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The High Cost of Saving Money:
Risks Associated
With Generic Drugs
Generic ophthalmic medications are appealing as cheaper alternatives to brand name
drugs up front, but the risk of inconsistent formulations and different inactive
ingredients can lead to more costly side effects in the long run.
By Johnny L. Gayton, MD, and Riley N. Sanders, BS
B
y the Food and Drug Administration’s definition, a
“generic drug is identical—or bioequivalent—to a
brand-name drug in dosage form, safety, strength,
route of administration, quality, performance characteristics, and intended use.” As we see in ophthalmic clinical
practice, this is not always the case, especially with respect to
nonsteroidal anti-inflammatory drugs (NSAIDs). Although
generic drugs are chemically identical to their branded counterparts, they are typically sold at a comparatively substantial
discount.1 For the manufacturer to obtain market approval
from the FDA, it must submit an abbreviated new drug
application for a generic product. The approval process for
a generic drug is less rigorous than that for a new one, as it
is assumed that safety and efficacy have been determined
by the trials for the branded agent. On June 23, 2001, the
Supreme Court ruled in a 5-4 decision that the manufacturers
of generic drugs cannot be sued for failing to warn consumers of the possible side effects of their products, as long as
they use the same warnings that are used on the brandname drug equivalent. Generic drug companies are not
required to update their warning labels when significant new
risks emerge, therefore, they do not share the same level of
responsibility as the makers of brand-name agents. This ruling
further potentiates the possibility for inconsistency in therapeutic quality and the potential for adverse events.
Equivalency
For pharmacists, generic drugs are more appealing,
because the profit margin and bonus structure are greater
with these products. For our patients, the generic drug is
38 Advanced ocular care March/april 2012
more appealing due to its lower cost. The oath that we
physicians take, however, requires that we warn patients of
the increased risks or lessened effects that we are aware of
for any ophthalmic agent, be it branded or generic. In fact, I
(JLG) require surgical patients to sign an informed consent
when they choose generic ophthalmic drugs. This consent
serves not only to educate patients about the differences
between branded and generic products, but it also puts the
medicolegal responsibility for the choice on them.
When the FDA approves a systemic generic medication,
bioequivalence is demonstrated by administering the drug
and then obtaining blood plasma levels showing concentrations between 85% and 125% of those measured during the
clinical trials of a branded drug.2 This measuring method
is not feasible for ophthalmic medications. The only federal regulations for ophthalmic drugs are that the same
concentration of the active ingredient is present and that
the dosage and the route of administration are the same.
Showing therapeutic equivalence is not required.3 Ocular
medications’ effectiveness and tolerance may be altered by
the inactive components. Preservatives, pH, and other inactive ingredients all play a part in bioavailability.
Steroids
Branded prednisolone acetate contains minute particles
in the suspension. In the late 1990s, reports emerged stating that the generic version did not suspend properly.4 The
Wittpenn study of the 1990s showed that patients who
received generic prednisolone had significantly higher rates
of punctate keratopathy and complained of burning and
cover story
(All photographs by Val Sanders, CRA, COT, Eyesight Associates, Warner Robins, GA)
A
B
Figure 1. A peripheral corneal melt (A). It was confirmed that this patient had used generic diclofenac in place of the prescribed brand-name Voltaren. The same eye with a pericardial graft repair (B).
stinging with generic prednisolone.5 More shaking was
required to suspend the drops, and the medication caked
and plugged the bottle’s tip.2,4 This raised the question of
what amount of the active drug was being delivered. When
two branded agents were compared with a generic, the
results showed that the smaller, more uniform particles
present in the brand-name product remained in the suspension longer rather than settling to the bottom of the
bottle.2 This homogeneity, therefore, increases consistent
ocular bioavailability.
Glaucoma Medications
Variance in pH levels affects the absorption and effectiveness of glaucoma medications. A comparison study from
India of generic latanoprost versus brand-name Xalatan
(Pfizer, Inc.) used among patients with primary open-angle
glaucoma or ocular hypertension showed that the generic
version was less effective at lowering intraocular pressure
than its brand-name counterpart.6 Generic latanoprost
ophthalmic solution manufactured in India had a higher
pH than the brand-name drug. The obvious concern is that
patients risk losing their eyesight if the therapeutic effect is
compromised by the generic formulation. In our clinic, we
have noted that the use of generic latanoprost results in
intraocular pressures that are generally the same or higher
than those associated with Xalatan. Any variability could be
related to the fact that there are multiple manufacturers of
the generic product, and the patient may get one made by
a different company with each refill.
Antibiotics
Inconsistencies between brand-name and generic antibiotics with regard to the active agent’s concentration have
also been reported.
John Wittpenn, MD, had generic gentamicin analyzed
after using the drug in a series of patients with conjunc-
tivitis.5 All of the patients initially improved, but then
worsened, showing symptoms consistent with conjunctival
burns. He found the tonicity to be more than 700 mOsm/L,
resulting in the osmotic depletion of fluid in patients’ conjunctival epithelial cells.5
A 2005 study showed that approximately 20% of
generic ciprofloxacin drops purchased over the counter
in India were not sufficiently potent.7 Because these concentrations are lower than the standard advised ranges,
A
B
Figure 2. A corneal melt with a positive Seidel test result
(A, B). This patient’s eye was repaired with suturing at the
corneal-scleral junction.
March/april 2012 Advanced ocular care 39
cover story
these drops pose a threat to the clinical
outcome for patients, and, ultimately,
could accelerate resistance to the active
ingredient.
sion, and the concentration of active
ingredients. With less FDA oversight
of generic drug approvals, we may
not know what drug the patient will
receive when we allow generic substiNSAID s
tutions. Unfortunately, to prescribe
At least 200 cases of corneal toxicbrand-name products we frequently
ity ranging from superficial punctate
have to communicate with the pharkeratopathy to full corneal melting were
macy, the patient, and the insurance
reported by members of the American
company. If we do not get approval
Society of Cararact and Refractive
for the brand-name agent, the patient
Surgery through a member survey in
may be unhappy at having to pay out
1999.9 Responses were received from
of pocket. We need to make sure our
1,033 physicians with 106 physicians
patients understand that purchasing
reporting adverse events. On August 11,
brand-name drugs may save them
1999, the American Society of Cataract Figure 3. Corneal melt believed to
both time and money in the long
be caused by generic diclofenac,
and Refractive Surgery/American
run because the therapeutic effects
Society of Ophthalmic Administrators which progressed to perforation and are more predictable. Patients who
required a penetrating keratoplasty. develop corneal issues due to their use
sent a letter to nonmembers suggesting generic diclofenac, and possibly
of generic NSAIDs can end up spendbrand-name Voltaren (Alcon Laboratories, Inc.), as the
ing large sums treating their condition and suffer significause. On August 20, 1999, the distribution of Falcon
cant morbidity. In trying to provide the best care for our
Pharmaceutical’s version of generic diclofenac was
patients, the use of generic ophthalmics of variable qualhalted, and on September 24th, 1999, the generic was
ity and consistency may prove to be a risky compromise
voluntarily recalled by Alcon Laboratories, Inc., the parbetween lower costs and safety. n
ent company of Falcon Pharmaceutical.9
Johnny L. Gayton, MD, is in private practice
with EyeSight Associates in Warner Robins,
Personal Experience
Georgia. He is a member of the speakers’
In our clinic in 1999, it was not uncommon to hear
bureau for Alcon Laboratories, Inc., and Ista
patients complain of transient burning, stinging, and
Pharmaceuticals, Inc. Dr. Gayton may be
conjunctival hyperemia with branded diclofenac and
reached at (478) 923-5872; [email protected].
ketorolac. Our NSAID of choice had been branded diclofRiley N. Sanders, BS, is a technician at EyeSight Associates
enac (Voltaren), but we had seen no cases of persistent
in Warner Robins, Georgia, and a first-year medical student
epithelial defects or corneal melting. Once the generic
at Ross University, Roseau, Commonwealth of Dominica,
diclofenac was introduced to our area, we had eight eyes
West Indies. He may be reached at
develop corneal melts. Of these, two required pericardial
[email protected]
grafts (Figure 1), one required suturing (Figure 2), and one
required a penetrating keratoplasty (Figure 3). The other
US Food and Drug Administration. Generic Drugs: Questions and Answers. http://www.fda.gov/Drugs/Resources
four healed without surgical intervention once the generic 1.ForYou/Consumers/QuestionsAnswers/ucm100100.htm
2. Roberts CW, Nelson PL. Comparative analysis of prednisolone acetate suspensions. J Ocul Pharmacol Ther.
diclofenac was stopped. In my (JLG) conversation with
2007;23(2):182-187.
Drs. Robert E. Fenzl and James P. Gills, we were able to
3. Cantor LB. Generic ophthalmic medications: as good as a Xerox? http://www.medscape.org/viewarticle/583866.
4. Fiscella RG, Jensen M, Van Dyck G. Generic prednisolone suspension substitution. Arch Ophthalmolisolate Falcon Pharmaceutical’s generic diclofenac as the
causative agent. After the previously mentioned recall, the ogy.1998;116(5):703.
5. Wittpenn J. Lack of testing for generic ophthalmic drugs seen as problematic by some experts. May 25, 2011. Ocular
Surgery News. http://www.osnsupersite.com/view.aspx?rid=83790.
incidence rate of nonhealing epithelial defects decreased
6. Fiscella RG. Weighing the choice between generic and branded drugs. Insert to: Cataract & Refractive Surgery Today.
to a nationally reported rate of 0.07%.10
2010;10(6):6-8.
Conclusions
With resistance to rising costs in health care, generics are here to stay. Although many systemic generics
may be bioequivalent, the absorption and efficacy of
generic formulations of ophthalmics is dependent on
inactive ingredients, pH, the size of particles in suspen40 Advanced ocular care March/april 2012
7. Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, crossover, open label pilot study to evaluate the
efficacy and safety of Xalatan in comparison with generic latanoprost (Latoprost) in subjects with primary open angle
glaucoma or ocular hypertension. Indian J Ophthalmol. 2007:55:127-131.
8. Weir R, Zaidi F, Charteris D, et al. Variability in the content of Indian generic ciprofloxacin eye drops. Br J Ophthalmol.
2005;89(9):1094-1096.
9. Flach A. Topically applied nonsteroidal anti-inflammatory drugs and corneal problems: an interim review and comment. Ophthalmology. 2000;107(7):1224-1226.
10. Rowsey JJ. Increased incidence of corneal melt postcataract extraction after the introduction of generic
diclofenac sodium. Presented at: The ASCRS Symposium on Cataract, IOL and Refractive Surgery
Congress. May
21, 2000. Boston, MA.