Andrea Novelli

Dipartimento di Scienze della Salute

Sezione di Farmacologia Clinica e Oncologia

Gli antibiotici generici

• Angelini

• Gilead

• Menarini Group

• Named

• MSD

• Valeas

• Zambon Group

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DEFINIZIONE DI FARMACO GENERICO / EQUIVALENTE

Un farmaco che ha la stessa composizione

qualitativa e quantitativa di sostanze attive e la

stessa forma farmaceutica del medicinale di

riferimento nonché una bioequivalenza con il

farmaco di riferimento dimostrata da studi

appropriati di biodisponibilità

art. 10, comma 5 DLvo n. 219/06;art. 10, comma 2 Direttiva europea 2001/83/CE

e successive modificazioni

Normativa italiana ed europea

In Italia, la regolamentazione dell’immissione in commercio deimedicinali equivalenti (nel senso di equivalenti terapeutici) èrelativamente recente, essendo entrata a regime solonell’ultimo decennio.

Va pertanto chiarito che due medicinali che contengono lastessa quantità di principio attivo ed hanno la stessa formafarmaceutica sono per definizione equivalenti farmaceutici manon sono necessariamente bioequivalenti né equivalenti dalpunto di vista terapeutico, poiché i diversi eccipienti possonomodificare la disponibilità del farmaco ad esercitare l’azioneterapeutica desiderata.

Dal Sito della Società Italiana di Farmacologia (SIF)*

Position Paper Farmaci Equivalenti

*Visitato il 16/09/2019

Antibiotici generici / equivalentiRequisiti fondamentali

• Perfetta corrispondenza nella potenza, e quindi nella quantità, del principio attivo

• Identiche caratteristiche di dissoluzione, biodisponibilità e dimensioni particelle

• Adeguata sterilità, assenza di contaminanti e sostanze allergizzanti

Common examples of adverse reactions to excipients

Excipient Function Caution in practice

Tartrazine Colouring agent Reported cases of hypersensitivity, and hyperkinetic activity in children

Aspartame Sweetener Caution in patients with phenylketonuria

Benzalkoniumchloride

Preservative Bronchoconstriction (nebuliser solutions) and ocular toxicity (soft contact lens solutions)

Sodiummetabisulphite

Antioxidant Hypersensitivity, including bronchospasm and anaphylaxis, are reported for all sulphites

Propyl gallate Antioxidant Contact sensitivity and skin reactions

Lactose Tablet filler Caution in patients with galactosaemia, glucose-galactose malabsorption syndrome, or lactase deficiency

Sesame oil Oil (injections) Hypersensitivity reactions reported

Lanolin (wool fat) Emulsifier (topical products) Skin hypersensitivity reactions, caution in patients with known sensitivity

Haywood A et al., Aust Prescr, 2011

Skin rash during treatment with generic itraconazole

Excipients present in brand and generic formulations

Capsule Capsule shell

Sporanox® Itraconazole Mylan generics®

Sporanox® Itraconazole Mylan generics®

Sugar spheres,hypromellose,macrogol

Sugar spheres (sucrose and maize starch), hypromellose (E464), sorbitan stearate (E491), silica colloidal idrata (E551)

Gelatine, titanium dioxide (E171), erythrosine (E127),indigotin (E132)

Gelatine; titaniumdioxide (E171), red iron oxide (E172)

De Vuono A et al., J Pharmacol Pharmacother, 2013

Antibiotici generici/equivalenti

Requisiti fondamentali

IDENTICHE CARATTERISTICHE DI DISSOLUZIONE, BIODISPONIBILITA’ E

DIMENSIONI PARTICELLE

Manufacturers Dissolution profile % dissolved at 30 minutes

f 2 value** Similarity % Pass/fall

Brand-name Reference Reference 100.75 Pass

Generic A 24 No 89.32 Pass

Generic B 32 No 104.03 Pass

Generic D NA NA 94.04 Pass

Levofloxacin tablets

Dissolution profile*

* In 34.2 mM NaCl, pH 1.2** dissolution curve similar to brand for f 2 > 50

Sun HY et al., Diagn Microbiol Infect Dis, 2016

Levofloxacin tablets

Dissolution testing*

* In 34.2 mM NaCl, pH 1.2

Sun HY et al., Diagn Microbiol Infect Dis, 2016

Levofloxacin tablets*

Mean variation of MIC values

* In comparison with the USP levofloxacin reference standardSun HY et al., Diagn Microbiol Infect Dis, 2016

CeftriaxonePreparations used in the present study

Preparations Company

A ROCEPHIN® IV 1g Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

B SEFIROM® ceftriaxone sodium hydrate Nichi-iko Pharmaceutical Co., Ltd., Toyama, Japan

C Ceftriaxone Na for IV injection 1g (SANDOZ) Sandoz Co., Ltd., Yamagata, Japan

D LIASOPHIN IV injection 1g Chemix Inc., Kanagawa, Japan

E CEFXONE Shiono Chemical Co., Ltd., Tokyo, Japan

F ROZECLART TAIYO Pharmaceutical Industry Co., Ltd., Aichi, Japan

G Ceftriaxone Na IV injection 1g «Mylan» Mylan Inc., Osaka, Japan

H CERONEED®CEFTRIAXONE Na

Sawai Pharmaceutical Co., Ltd., Osaka, Japan

Tange M et al., Chem Pharm Bull, 2013

CeftriaxoneDissolution time of different sodium preparations

** p<0.01, versus preparation A, ## p<0.01, versus preparation C

Tange M et al., Chem Pharm Bull, 2013

BRAND

CeftriaxoneMicroscopic photographs of different sodium preparations

Stereomicroscope photographsBRAND

Tange M et al., Chem Pharm Bull, 2013

Ceftriaxone sodium

Correlation between dissolution time and amount of moisture adsorbed

Tange M et al., Chem Pharm Bull, 2013

Meropenem

Electron micrographs of drug particles (x1000)

Brand name meropenem

A-H generic drugsFujimura S & Watanabe A, J Infect Chemother, 2012

Meropenem

Dissolution time

A-H generic drugs

* P < 0.001 versus brand name drug; ** P < 0.001 versus generic A drug; *** P < 0.001 versus generic B drug

Fujimura S & Watanabe A, J Infect Chemother, 2012

Even Apparently Insignificant Chemical Deviations amongBioequivalent Generic Antibiotics Can Lead to TherapeuticNonequivalence: the Case of Meropenem

Agudelo M, Rodriguez CA, Pelaez CA, Vesga O

• Meropenem generics were compared with the innovator in vitro (bioassay, MIC,and LC/MS analysis) and in vivo (neutropenic guinea pig soleus model, mousethigh, brain, and lung models) adding cilastatin in different proportions to thecarbapenem

• We found that the concentration and potency of the active pharmaceuticalingredient, in vitro susceptibility testing, and mouse kinetics were identical forall products

• Two generics differed significantly from the innovator in the guinea pig andmouse models

• Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-Ihydrolysis and less stable at room temperature, explaining its therapeuticnonequivalence

• These failing generics are compliant with USP requirements and would remainundetectable under current regulations

Antimicrobial Agents and Chemotherapy, Volume 58 Number 2, p. 1005–1018, 2014

Meropenem

Hydrolysis by mDHP-I of innovator (iMer) and generic formulation (gMer)

Agudelo M et al., Antimicrob Agents Chemother, 2014

MEROPENEM

Pharmacodynamics of 3 generics compared with the innovator*

Agudelo M et al., Antimicrob Agents Chemother, 2014

*in the neutropenic guinea pig soleus P. aeruginosa infection model

B

G

Cefotaxime

Particulate matter contamination in 3 different antibiotic formulations

Antibiotic

A (Clarofan) B (Cefantral) C (Taxim)

HIAC (no. of particles)> 2 µm> 10 µm> 25 µm

539121

167288710

1736215213

Filter (no. of particles)> 25 µm50 - 100 µm> 100 µm

310

3292

80167

Lehr HA et al., Am J Respir Crit Care Med, 2002

FCDHistological examination of muscle tissue

Lehr HA et al., Am J Respir Crit Care Med, 2002

Antibiotici generici/equivalenti

Requisiti fondamentali

PERFETTA CORRISPONDENZA NELLA POTENZA, E QUINDI NELLA QUANTITA’, DEL PRINCIPIO ATTIVO

Country of origin % variation

Australia (India) - 42

Brazil - 26- 27- 27

China - 23

Czech Republic (Italy) - 21- 26

India - 24- 26

Jordan - 27

Philippines - 21- 22

Portugal - 35

Spain - 23

Piperacillin/tazobactamGeneral products with > 20% loss in activity in comparison to

branded formulation

Jones RN et al., 2008; Moet GJ et al., 2009

Piperacillin/tazobactam

In vitro activity of brand and different generics

Product name

Manufacturer Country Potency variation %

E. coli K. pneumoniae P. aeruginosa

Zosyn Pfizer USA ─ ─ ─

Tazar Astral SteriTech India - 20% - 25% - 20%

Tazilin Cadila Healthcare India - 11% - 36% - 20%

Tazcan Cipla India - 20% - 36% - 20%

Futaz Fusion Healthcare India - 11% - 25% - 20%

Tazpen Mylan India - 11% - 36% - 20%

Das P et al., J Infect Public Health, 2017

Generic and innovator meropenem brands

Main characteristics

Manufacturer Product name Lot number Price in US dollar

Mylan Pharmaceutical Merolan MI0116019A 6.22

United Biotech (P) Ltd Menem MNDJ5B8 28.10

Zuventus Healthcare Ltd Merotec Z1D16005 8.70

Fusion Healthcare MeroReach 1716002 11.20

Lupin Ltd Merotrol ZLM6107 12.30

AstraZeneca Pharma India Ltd Meronem MJ984 34.06

Das P et al., Indian J Med Microbiol, 2019

Product name

K. pneumoniae ATCC 700603 (MIC≤1mg/l)

Variation (%)

E. coli ATCC 25922 (MIC≤1mg/l)

Variation (%)

P. aeruginosa (MIC≤2mg/l)

Variation (%)

Merolan 39 + 1.7 39 - 19 39 Same

Menem 37 Same 37 - 45 34 - 26

Merotec 35 - 34 37 - 45 35 - 11

MeroReach 34 - 48 37 - 45 34 - 26

Merotrol 36 - 20 37 - 45 37 - 10

Meronem 37 NA 40 NA 39 NA

Das P et al., Indian J Med Microbiol, 2019

Generic and innovator meropenem brands

Antimicrobial activity against Gram-negative rods

Antibiotici generici/equivalenti

Requisiti fondamentali

PERFETTA CORRISPONDENZA NELLA QUANTITA’ DEL PRINCIPIO

ATTIVO E NELLA POTENZA

IN VITRO, MA NON IN VIVO

Generic vancomycin products fail in vivo despite being pharmaceutical equivalents of the innovator

Omar Vesga, Maria Agudelo, Beatriz E. Salazar, Carlos A. Rodriguez, and Andres F. Zuluaga

Antimicrobial Agents and Chemotherapy, 2010, Vol. 54, No. 8, p. 3271–3279

Except for one product exhibiting slightly greaterconcentration, vancomycin generics were undistinguishablefrom the innovator based on concentration and potency,protein binding, in vitro antibacterial effect determined byminimal inhibitory or bactericidal concentrations and serumpharmacokinetics.

VancomycinIn vivo efficacy against S. aureus GRP-0057*

* 4.30 ± 0.05 log10 CFU per thigh

Vesga O et al., Antimicrob Agents Chemother, 2010

Despite such similarities, all generic products failed in vivo to kill S. aureus

Piperacillin/tazobactam

In vivo dose–effect relationship with innovator and generic (TZP) versus E. coli 35218R*

Rodriguez CA et al., Int J Antimicrob Agents, 2017

* Mixed inoculum experiments

Piperacillin/tazobactam

PTA for resistance suppression in humans after 3.375 g every 6 h

Rodriguez CA et al., Int J Antimicrob Agents, 2017

Clinical and economic impact of generic versus brand name meropenem use in an intensive care unit in Colombia

• The present study was designed to determine the clinical outcome between theuse of generic meropenem (GM) and brand-name meropenem (BNM)

• Findings: A total of 168 patients were included; survival rate for the 68 patientstreated with GM was 38% compared to 59% in patients with BNM. Multivariateanalysis showed that the variables most strongly- associated with mortalitywere cardiovascular disease (OR 18.18, p = 0.033) and treatment with genericmeropenem (OR18.45, p = 0.024)

• Interpretation: The present study suggests that patients treated with GMhave a risk of death18 times higher compared to those treated withBNM

Ordóñez K, Feinstein MM, Reyes S, Hernández-Gómez C, Pallares C, Villegas MV

Brz J Infect Dis, 2019

Meropenem

Cost effectiveness decision tree model

Ordóñez K et al., Brz J Infect Dis, 2019

Efficacy and quality of antibacterial generic products approved for human use: a systematic review

Tattevin P, Crémieux AC, Rabaud C, Gauzit R

• Background. Concerns have recently emerged about the efficacy and the quality of antibacterial generic products approved for use in humans

• Results. We selected 37 original research articles: 15 on β-lactams, 10 on glycopeptides, and 12 on other antibacterial agents

• Of the 37 studies, 14 (37.8%) suggested that some generic products may be inferior to the innovator in terms of purity (n = 2), in vitro activity (n = 3), in vivo efficacy in experimental models (n = 4), clinical efficacy (n = 2), taste (n = 2), or compliance and acceptability in children (n = 1)

• The majority of in vitro studies (78.6%) found no significant difference between generic products and the innovator

• Conclusions. Published data on antibacterial generic products are limited and heterogeneous, thus precluding any attempt to generalize the study results

Clinical Infectious Diseases, 2014

Conclusioni• I farmaci generici sono una risorsaimportante nell’armamentario terapeutico,permettendo di risparmiare risorse.

• Tuttavia, con particolare riferimento agliantibiotici iniettivi, è necessario chesoddisfino tutti i requisiti di equivalenza equalora vi siano differenze importanti,anche se ammesse (ad esempio neglieccipienti), è importante che venganoadeguatamente segnalate.

• In modo da salvaguardare i valori deiparametri PK-PD necessari all’ottenimen-to di una elevata efficacia terapeutica enon incorrere in possibili errori.

Ignác Fülöp Semmelweis(1July 1818 – 13 August 1865)