Generic medication for Generic medication for glaucomaglaucoma

Generic medication for Generic medication for glaucomaglaucoma

Pr. Jean-Philippe NordmannPr. Jean-Philippe Nordmann

University Paris V,University Paris V,

Hôpital des Quinze-VingtsHôpital des Quinze-Vingts

Pfizer

Xalatan

Xalacom

There is increasingly a choice of both branded There is increasingly a choice of both branded and generic IOP-lowering drugsand generic IOP-lowering drugs

There is increasingly a choice of both branded There is increasingly a choice of both branded and generic IOP-lowering drugsand generic IOP-lowering drugs

EXCLUSIVITY EXPIRATION

Merck/Santen TrusoptCosop

t

Novartis

Azopt

Duotrav

Travatan

Azarga

Allergan

Ganfort

Lumigan 0.01%

France – Market share of Generic LatanoprostFrance – Market share of Generic LatanoprostFrance – Market share of Generic LatanoprostFrance – Market share of Generic Latanoprost

60%

Italy – Market share of Generic LatanoprostItaly – Market share of Generic LatanoprostItaly – Market share of Generic LatanoprostItaly – Market share of Generic Latanoprost

0

50

100

150

200

250

mai-10 juin-10 juil-10 août-10 sept-10 oct-10 nov-10 déc-10

Num

ber

of U

nits

sol

d

Generic latanoprost Xalatan

66%

What is the effect of generics in What is the effect of generics in clinical practice?clinical practice?

What is the effect of generics in What 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

Generics and brands: Generics and brands: similar or identical?similar or identical?

Generics and brands: Generics and brands: similar or identical?similar or identical?

Generic drugs: propertiesGeneric drugs: propertiesGeneric drugs: propertiesGeneric drugs: properties

1. Facts and myths about generic drugs. FDA. Available from: www.fda.gov .Accessed Jan 20122. 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

How is bioequivalence of systemic How is bioequivalence of systemic generics demonstrated?generics demonstrated?

How is bioequivalence of systemic How is bioequivalence of systemic generics demonstrated?generics demonstrated?

A generic is considered A generic is considered bioequivalent to the brand if the bioequivalent to the brand if the same levels of drug are shown same levels of drug are shown to be absorbed into the to be absorbed into the bloodstreambloodstream

In other words, equivalent In other words, equivalent bioavailability must be shown, as bioavailability 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)

Dru

g co

ncen

trat

ion

(mg/

mL)

Time after dose (h)

Cmax

Tmax

Brand

Generic

AUC

Non systemic generics: Non systemic generics: Bioequivalence does not need to be shown Bioequivalence does not need to be shown

Non systemic generics: Non systemic generics: Bioequivalence does not need to be shown Bioequivalence does not need to be shown

For agents with local rather than systemic activity For 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 be Bioequivalence 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

Is there therapeutic equivalence between Is there therapeutic equivalence between branded and generic ophthalmic agents?branded and generic ophthalmic agents?Is there therapeutic equivalence between Is there therapeutic equivalence between branded and generic ophthalmic agents?branded and generic ophthalmic agents?

• Some data show equivalence of brand to Some data show equivalence of brand to genericgeneric

− A 6-week randomised, multicentre, A 6-week randomised, multicentre, investigator-masked study of 266 investigator-masked study of 266 patients with POAG or OH found patients with POAG or OH found generic latanoprost was non-inferior generic 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

Mea

n IO

P re

ducti

on (

mm

Hg)

at 6

wee

ks

p = ns

IOP reduction Xalatan vs generic latanoprost1

Is there therapeutic equivalence between Is there therapeutic equivalence between branded and generic ophthalmic agents?branded and generic ophthalmic agents?Is there therapeutic equivalence between Is there therapeutic equivalence between branded and generic ophthalmic agents?branded and generic ophthalmic agents?

• Some show differencesSome show differences

− A randomised, open-label, A randomised, open-label, crossover study of 30 patients crossover study of 30 patients with glaucoma reported a with glaucoma reported a significant difference in IOP significant difference in IOP reduction between Xalatan and a reduction 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

88 years old Japanese patient88 years old Japanese patient

Switch from Xalatan (Pfizer) Switch from Xalatan (Pfizer) to Latanoprost generic to Latanoprost generic (Kaken Pharmaceutical)(Kaken Pharmaceutical)

Corneal ulceration appearing Corneal ulceration appearing after each of the two attempts after each of the two attempts to switchto switch

May be due to a surfactant May 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 a Y, 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.

Composition differences in genericsComposition differences in genericsComposition 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

For Latanoprost generic : Yes!For Latanoprost generic : Yes!

For generic drugs before 1992: It depends!For generic drugs before 1992: It depends!

Current required policy for generic drugCurrent required policy for generic drugCurrent required policy for generic drugCurrent required policy for generic drug

Same active ingredient Same active ingredient andand And the same inactive ones which are listed on the And the same inactive ones which are listed on the

package insertpackage insert– In case of a solution, it is impossible to have differences In 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 the Better to evaluate the methodology to replicate the productproduct

– Variation of +/-10% is acceptableVariation of +/-10% is acceptable

Before 1992Before 1992Before 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 : 38 Drop size : 38 l vs 24 l vs 24 ll

– 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.

Comments from patients with Latanoprost GenericComments from patients with Latanoprost GenericComments 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

SummarySummarySummarySummary

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.