Therapeutic SubstitutionTherapeutic Substitution

Robert L. Talbert, Pharm. D.College of Pharmacy – UT Austin

School of MedicineSchool of MedicineUT Health Science Center San Antonio

Therapeutic Equivalence-Related TTerms

• Approved Drug Products with TherapeuticApproved Drug Products with Therapeutic Equivalence– “Orange Book”Orange Book

• Pharmaceutical equivalents– Same active ingredient same dosage form routeSame active ingredient, same dosage form, route

of administration, same strength or concentration– May differ in shape, scoring, packaging, y p , g, p g g,

excipients• Eg. Chlordiazepoxide hydrochloride (Librium) 5 mg

capsulescapsules

Therapeutic Equivalence-Related TTerms

• Pharmaceutical alternativesPharmaceutical alternatives– Same therapeutic moiety but different salts,

esters or complexesesters or complexes• Tetracycline hydrochloride 250 mg capsule vs.

tetracycline phosphate complex 250 mg capsule• Extended release vs. immediate release products

with the same active ingredient

Therapeutic Equivalence-Related TTerms

• Therapeutic equivalentsTherapeutic equivalents– Pharmaceutical equivalents and expected to

have the same clinical effect and safety profile• Therapeutically equivalent products are

– Approved as safe and effectpp– Pharmaceutical equivalent

• Identical amounts of the same drug, same dosage f t f d i i t tiform, route of administration

• Meet compendial standards (USP) for strength, quality, purity and identity

Therapeutic Equivalence-Related T (C )Terms (Cont.)

• BioequivalentBioequivalent– Do not present bioequivalence problem and meet

appropriate bioequivalence standards• Adequately labeled• Manufactured in compliance with GMP

l tiregulations• Therapeutic equivalence does not

encompass t o different ingredient that areencompass two different ingredient that are use to treat the same condition– Eg Ibuprofen vs naproxen– Eg. Ibuprofen vs. naproxen

BioavailabilityBioavailability• Rate and extent active moiety is absorbed y

from a drug product– Parameters of bioavailability

• Cmax peak blood concentration• Cmax – peak blood concentration• Tmax – time of the peak blood concentration• AUC – area under the concentration time curve

F t d t b d l d bi i l t• For two drugs to be declared bioequivalent mean and confidence interval must be in the range of 80-125% of the reference productg p

• Bioequivalent products are “AB” rated– “BX” means the products are not equivalent

Pharmacokinetic StudiesKey MeasurementsKey Measurements

• AUCStudy Compound

• AUC– Area under the concentration-

time curve• Cmax

Reference Compound

Cmax

max– Maximum concentration– A difference of greater than 20%

in Cmax or the AUC represents a significant difference between theat

ion

significant difference between the study and reference compounds

• Tmax– Time to maximum concentrationCo

ncen

tra

AUC

Time

C

T

AUC

TimeTmax

Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence‐Related Terms. Accessed

September 29, 2003.

Levothyroxine BioequivalenceLevothyroxine BioequivalenceAUC and Cmax 90% confidence intervals of the study drug must be

within 80 to 125% of a reference compound

125%

etic

nge

100%

arm

acok

ine

fere

nce

Ran

80%

Ph Re

8

Reference Drug

Product ABioequivalent

Product BNot Bioequivalent

Levothyroxine BioequivalenceTh i P d t St tThyroxine Product Status

9http://www.aace.com/pub/pdf/guidelines/AACE‐TES‐ATA‐ThyroxineProducts.pdf

Generic SubstitutionGeneric Substitution

• Substitution of therapeutically equivalentSubstitution of therapeutically equivalent products– Amoxicillin by Smith for amoxicillin by Jonesy y

• Generic substitution is commonly done in inpatient and outpatient (community) p p ( y)pharmacies

• Law varies from state to state• “Medically necessary” “Do not substitute”

Generic Substitution in TexasGeneric Substitution in Texas

• All of the following conditions are metAll of the following conditions are met– Generic product costs the patient less

Patient does not refuse substitution– Patient does not refuse substitution– Prescriber does not prohibit substitution

Ph i t b tit t i ll• Pharmacist may substitute a generically equivalent drug unless– “Brand Necessary” or “Brand Medically

Necessary” written by hand

Why Generic SubstitutionWhy Generic Substitution

• Generics are usually less expensiveGenerics are usually less expensive• Substitution is not a problem if the drug is

NOT a “Narrow Therapeutic Index” (NTI) drugNOT a Narrow Therapeutic Index (NTI) drug– Levothyroxine– LithiumLithium– Warfarin– PhenytoinPhenytoin– Digoxin

• Prescription co-pay should be consideredPrescription co pay should be considered

Therapeutic SubstitutionTherapeutic Substitution• Substitution of one drug for for another withinSubstitution of one drug for for another within

the same class– Enalapril for lisinopril (ACEI to ACEI)

• Same potency

• Substitution of one drug for a drug from a different class with similar pharmacologicdifferent class with similar pharmacologic effect– Enalapril for amlodipine (ACEI to CCB)Enalapril for amlodipine (ACEI to CCB)

• Both lower blood pressure• Roughly similar potency but different mechanism of

actionaction

Therapeutic SubstitutionTherapeutic Substitution• Setting where therapeutic substitution is likelySetting where therapeutic substitution is likely

to occur– Hospital protocols– Federal facilities– Collaborative drug management

I ti t t ti t tti• Inpatient or outpatient settings• Protocol between a prescriber and a pharmacist

• Unlikely to occur between PCP andUnlikely to occur between PCP and community pharmacies (independent or chain)

Therapeutic SubstitutionTherapeutic Substitution

• PBM plans routinely try to implementPBM plans routinely try to implement therapeutic substitution

Often driven by contractual arrangements– Often driven by contractual arrangements– Frequent calls/fax to physicians to influence

prescribingprescribing– Use of co-pays for prescriptions to increase

the use of preferred drugsthe use of preferred drugs• Formulary vs non-formulary• Preferred vs non-preferredp

AMA Policy on Therapeutic S b i iSubstitution

AMA 53rd Assembly June 2009

American Society of Health-System Ph i tPharmacists

Role of the Pharmacy and Therapeutics CommitteeRole of the Pharmacy and Therapeutics Committee

Endorsed by ASHP BOD June 4, 2000

American Pharmacists AssociationAmerican Pharmacists Association

APhA Adopted Resolutions

Possible Consequences of Th i S b i iTherapeutic Substitution

• Under/over treatmentUnder/over treatment– Substitution of simvastatin for Lipitor®

Adverse effects improved/worsened• Adverse effects improved/worsened• Adverse effects different • Lower or higher cost of prescription

– Consider co-paysp y– Big box generics– Medicaid limit of 3 Rx per monthp