Moxifloxacin safety data review

Moxifloxacin safety data review Paul M. Tulkens, MD, PhD * a Cellular and Molecular Pharmacology Unit & Centre for Clinical Pharmacy Louvain Drug Research Institute Université catholique de Louvain, Brussels, Belgiuma * also Emeritus Professor of Human Biochemistry and Biochemical Pathology Université de Mons/Hainaut, Mons, Belgium Former member of the EUCAST (European Committee for Antibiotic Susceptibility Testing) steering committee founding member and past-president of the International Society of Anti-infective Pharmacology 8. Forschungswerkstatt Moxifloxacin 2 Leverkusen -- 7./8. November 2 8--2 Leverkusen

Einige Wörter Ich bedauere, diese Darstellung nicht auf deutsch geben zu können... Die Deutsche Sprache ist jedoch sowohl sehr schön als auch sehr logisch... Und ich bin ein begeisteter Zuhörer von J.S. Bach's Passionnen oder Operns von Wagner... Aber ich musste bereits alle Tage Französisch, Flämisch und Englisch sprechen... und Deutsch ist für einen Französigsprachigen schwierig... Ich werde versuchen, die Fragen auf deutsch zu verstehen... Die Lokalisierung der Université catholique de Louvain in Brüssel Die Gebäude der medizinischen Fakultät und das Krankenhaus Die Gruppe der Pharmakologie/Toxikologie der Antibiotika 8--2 Leverkusen 2

Fluoroquinolone selection: appropriate benefit-risk profiles Paul M. Tulkens, MD, PhD * a Cellular and Molecular Pharmacology Unit & Centre for Clinical Pharmacy Louvain Drug Research Institute Université catholique de Louvain, Brussels, Belgiuma * also Professor of Human Biochemistry and Biochemical Pathology Université de Mons/Hainaut, Mons, Belgium member of the EUCAST (European Committee for Antibiotic Susceptibility Testing) steering committee founding member and past-president of the International Society of Anti-infective Pharmacology 7. Forschungswerkstatt Moxifloxacin 29 Leverkusen 26-27 June 29 8--2 Leverkusen 3

Contents of the Presentation All antimicrobials have associated toxicity risks Major non-serious and serious side-effects associated with the main antimicrobials used in the treatment of CAP ( -lactams, macrolides, tetracyclines, fluoroquinolones). Adverse effects of moxifloxacin vs other agents a comprehensive analysis The risk of bacterial failure are guidelines "safe"? Conclusions 8--2 Leverkusen 4

All antimicrobials have associated risks * Class Drugs Frequent or serious side effects fluoroquinolones levofloxacin Anaphylactic reactions and allergic skin reactions Clostridium difficile-associated colitis Hematologic toxicity Hepatotoxicity Central nervous system effects: headache, insomnia, dizziness, convulsions Musculoskeletal: tendinopathies Peripheral neuropathy Prolongation of the QTc interval and isolated cases of torsade de pointes Digestive tract: nausea, diarrhoea moxifloxacin * based on an analysis of the respective labelling (SmPC or equivalent) Conclusions (# ): Anaphylactic reactions and allergic skin reactions Clostridium difficile-associated colitis Musculoskeletal: Tendinopathies Peripheral neuropathy Prolongation of the QT interval Central nervous system effects: headache, insomnia, dizziness, convulsions Digestive tract: nausea, diarrhoea All antimicrobials used in RTI are associated with known toxicities The main point will be the recognition of patients at risk (exclusions) The next point will be a correct evaluation of the benefit / risk ratio in the specific environment and for the specific patient Carbonnelle et al., in preparation 8--2 Leverkusen 5

The "end result" 8--2 Leverkusen 6

Where are we now with moxifloxacin? Hepatotoxicity: is this a real issue? What do the "whole clinical trial data base" tells us? Is moxifloxacin still effective? 8--2 Leverkusen 7

Hepatic toxicity of antibiotics Usually idiosyncratic (can be associated with other allergic reactions). Clavulanic acid: genetic deficiency in glutathione S-transferases? 2 (longer latency period than other antibiotics ) Macrolides: related to reactive metabolites (nitrosoalkanes) that covalently bind to proteins, forming modified antigens (immunoallergic hepatitis) 3 Tetracyclines: related to inhibition of mitochondrial -oxidation of fatty acids 4 Fluoroquinolones: remains anecdotal and unpredictable, except for for molecules with substituent-generating reactive intermediates difluoroaniline (temafloxacin and trovafloxacin) 5 cyclopropylamine (trovafloxacin; for which co-exposure to lipopolysaccharide may also be critical) 6. Robles M, Andrade RJ. Rev Esp Quimioter. 28 Dec;2(4):224-33 2. Lucena et al., Hepatology. 28 Aug;48(2):588-96. 3. Pessayre et al. J Antimicrob Chemother 985 Jul; 6 Suppl A: 8-94 4. Freneaux et al. Hepatology 988 Sep; 8(5): 56-62 5. Blum et al. Clin Infect Dis 994 Jun; 8(6): 946-5; Chen et al. N Engl J Med 2 Feb 3; 342(5): 359-6; Lucena et al. Clin Infect Dis 2 Feb; 3(2): 4-6. Sun et al. Chem Res Toxicol 28 Mar; 2(3): 7-9 7. Shaw et al. Toxicol Sci. 29 Jan;7():27-8 8--2 Leverkusen 8

Patients with possible drug-related hepatic disorders in comparative clinical trials (oral moxifloxacin) Moxifloxacin (N=9394) Comparators (N=9359) AE [ADR] (Sub-)SMQ Total Serious Fatal Total Serious Fatal Comprehensive search All cases Liver-related investigations, signs and symptoms * Cholestasis and jaundice of hepatic origin Possible liver-related coagulation and bleeding disturbances Possible drug-related hepatic disorders - severe events only 29 (2.3%) [53 (.6%)] 6 (<.) [3 (<.)] 8--2 Leverkusen 9 [( )] 223 (2.4%) [39 (.5%)] 8 (<.%) [3 (<.%)] 2 (<.%) [ ( )] 8 [2] 4 [2] [] 98 [24] 4 [] [] 3 [9] [] [] 6 [4] [] [] 7 [5] [] [] 3 [8] [] [] 9 [6] 2 [] [] 7 [7] 3 [] [] Hepatitis, non-infectious 7 [7] [] [] 6 [3] [] [] Hepatic failure, fibrosis and cirrhosis and other liver damagerelated 2 [9] [] [] 9 [4] [] [] conditions Liver neoplasms, benign [] [] [] [] [] [] Liver neoplasms, malignant and unspecified [] [] [] 2 [] 2 [] [] AE: adverse event; ADR: adverse drug reaction; SMQ: Standard MedDRA Query The allocation of a liver-related adverse event to any of the sub-smqs is not mutually exclusive. One patient can have one event allocated to several sub-smqs, or several events located to different sub-smqs. In consequence, the overall number of patients identified with the comprehensive search is smaller than the sum of all patients allocated to the sub-sqms. * similar to published studies

SMQ-search for "severe events": Hepatic overview by event type/diagnosis Moxifloxacin AE [ADR] Comparator AE [ADR] Total 9 [6] 7 [7] Hepatitis CTC grade 3 (severe) CTC grade <3 (non-severe) Hepatic failure CTC grade 3 (severe) CTC grade <3 (non-severe) Liver disorder CTC grade 3 (severe) CTC grade <3 (non-severe) 3 [2] 4 [4] [] 2 [2] 9 [8] 8--2 Leverkusen [] 5 [3] [] 3 [] 5 [2] Liver neoplasm 2 [] Outcomes Resolved/improved Unchanged Worsened/death Unknown 7 AE: adverse event; ADR: adverse drug reaction Common Terminology Criteria for Adverse Events v3.: AP, GGT, AST, ALT: Grade (mild), >ULN 2.5x ULN; Grade 2 (moderate), >2.5 5.x ULN; Grade 3 (severe), >5. 2.x ULN; Grade 4 (life-threatening), >2.x ULN Total bilirubin: Grade (mild), >ULN.5x ULN; Grade 2 (moderate), >.5 3.x ULN; Grade 3 (severe), >3..x ULN; Grade 5 (lifethreatening), >.x ULN 2 4

Crude incidence rates of acute liver injury caused by antibiotics * Incidence rate (CI) Antibiotic population per, users per, prescriptions endpoint reference fluoroquinolones (w/o moxifloxacin) Outpatient clinic, Sweden (995-25).7 (.5-.) International consensus [] moxifloxacin Outpatient clinic, Sweden (995-25).8 (.-.5) International consensus [] cotrimoxazole Saskatchewan Health Plan, Canada (982-986). (.2-5.7) 4.9 (.9-27.6) International consensus, hospitalisati on [2] erythromycin Saskatchewan Health Plan, Canada (982-986) 2. (.7-5.9) 4. (4.8-4.2) International consensus, hospitalisati on [2] amoxicillinclavulanic acid General practice research database, United Kingdom (99-992) 22.5 (4.7-34.4) 7.4 (.4-26.5) International consensus [3] * see Van Bambeke & Tulkens, Drug Safety (in press) for full Table and details. De Valle et al. Aliment Pharmacol Ther 26 Oct 5; 24(8): 87-95 2. Perez et al. Epidemiology 993 Nov; 4(6): 496-5 3. Garcia-Rodriguez et al. Arch Intern Med 996 Jun 24; 56(2): 327-32 8--2 Leverkusen

An extensive review 8--2 Leverkusen 2

An extensive review 8--2 Leverkusen 3

An extensive review 8--2 Leverkusen 4

Moxifloxacin hepatotoxicity (confirmation) There is no evidence from currently available data that reactions are more frequent than with comparators Clinical trials: Apparent imbalance in drug-related severe events detected in the EU Periodic Safety Report was based on clinically non-severe, non-serious events (the number of serious, or clinically severe ADRs is too small for meaningful conclusions) Spontaneous and registry data: all data show a lower incidence for fluoroquinolones vs macrolides and amoxicillin/clavulanic acid No signal in EBGM analysis conducted by FDA in 26 8--2 Leverkusen 5

The whole clinical trial data base 8--2 Leverkusen 6

The whole clinical trial data base Submitted on 4 November 2 8--2 Leverkusen 7

Which patients and which comparators? open-label and double-blind actively controlled clinical trials included in the clinical trial database of moxifloxacin 4 mg oncedaily performed by the registration holder (currently Bayer HealthCare) as part of the phase II-IV programmes initiated, completed and with raw data reported to the sponsor between 996 and 2 8--2 Leverkusen 8

Which global results? 8--2 Leverkusen 9

Which global results? AE, ADR and SADR were mainly gastrointestinal disorders and "changes observed during investigations" such as asymptomatic QT prolongation). Incidence rates of hepatic disorders, tendon disorders, surrogates of QT prolongation, serious cutaneous reactions and Clostridium difficile-associated diarrhoea were similar with moxifloxacin and comparators. 8--2 Leverkusen 2

And for patients at risk? PO sequential IV age (> 65 y) n = 255 vs. 243 n = 373 vs. 334 n = 7 vs. 9 AE 5 / 2 929 / 9 83 / 8 ADR 44 / 448 348 / 37 27 / 3 SAE 27 / 84 298 / 29 32 / 24 SADR 6 / 8 49 / 3 4 / 6 discont. AE 6 / 9 3 / 4 / discont. ADR 78 / 74 62 / 42 4 / 6 death AE 29 / 32 / 98 3 / death ADR. 3 / 2 / 3 /..2.5 2 5..2.5 2 5..2.5 2 5 relative risk estimate (moxifloxacin / comparator) diabetes n = 777 vs. 77 n = 926 vs. 97 n = 8 vs. 72 AE 355-3 587 / 565 42-35 ADR 58-26 96 / 74 3-4 SAE 78-56 98 / 82 6 - SADR - 3 22 / 2-2 discont. AE 34-26 78 / 64 6-6 discont. ADR 22-4 38 / 2-4 death AE - 6 46 / 23 9-4 death ADR. - 2 / 2 -..2.5 2 5..2.5 2 5..2.5 2 5 relative risk estimate (moxifloxacin / comparator) 8--2 Leverkusen 2

And for patients at risk? PO sequential IV renal impairment n = 283 vs. 229 n = 889 vs. 863 n = 23 vs. 28 AE 283-229 572-549 2-92 ADR 259-229 96-8 3-32 SAE 94-8 22-8 26-22 SADR 9-9 3-23 2 - discont. AE 49-53 75-78 - 7 discont. ADR 27-33 28-25 2-3 death AE 2-4 58-67 - 7 death ADR. - 3 3-3 -..2.5 2 5..2.5 2 5..2.5 2 5 relative risk estimate (moxifloxacin / comparator) hepatic impairment n = 46 vs. 63 n = 83 vs. 96 n = 46 vs. 46 AE 69-7 83-96 23-8 ADR 37-32 43-43 7-6 SAE 5-7 6-53 7-7 SADR - - 7 - discont. AE 6-7 24-24 - discont. ADR 6-3 - 7 - death AE 2-4 4-24 2 - death ADR. - - 2 -..2.5 2 5..2.5 2 5..2.5 2 5 relative risk estimate (moxifloxacin / comparator) 8--2 Leverkusen 22

And for patients at risk? PO sequential IV cardiac disorders n = 476 vs. 44 n = 476 vs. 36 n = 6 vs. 4 AE 77-655 84-84 63-57 ADR 34-297 35-293 6-25 SAE 32-25 - 246 23 - SADR 4-8 43-35 3-2 discont. AE 7-64 9-96 7-3 discont. ADR 43-45 59-43 - death AE - 25 69-75 - 8 death ADR. - 2 3-4 -..2.5 2 5..2.5 2 5..2.5 2 5 relative risk estimate (moxifloxacin / comparator) BMI < 8 n = 38 vs. 365 n = 6 vs. 5 n = 45 vs. 53 AE 3-7 89-83 7 - ADR 7-96 26-27 5-3 SAE - 28 36-3 3-3 SADR - 5 5-4 - discont. AE 4-27 - - discont. ADR 2-2 6-9 - death AE 3-5 5-5 - death ADR. - - -..2.5 2 5..2.5 2 5..2.5 2 5 relative risk estimate (moxifloxacin / comparator) 8--2 Leverkusen 23

And what if we compare drugs? A. oral therapy. moxifloxacin vs -lactams risk factor: age > 65 y (n= 99 vs 788) diabetes (n = 282 vs 27) renal impairment (n = 347vs 38) hepatic impairment (n = 47 vs 53) cardiac disorders (n = 526 vs 444) BMI < 8 (n = 7 vs 76) AE ADR 7-5 SAE SADR discont. AE discont. ADR 3 - death AE death ADR 2. moxifloxacin vs macrolides relative risk estimate (moxifloxacin / comparator) risk factor: age > 65 y (n = 252 vs 942) diabetes (n = 329 vs 255) renal impairment (n = 484 vs 427) hepatic impairment (n = 44 vs 64) cardiac disorders (n = 794 vs 623) BMI < 8 (n = vs 4) AE ADR SAE SADR discont. AE discont. ADR death AE death ADR relative risk estimate (moxifloxacin / comparator) 8--2 Leverkusen 24

And what if we compare drugs? B. sequential therapy. moxifloxacin vs -lactam alone risk factor: age > 65 y (n= 44 vs 422) diabetes (n = 562 vs 56) renal impairment (n = 329 vs 324) hepatic impairment (n = 89 vs 73) cardiac disorders (n = 438 vs 46) BMI < 8 (n = 4 vs 36) AE 332-276 ADR 2-75 7-5 SAE SADR 3-3 discont. AE 52-28 discont. ADR 24-6 death AE death ADR 2. moxifloxacin vs -lactam alone or combined with a macrolide relative risk estimate (moxifloxacin / comparator) risk factor: age > 65 y (n = 223 vs 235) diabetes (n = 69 vs 99) renal impairment (n = 68 vs 6) hepatic impairment (n = 37 vs 42) cardiac disorders (n = 75 vs 68) BMI < 8 (n = 25 vs 25) AE ADR SAE SADR 3 - discont. AE discont. ADR death AE death ADR - - relative risk estimate (moxifloxacin / comparator) 8--2 Leverkusen 25

And what if we compare drugs? C. intravenous therapy. moxifloxacin vs -lactam risk factor: age > 65 y (n= 92 vs 9) diabetes (n = 46 vs 33) renal impairment (n = 9 vs 85) hepatic impairment (n = 3 vs 35) cardiac disorders (n = 7 vs 6) BMI < 8 (n = vs 6) AE 52-35 ADR 2 - SAE SADR 2 - - discont. AE 6-4 - discont. ADR death AE - 2 - - death ADR 2. moxifloxacin vs another fluroquinolone relative risk estimate (moxifloxacin / comparator) risk factor: age > 65 y (n = 6 vs 74) diabetes (n = 27 vs 3) renal impairment (n = 77 vs 86) hepatic impairment (n = 7 vs 5) cardiac disorders (n = 32 vs 38) BMI < 8 (n = 26 vs 37) AE - ADR - SAE SADR discont. AE - - discont. ADR - - death AE death ADR relative risk estimate (moxifloxacin / comparator) 8--2 Leverkusen 26

Conclusions (at this point) The overall safety profile of moxifloxacin is similar to that of comparators from clinical trials More specifically, and with regard to recent questions: Hepatic events reactions were very low and not superior in a statistically significant manner to comparators even if considering patients with hepatic disorders While QTc prolongation were observed, no increase clinical adverse effects were seen even in patients with prexisting cardiac disorders vs. the comparator(s) Specific toxicities (tendonitis, e.g.) remained exceedingly rare with no difference between moxifloxacin and the fluroquinolone comparator Skin events were extremely are and less frequent than with -lactams 8--2 Leverkusen 27

But what is "risk"? side effects? therapeutic failure? 8--2 Leverkusen 28

Is moxifloxacin still effective? wild type population (EUCAST) clinical breakpoint: EUCAST CLSI 9 8 7 6 5 amoxicillin cefuroxime (oral) 9 8 7 6 5 4 4 3 3 2 2 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 6 32 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 6 32 9 clarithromycin telithromycin 9 8 8 7 6 5 4 3 2 7 6 5 4 3 2 cumulative percentage 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 6 32 64 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 9 levofloxacin moxifloxacin 9 8 8 7 7 6 6 5 5 4 4 3 3 2 2 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 6 32 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 6 32 MIC (mg/l) 8--2 Leverkusen 29

Is moxifloxacin still effective? wild type population (EUCAST) clinical breakpoint: EUCAST CLSI 9 8 amoxicillin cefuroxime (oral) 9 8 7 7 6 6 5 5 S. pneumoniae N= 249 (non-duplicates) clinically-confirmed CAP moxifloxacin 4 3 2 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 9 4 3 2 6 32 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 6 32 8 9 clarithromycin 8 7 telithromycin 9 8 7 6 5 4 3 2 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 7 6 5 4 3 2 6 32 64 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 9 levofloxacin 6 5 4 cumulative percentage 3 2 moxifloxacin 9 8 7 8 7 6 5 4 3 2 6 5 4 3 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 6 32 2 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 6 32 2. -3 3.9-3 7.8-3.5625.325.625.25.25.5 2 4 8 6 32 MIC (mg/l) 8--2 Leverkusen 3

Moxifloxacin MIC's against S. pneumoniae have not increased in Belgium from 999 to 28 S. pneumoniae susceptibility to moxifloxacin in Belgium Facts: cumulative percentage 75 5 25.7825.5625.325.625.25 MIC.25 EUCAST breakpoint.5 MXF 999 MXF 28 Similar curves for 2, 23, and 24 to 27 2 4 From data of a national collection * independent from our own collection (shown on the previous slide) No change (and even improvement) in S. pneumoniae susceptibility to moxifloxacin from 999 (pre-commercialization) to 28 (7 years after launching **) in 28, 99.3 % isolates were still below the EUCAST breakpoint (.5 mg/l) and at MIC values > -fold lower than the C max. * Non invasive respiratory tract infections ** st respiratory quinolone in BE Surveys from the Belgian Scientific Institute for Public Health for S. pneumoniae from community isolates (n=56 in 999 and 448 in 28) http://www.iph. fgov.be Data available yearly for 999 through 28. Presented at 9th ECCMID, May 29, Helsinki, Finland (Vanhoof et al.) 8--2 Leverkusen 3

Conclusions (Altogether) Moxifloxacin has kept over years an excellent activity against S. pneumoniae (and wil be effective against S. aureus up to an MIC of.25- mg/l) and should, therefore stand a as a useful alternative when so-called " st line antibiotics" (for CAP, COPD or skin infections) have "stopped to work" The safety profile of moxifloxacin at 4 mg/day remains excellent with no statistically or medically significant difference with comparators (used often at a lower dose than recommended today) Thus, and based on all available evidence, the use of moxifloxacin should not be vitiated by excessive toxicity if it is prescribed for the correct indications and with due attention to the contraindications and warnings mentioned in the labeling (Van Bambeke & Tulkens, Drug Saf. 29;32(5):359-78 Tulkens et al. in preparation) Flämischer Maler Hieronymus Bosch (c45-56) zeigt großer Fantasie in seinem Triptychon Altarpiece das letzte Urteil (c5-5, Akademie, Wien) 8--2 Leverkusen 32

Disclosures Financial support from the Belgian Fonds de la Recherche Scientifique (and other federal and regional funding agencies) for basic research on pharmacology and toxicology of antibiotics and related topics the Public Federal Service "Public Health" for "Appropriate antibiotic use" studies in General Practice Pharmaceutical Industry for specific drug-related studies Note: all work, irrespective the source of funding, is published in peer-reviewed journals and is available from our web site * P.M. Tulkens is member of the Committee organising public campaigns for appropriate use of antibiotics in Belgium since 2 ** * http://www.facm.ucl.ac.be/publicat_facm.htm ** http://www.antibiotiques.org/ Selected publications in relation to this presentation: "Was auch als Wahrheit oder Fabel In tausend Büchern dir erscheint, Das alles ist ein Turm zu Babel, Wenn es die Liebe nicht vereint." J.W. von Goethe Van Bambeke F, Tulkens PM. Safety profile of the respiratory fluoroquinolone moxifloxacin: comparison with other fluoroquinolones and other antibacterial classes. Drug Saf. 29;32(5):359-78. PubMed PMID: 949232. Van Bambeke F, Reinert RR, Appelbaum PC, Tulkens PM, Peetermans WE. Multidrug-resistant Streptococcus pneumoniae infections: current and future therapeutic options. Drugs. 27;67(6):2355-82. Review. PubMed PMID: 7983256. Lismond et al. Antimicrobial susceptibility of Streptococcus pneumoniae isolates from vaccinated and non-vaccinated patients with a clinically-confirmed diagnosis of community-acquired pneumonia (CAP) in Belgium. Intern. J. Antimicrob. Agents, 2, in press 8--2 Leverkusen 33