This document discusses generic glaucoma medications. While generics do not need to demonstrate bioequivalence like systemic drugs, evidence suggests they may differ from brands in composition and efficacy. Specifically, one study found generic latanoprost reduced IOP less than the branded Xalatan. Differences in inactive ingredients between generics and brands before 1992 may also impact tolerability and efficacy. Close monitoring of IOP is recommended when switching patients to a generic drug.
1. Generic medication forGeneric medication for
glaucomaglaucoma
Pr. Jean-Philippe NordmannPr. Jean-Philippe Nordmann
University Paris V,University Paris V,
Hôpital des Quinze-VingtsHôpital des Quinze-Vingts
2. Pfizer
Xalatan
Xalacom
There is increasingly a choice of both branded andThere is increasingly a choice of both branded and
generic IOP-lowering drugsgeneric IOP-lowering drugs
EXCLUSIVITY EXPIRATION
Merck/Santen
Trusop
tCosop
t
Novartis
Azopt
Duotrav
Travatan
Azarga
Allergan
Ganfort
Lumigan 0.01%
3. France – Market share of Generic LatanoprostFrance – Market share of Generic Latanoprost
60%
5. What is the effect of generics inWhat is the effect of generics in
clinical practice?clinical practice?
Physicians
• Possibility of less
prescribing control
due to generic
substitution3,4
Third
parties
Patients
• Payers: potential for
cost-saving1
• Pharmacists: potential
for generic substitution
• Government
regulators: could
legislate that generics be
prescribed where
possible (as in France,
Spain2, …
)
1. Pechlivanoglou et al. BMC Health Serv Res 2011;11:89.
2. Rada. BMJ 2011;343:epub.
3. Lindstrom. Ocular Surgery News US edition 25 May 2011. Available from:
http://www.osnsupersite.com/view.aspx?rid=83789 .Accessed Jan 2012.
4. Holmes et al. Circulation 2011;124:1290–13104. 5. Greene. Lancet 2011;378:120−121.
• Change in a drug’s
appearance can
influence compliance5
6. Generics and brands:Generics and brands:
similar or identical?similar or identical?
Generics and brands:Generics and brands:
similar or identical?similar or identical?
7. Generic drugs: propertiesGeneric drugs: properties
1. Facts and myths about generic drugs. FDA. Available from: www.fda.gov .Accessed Jan 2012
2. EMEA Guideline on the Investigation of Bioequivalence, 2010. Available from:
www.ema.europa.eu Accessed Jan 2012
Generic drugs must
have the same
quality and
performance as the
brand name drugs1
Same active
ingredient, strength,
dosage form and
route of administration
as the branded drug1,2
Bioequivalence i.e.
blood levels similar to
those of reference
drug1,2
Properties of
systemic generics
However, inactive ingredients can differ
from the brand product e.g.
Preservatives, pH-adjusters,
antioxidants, buffers, thickening agents
8. How is bioequivalence of systemic genericsHow is bioequivalence of systemic generics
demonstrated?demonstrated?
A generic is consideredA generic is considered
bioequivalent to the brand if thebioequivalent to the brand if the
same levels of drug are shownsame levels of drug are shown
to be absorbed into theto be absorbed into the
bloodstreambloodstream
In other words, equivalentIn other words, equivalent
bioavailability must be shown, asbioavailability must be shown, as
assessed byassessed by
− Maximum blood concentration (CMaximum blood concentration (Cmaxmax))
− Time to reach maximum concentration (TTime to reach maximum concentration (Tmaxmax))
− Area under the curve (AUC)Area under the curve (AUC)
Drugconcentration(mg/mL)
Time after dose (h)
Cmax
Tmax
Brand
Generic
AUC
9. Non systemic generics:Non systemic generics:
Bioequivalence does not need to be shownBioequivalence does not need to be shown
For agents with local rather than systemic activityFor agents with local rather than systemic activity
(such as eye drops), bioavailability studies using(such as eye drops), bioavailability studies using
blood samples are difficult to performblood samples are difficult to perform11
Bioequivalence thus does not need to beBioequivalence thus does not need to be
demonstrated fordemonstrated for22
– GasesGases
– Ophthalmic products prepared as aqueous solutionsOphthalmic products prepared as aqueous solutions
– Topical products prepared as solutionsTopical products prepared as solutions
1. Cantor. J Glaucoma 1997;6:344–9.
2. EMEA Guideline on the Investigation of Bioequivalence, 2010. Available from: http://www.ema.europa.eu.
3. Vesga et al. Antimicrob. Agents Chemother 2010;54:3271–9.
Therapeutic equivalence is often assumed3
10. Is there therapeutic equivalence between brandedIs there therapeutic equivalence between branded
and generic ophthalmic agents?and generic ophthalmic agents?
• Some data show equivalence of brand toSome data show equivalence of brand to
genericgeneric
− A 6-week randomised, multicentre,A 6-week randomised, multicentre,
investigator-masked study of 266investigator-masked study of 266
patients with POAG or OH foundpatients with POAG or OH found
generic latanoprost was non-inferiorgeneric latanoprost was non-inferior
to Xalatan in IOP-lowering efficacyto Xalatan in IOP-lowering efficacy11
1. Allaire et al. Eur J Ophthalmol 2012;22:19–27.
-7.54 -7.29
-8
-7
-6
-5
-4
-3
-2
-1
0
Xalatan latanoprost
MeanIOPreduction(mmHg)at6weeks
p = ns
IOP reduction Xalatan vs generic latanoprost1
11. Is there therapeutic equivalence between brandedIs there therapeutic equivalence between branded
and generic ophthalmic agents?and generic ophthalmic agents?
• Some show differencesSome show differences
− A randomised, open-label,A randomised, open-label,
crossover study of 30 patientscrossover study of 30 patients
with glaucoma reported awith glaucoma reported a
significant difference in IOPsignificant difference in IOP
reduction between Xalatan and areduction between Xalatan and a
generic productgeneric product22
1. Narayanaswamy et al. Indian J Ophthalmol 2007;55:127–31.
Xalatan
IOP reduction of Xalatan vs generic latanoprost1
12. 88 years old Japanese patient88 years old Japanese patient
Switch from Xalatan (Pfizer)Switch from Xalatan (Pfizer)
to Latanoprost genericto Latanoprost generic
(Kaken Pharmaceutical)(Kaken Pharmaceutical)
Corneal ulceration appearingCorneal ulceration appearing
after each of the two attemptsafter each of the two attempts
to switchto switch
May be due to a surfactantMay be due to a surfactant
agent (Stearic Acid Polyester)agent (Stearic Acid Polyester)
Takada Y, Okada Y, Fujita N, Saita S. A Patient with corneal epithelial disorder that developped after administration of aY, Okada Y, Fujita N, Saita S. A Patient with corneal epithelial disorder that developped after administration of a
latanoprost generic, but not a brand-name drug eye drop. Case Rep Ophthalmol Med, 2012, 536746.latanoprost generic, but not a brand-name drug eye drop. Case Rep Ophthalmol Med, 2012, 536746.
13. Composition differences in genericsComposition differences in generics
• A study compared concentration of active
ingredients in brand vs generic glaucoma
medications
• Mean concentration of active ingredient in the
brand (Xalatan) was unchanged by increasing
temperature but was significantly reduced in the
generic versions (LT1 and LT2)
• Significantly higher levels of particulate matter
were found in the generic bottles vs brand
Kahook et al. Curr Eye Res 2011;epub
a
The summary of product characteristics for Xalatan states that the product should be stored in a refrigerator (2°C – 8°C)
and, once open, stored below 25°C and used within 4 weeks. http://www.medicines.org.uk
14. For Latanoprost generic : Yes!For Latanoprost generic : Yes!
For generic drugs before 1992: It depends!For generic drugs before 1992: It depends!
15. Current required policy for generic drugCurrent required policy for generic drug
Same active ingredientSame active ingredient andand
And the same inactive ones which are listed on theAnd the same inactive ones which are listed on the
package insertpackage insert
– In case of a solution, it is impossible to have differencesIn case of a solution, it is impossible to have differences
between productsbetween products
In consequence, no utility to conduct clinical trialsIn consequence, no utility to conduct clinical trials
– Better to evaluate the methodology to replicate theBetter to evaluate the methodology to replicate the
productproduct
– Variation of +/-10% is acceptableVariation of +/-10% is acceptable
16. Before 1992Before 1992
Inactive ingredients were not always identicalInactive ingredients were not always identical
May induce differences in efficacy and tolerabilityMay induce differences in efficacy and tolerability
In the US: brand-nameTimoptic XE vs genericIn the US: brand-nameTimoptic XE vs generic
– Drop size : 38Drop size : 38 µµl vs 24l vs 24 µµll
– Bottle tip : 3,5 vs 1Bottle tip : 3,5 vs 1
– Viscosity : 20 vs 1Viscosity : 20 vs 1
– Surface tension : 1,5 vs 1Surface tension : 1,5 vs 1
Mammo ZN, Flanagan JG, James DF, Trope GE. Generic versus brand-name North American topical glaucoma drops. Can J Ophthalmol, 2012,
47, 55-61.
17. Comments from patients with Latanoprost GenericComments from patients with Latanoprost Generic
« Does it have same efficacy? »« Does it have same efficacy? »
« I prefer the original brand for my eye »« I prefer the original brand for my eye »
Problem of packagingProblem of packaging
Problem of bottle quality (« squizzability »)Problem of bottle quality (« squizzability »)
Problem of color and shape of the bottleProblem of color and shape of the bottle
18. SummarySummary
As more IOP-lowering agents lose their patent, generics are likely
to occupy a greater space in the ophthalmology market
Non-systemic generics such as IOP-lowering eye drops do not
need to demonstrate bioequivalence to the brand
Evidence suggests that generics should not be considered identical
to brands due to differences in composition and, possibly, efficacy
Re-evaluation of IOP reduction when switching to generic drug
seems reasonable.
Editor's Notes
Generic substitution refers to switching between a branded drug and its therapeutically equivalent generic version ( Holmes et al. Circulation 2011;124:1290–1310).
