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
ugs,” 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
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
Pilocarpine HCl 4% gel Alcon Laboratories,
Dipivefrin hydrochloride 0.1% Bausch & Lomb
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.
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
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
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
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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13. Shedden A, Laurence J, Tipping R. Efficacy and tolerability of timolol maleate ophthalmicgel-forming solution versus timolol ophthalmic solution in adults with open-angle glaucoma or
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ocular hypertension: a six-month, double-masked, multicenter study. Clin Ther. 2001;23:440-
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