P R OVA L P R O C E S S
company applying to the FDA must also provide evi- Prior to the FDA’s legislative hallmark, the Drug Price dence of its compliance with the federal regulation of Competition and Patent Term Restoration Act of 1984 good manufacturing practices and demonstrate that (Hatch-Waxman Act), generic medications composed a finished materials meet the specifications of the US small portion of the drug industry. The Hatch-Waxman 32 I GLAUCOMA TODAY I JANUARY/FEBRUARY 2006
Once approved, generic medications receive a rating generic medications have the same level of bioequiva- based on their equivalence to the branded drug as de- lence, because they are required to contain the same termined by the FDA. There are four different rating active ingredient as the brand-name drug. Their inactive categories: (1) A-rated (considered equivalent and can ingredients may differ, however. Inactive ingredients be substituted by a pharmacist when filling a prescrip- include preservatives and adjusters of pH and tonicity.
tion); (2) B-rated (has not demonstrated evidence of They can affect the bioavailability of the drug by inter- bioequivalence and should not be substituted for a fering with its solubility and ocular penetration, and branded product); (3) AB-rated (has undergone some inactive ingredients may ultimately affect the drug’s in vitro and in vivo testing and may have probable or actual bioequivalence to the branded product); and Preservatives alone can influence a drug’s ability to (4) AT-rated (topical product that has probable bioe- penetrate the eye. Animal studies performed by both quivalence to the branded product). Ophthalmic Dong et al6 and Acheampong et al7 provided evidence preparations typically receive an AT rating. that brimonidine tartrate preserved with chlorine diox-ide (Purite; Allergan, Inc., Irvine, CA) had superior ocu- CO N C E R N S W I T H G E N E R I C O C U L A R
lar penetration and aqueous levels compared with bri- H Y P OT E N S I V E M E D I C AT I O N S
monidine tartrate preserved with benzalkonium chlo- A concern among clinicians is whether generic ocular ride. Moreover, the addition of sorbic acid has been hypotensive agents are as effective at reducing IOP as shown to improve the ocular bioavailability of timolol their brand-name predecessors. One presumes that TABLE 1. COMMONLY USED GLAUCOMA MEDICATIONS WITH GENERIC EQUIVALENTS
ACTIVE INGREDIENT COMPANY
Timolol maleate solu- Merck & Co., Inc.
Betaxolol HCl 0.25% and 0.5% Bausch & Lomb Cholinergic agonists
Pilocarpine HCl 4% gel Alcon Laboratories, Sympathomimetics
Dipivefrin hydrochloride 0.1% Bausch & Lomb Systemic CAIs
Data adapted from Physicians' Desk Reference for Ophthalmic Medicines. 34th ed. Montvale, NJ: Thomson PDR; 2006.
*There are several manufacturers of generic pilocarpine hydrochloride and acetazolamide. Due to limited space, only one company was listed in the table. JANUARY/FEBRUARY 2006 I GLAUCOMA TODAY I 33
Without published head-to-head clinical trials com- The patent on the original Alphagan solution has paring the safety, side-effect profile, and efficacy of topi- expired, and two generic equivalents are available in the cal generic ophthalmic drugs to brand-name agents, it US from Falcon Pharmaceuticals, Ltd., and Bausch and is difficult to ascertain whether generic ocular agents Lomb (Rochester, NY). To our knowledge, there are no are truly equivalent. There have already been reports of published peer-reviewed studies comparing the efficacy the differences of generic ophthalmic medications pre- and safety of these two generic agents to Alphagan. viously on the market. For instance, the generic topicalnonsteroidal anti-inflammatory 1% diclofenac sodium Beta-Adrenergic Antagonists
ophthalmic solution manufactured by Falcon Pharma- Timolol maleate is a nonselective topical beta-blocker ceuticals, Ltd. (Fort Worth, TX), was associated with a for treating ocular hypertension and glaucoma, and the high incidence of corneal toxicity, including several agent is typically administered b.i.d. when in solution.
cases of corneal melt that ultimately led to the agent’s Timoptic XE 0.5% ophthalmic solution (Merck & Co., voluntary recall from the market.9 Cases of differences Inc, West Point, PA) is a gel formulation of timolol for generic prednisolone acetate have also been report- maleate that was developed to enhance the drug’s delivery into the eye and to lower systemic absorptionby providing a longer ocular contact time. The efficacyand safety of Timoptic XE 0.5% administered q.d. is sim- ilar to timolol maleate 0.5% solution used b.i.d.13 Two additional formulations of timolol maleate are clinical trials comparing . topical generic available in the US. Timolol GFS 0.5% (Falcon Pharma- ceuticals, Ltd.) is a generic version of Timoptic XE 0.5%.
Clinical studies have shown this agent to be equally agents, it is difficult to ascertain whether effective at reducing IOP as its brand-name predeces- sor.14 A newly developed timolol maleate solution re-cently came to market that is preserved with potassiumsorbate (Istalol; ISTA Pharmaceuticals, Inc., Irvine, CA).
AVA I L A B L E G E N E R I C G L AU CO M A
The agent has been shown to be as effective and safe as M E D I C AT I O N S
There are few published reports comparing the safety and efficacy of generic agents with the brand-name Systemic Acetazolamide
drugs of the same class. Clinical trials, however, are Diamox (Duramed Pharmaceuticals Inc., Cincinnati, sometimes conducted when a medication is altered by OH) is an oral CAI that is very effective at reducing IOP.
changing the drug’s delivery vehicle or preservative in The systemic administration of a CAI is usually reserved the solution. These studies not only help provide evi- for patients with uncontrolled IOP who are on maximal dence of the agent’s equality, but they may also aid the tolerated topical medical therapy. A study comparing marketing efforts of the pharmaceutical companies.
oral Diamox to generic acetazolamide found the two Currently, the selective alpha-2 adrenergic agonists, drugs to be similar in safety and efficacy.16 In a cost cholinergic agonists, selective and nonselective beta- comparison, the generic acetazolamide was 37% less adrenoreceptor antagonists, and oral CAIs have generic equivalents available on the market (Table 1). Theprostaglandin analogs and topical CAIs are still under D I S C U S S I O N
Because they can reduce costs to patients,17 generic medications are becoming more widely used in the Alpha-2 Adrenergic Agonists
treatment of glaucoma. As the overall price of health- Allergan, Inc., developed the first selective alpha-2 care rises, these agents’ popularity should continue to adrenergic agonist, brimonidine tartrate 0.2%, preserved grow. The use of some, but not all, generic medications with benzalkonium chloride (Alphagan). This agent was is supported by published head-to-head clinical trials in introduced to the US market in 1996. It has since been the literature. Until more peer-reviewed, published reformulated by reducing the concentration of the active studies are available, however, clinicians must closely ingredient, brimonidine tartrate, to 0.15%, and by replac- monitor patients after they switch from a brand-name ing the preservative with Purite (Alphagan-P; Allergan, drug to a generic equivalent in order to ensure the safe- Inc.). The two drugs reduce IOP comparably.11,12 34 I GLAUCOMA TODAY I JANUARY/FEBRUARY 2006
Richard G. Fiscella, RPh, MPH, is Clinical Professor, Department of Pharmacy Practice,University of Illinois, Chicago. He acknowledgedno financial interest in the products or compa-nies mentioned herein. Mr. Fiscella may bereached at (312) 413-3687; [email protected] Mark J. Gallardo, MD, is Assistant Instructor for the Department of Ophthalmology, Universityof Texas, Southwestern Medical Center, Dallas.
He acknowledged no financial interest in theproducts or companies mentioned herein. Dr. Gallardo may be reached at (214) 648-4733; [email protected] Jess T. Whitson, MD, FACS, is Associate Professor, Department of Ophthalmology,University of Texas, Southwestern MedicalCenter, Dallas. He acknowledged no financialinterest in the products or companies mentionedherein. Dr. Whitson may be reached at (214) 648-4733;[email protected] 1. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relation-ship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol.
2. Kass MA, Heuer DK, Higginbotham EJ, et al, for the Ocular Hypertension Treatment StudyGroup. The Ocular Hypertension Treatment Study: a randomized trial determines that topicalocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma.
Arch Ophthalmol. 2002;120:701-713. 3. Heisler M, Wagner TH, Piette JD. Patient strategies to cope with high prescription medicationcosts: who is cutting back on necessities, increasing debt, or underusing medications? J BehavMed. 2005;28:43-51.
4. Haas HS, Phillips KA, Gersternberger EP. Potential savings from substituting generic drugsfor brand-name drugs: medical expenditure panel survey, 1997-2000. Ann Intern Med.
5. Food and Drug Administration. New FDA initiative on “Improving Access to generic Drugs.”Available at: http://www.fda.gov/oc/initiatives/generics/whitepaper.html. Accessed November 14,2005.
6. Dong JQ, Babusis DM, Welty DF, et al. Effects of the preservative Purite on the bioavailabilityof brimonidine in the aqueous humor of rabbits. J Ocul Pharmacol Ther. 2004;20:285-292.
7. Acheampong AA, Small D, Baumgarten V, et al. Formulation effects on ocular absorption ofbrimonidine in rabbit eyes. J Ocul Pharmacol Ther. 2002;18:325-337.
8. Higashiyama M, Inada k, Ohtori A, et al. Improvement of the ocular bioavailability of timololby sorbic acid. Int J Pharm. 2004;272:91-98.
9. Flach A. Topically applied nonsteroidal anti-inflammatory drugs and corneal problems: aninterim review and comment. Ophthalmology. 2000;107:1224-1226.
10. Fiscella RG. Generic prednisolone suspension substitution. Arch Ophthalmol.
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11. Mundorf T, Williams R, Whitcup S, et al. A 3-month comparison of efficacy and safety ofbrimonidine-purite 0.15% and brimonidine 0.2% in patients with glaucoma or ocular hyperten-sion. J Ocul Pharmacol Ther. 2003;19:37-44.
12. Katz LJ. Twelve-month evaluation of brimonidine-Purite versus brimonidine in patients withglaucoma or ocular hypertension. J Glaucoma. 2002;11:119-126.
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DETERMINACIÓN DE NIVELES RESIDUALES DE TETRACICLINA EN CANALES BOVINAS POR LA TÉCNICA DE ELISA EN EL FRIGORÍFICO FRIOGAN (LA DORADA) DETERMINATION OF RESIDUAL TETRACYCLINE LEVELS IN En las políticas sanitarias colombianas se BOVINE CARCASSES BY MEANS estableció la importancia del control de residuos OF ELISA IN THE FRIOGAN de medicamentos veterinarios, consid