1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. Tulathromycin Solution for Parenteral Injection for Treatment of Swine and Bovine Respiratory Disease Microbiological Effects on Bacteria of Human Health Concern: A Qualitative Risk Estimation Scott A. Brown, DVM, PhD, Dipl ACVCP Senior Director, Metabolism & Safety Pfizer Animal Health

3. Overview Guidance #152 risk analysis terminology Hazard Characterization Tulathromycin risk estimation summary Qualitative Risk Estimation –Release assessment –Exposure assessment –Consequence assessment –Overall risk estimation Conclusions

4. Indications and Regimen For the treatment of bovine respiratory disease (BRD) associated with label pathogens, and for the control of BRD in cattle at high risk of BRD For the treatment of swine respiratory disease (SRD) associated with label pathogens Single parenteral injection (cattle and swine) Not for use in lactating dairy cows or preruminant calves

5. Guidance #152 Risk Analysis Terminology

6. FDA/CVM Guidance #152 Evaluating the Safety of Antimicrobial New Animal Drugs With Regard to their Microbiological Effects on Bacteria of Human Health Concern “Microbial Safety File” Guidance Released October 23, 2003

7. Guidance #152 Risk Analysis Terminology Release Assessment Exposure Assessment Consequence Assessment Risk Estimation Hazard Characterization

8. Focus on Campylobacter –Macrolides are used to treat campylobacteriosis when antimicrobial therapy is indicated –Macrolides are not used to treat Salmonella, E. coli –Macrolides are not used to treat Enterococcus infections High macrolide resistance rates for clinical isolates since 70s Other therapeutic options available –Macrolide resistance determinants are transferable in Enterococcus, but tulathromycin activity is attenuated in colonic contents, feces due to binding, pH Tulathromycin Hazard Characterization (FDA/CVM Guidance #152)

9. The “Hazard” is –human illness (campylobacteriosis), –caused by an antimicrobial-resistant bacteria (macrolide-resistant Campylobacter), –attributable to an animal-derived food commodity (beef or pork), and –treated with the human antimicrobial drug of interest (a macrolide)

10. Tulathromycin Hazard Characterization (FDA/CVM Guidance #152 ) The “Hazardous Agent” is –antimicrobial-resistant food-borne bacteria (macrolide-resistant Campylobacter) of human health concern –that are in or on a food-producing animal (beef cattle or swine) –as a consequence of the proposed use of the antimicrobial new animal drug (tulathromycin)

11. Tulathromycin Hazard Characterization (FDA/CVM Guidance #152) The “Specific Risk” is –the probability that human food-borne illness (campylobacteriosis) is caused by an antimicrobial- resistant bacteria (macrolide-resistant Campylobacter), attributable to an animal-derived food commodity (beef or pork), and treated with the human antimicrobial drug of interest (a macrolide)

12. Summary of Risk Estimation

13. Release Assessment Summary “Low” probability that macrolide-resistant (Mac R ) Campylobacter will be selected as a result of proposed tulathromycin use –Attenuated microbiological activity of tulathromycin in colonic contents: Low pH Binding to fecal substrates –Mac R occurs by mutation in Campylobacter Frequency of spontaneous mutation is low (<10 -9 ) No evidence of transferable macrolide resistance –No unique resistance mechanisms detected

14. Release Assessment Summary Proposed use of tulathromycin supports “Low” Release: –Parenteral use under veterinary prescription only –Individual animal treatment (not pre-ruminants) –Single dose = full course of therapy –Treatment of BRD and SRD usually occurs at a time substantially before slaughter

15. Release Assessment Summary Expect selection pressure by tulathromycin will be no greater than that for macrolides currently used in livestock: –Tulathromycin activity attenuated in colonic content, feces –Tulathromycin mechanism of action, cross-resistance profile same as current-use macrolides –Macrolides are currently used for SRD, BRD –Macrolide resistance in Campylobacter acquired by mutation, not gene acquisition –Despite >30 years of macrolide use in livestock (parenteral, in-feed, water medications), Mac R C. jejuni from humans is low (1-3%); no trends over time

16. Campylobacter in Beef Exposure Recommendation* Probability of human exposure to Campylobacter Amount of beef contamination Beef Consumption HighMediumLow High Medium HighMediumLow Low (<5%)MediumLow *Sponsor accepts the default recommendation

17. Campylobacter in Pork Exposure Default (G#152) Probability of human exposure to Campylobacter Amount of pork contamination Pork Consumption HighMediumLow High (Carcass)High Medium HighMediumLow MediumLow

18. Campylobacter in Pork Exposure Recommendation* Probability of human exposure to Campylobacter Amount of pork contamination Pork Consumption HighMediumLow High Medium HighMediumLow Low (retail)Medium*Low *Sponsor recommendation

19. Consequence Assessment Summary Guidance #152 defines macrolides as “Critically Important” in human medicine –For the treatment of Legionnaire’s disease; and atypical Mycobacterium (Mycobacterium avium complexus/M. avium intracellulaire) prophylaxis and therapy –For the treatment of foodborne diseases (i.e., Campylobacter)

20. Sponsor Conclusions: Microbial Safety of Tulathromycin The proposed label use of tulathromycin includes management considerations of: – prescription status – inherent low extent of use due to parenteral single dose administration –Advisory Committee Review Mac R is currently monitored by NARMS With these management considerations, approval of the proposed indications for injectable tulathromycin in cattle and swine poses no appreciable risk to public health with respect to microbial food safety.

21. Qualitative Risk Estimation Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

22. Qualitative Risk Estimation Release Assessment Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

23. Qualitative Risk Estimation Release Assessment Chemistry and Disposition Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

24. Release Assessment Exposure Assessment Consequence Assessment Risk Estimation Tulathromycin Chemistry 3 basic amino groups = highly charged form in solution –pK a 8.6, 9.6, 9.9 –aids penetration of the outer membrane of Gram-negative bacteria. –Lipophilic when unionized –Metabolically stable molecular weight: 806.23 C 41 H 79 N 3 O 12 Letavic et al., 2002; Norcia et al., 2004

25. Release Assessment Exposure Assessment Consequence Assessment Risk Estimation Tulathromycin Mechanism of Action/Spectrum of Activity Mechanism: Inhibits protein synthesis –Similar to other macrolides (e.g., erythromycin, tilmicosin) –Binds to the 23s rRNA of bacterial ribosomes Competes for erythromycin-binding Binds to erythromycin-sensitive ribosomes No binding to erythromycin-resistant ribosomes Spectrum: Broad-spectrum activity against bacterial respiratory disease pathogens in cattle and swine

26. Microorganism No. strains MIC (  g/ml) RangeMIC50MIC90 Campylobacter spp 1 300.25 – 1280.564 Enterococcus faecalis 94.0 - >1288.0NA E. faecium 214.0 - > 1288.0>128 Enterococcus spp 2 84.0 - >1284.0NA Escherichia coli 164.0 – 8.08.0 Salmonella spp 3 15 4.0->128 4.08.0 1 Includes: 2 C. fetus, 13 C. jejuni, 15 Campylobacter spp. 2 Includes: 1 E. avium, 7 E. gallinarium 3 Includes: 7 S. choleraesuis, 6 S. dublin, 2 S. enteritidis MICs of Tulathromycin Tested Against Foodborne Microorganisms Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

27. Effects of pH on Tulathromycin Activity Microorganism Mean MIC (  g/mL) at pH: 6.57.07.27.47.68.0 E. coli ATCC 25922 >12818.44.592.0 E. faecalis ATCC 29212 >12836.812.13.482.02.30 S. aureus ATCC 29213 >12824.38.003.031.742.0 Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

28. Tulathromycin Pharmacokinetics Bovine Plasma Profile Parenteral dosingPlasma T max (hours) 1 C max (µg/mL) 0.5 t 1/2 (hours) 90 AUC 0-¥ h (ng·h/mL) 16,700 V SS (L/kg) 11 F (%) 87.70 T max = time to maximum concentration; C max = maximum concentration; t 1/2 = half life; AUC = area under conc.-time curve; Vss = volume of distribution at steady state; F = bioavailability Fast-acting due to rapid release from injection site Extensively distributed; high volume of distribution Extended half-life; prolonged duration High bioavailability Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

29. Tulathromycin Pharmacokinetics Swine Plasma Profile Parenteral DosingPlasma T max (hours) 0.92 C max (µg/mL) 0.581 t 1/2 (hours) 91 AUC 0-¥ h (ng·h/mL) 12,200 V SS (L/kg) 13.2 F (%) 88 T max = time to maximum concentration; C max = maximum concentration; t 1/2 = half life; AUC = area under conc.-time curve; Vss = volume of distribution at steady state; F = bioavailability Fast-acting due to rapid release from injection site Extensively distributed; high volume of distribution Extended half-life; prolonged duration High bioavailability Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

30. Metabolism/Excretion in Feces 30-60% of total dose excreted in feces, depending on the species –Peak concentrations 30-100  g total drug residues/g 90% as unchanged drug Tulathromycin activity in colon contents and feces is substantially attenuated –Significant percentage (>70%) binds to fecal solids –In vitro activity of tulathromycin is reduced when sterilized feces added to growth media E. coli Enterococcus Bifidobacterium Fusobacterium Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

31. Tulathromycin Chemistry and Disposition Conclusions Low in vitro activity against enteric foodborne pathogens Attenuated activity at pH found in colonic contents High fecal binding of drug Transient concentrations in colon Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

32. Resistance Mechanisms, Genetics, and Location Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

33. Mechanisms of Macrolide Resistance Target site modification –Sequence change in ribosome due to mutation –rRNA methylation (e.g., ermA, ermB) Inducible (erythromycin does; tilmicosin and tulathromycin do not) Constitutive Drug inactivation –Phosphorylation (e.g., mphA or mphB) –Hydroxylation (e.g., ereA and ereB) Drug efflux pumps (e.g., msrA and mefA) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

34. Transferable Resistance Macrolide resistance genes are transferable –Study showed no difference in transfer frequency of plasmid-mediated macrolide resistance when tulathromycin was added to E. faecalis mating pair –Tulathromycin activity is attenuated due to pH and binding, thus limiting tulathromycin’s ability to select for enterococci containing these genetic elements Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

35. Transferable Resistance Determinants Transferable genes for MAC R have not been reported in Campylobacter* –Unlike other bacteria, erm gene resistance has not been reported in Campylobacter –Macrolide resistance due to mutation only Release Assessment Exposure Assessment Consequence Assessment Risk Estimation *Jensen & Aarestrup, 2001; Yan & Taylor, 1991

36. Cross-Resistance Constitutively expressed erm genes confer cross- resistance to macrolides, lincosamides, streptogramin B (MLS B ) –Tulathromycin and tilmicosin have similar cross-resistance profiles for human pathogens, both are weak inducers of erm genes Efflux pumps Campylobacter having high erythromycin MIC’s have high tulathromycin MIC’s (I.e., are cross-resistant) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

37. Cross- and Co-Resistance in Gram-Positive Cocci The relative impact of current use patterns on resistance propagation is difficult to discern –Erm genes have been broadly disseminated since the 1980’s in isolates from humans –MLS B resistance in streptococci/enterococci in livestock are broadly disseminated –Organisms carrying the erm gene also often carry resistance determinants to other classes of antibiotics, so resistance co-selection can occur Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

38. Point Mutations E. coli, Salmonella, Enterococcus, and Campylobacter studies: –No tulathromycin- or macrolide- resistant mutants found at the frequency expected for spontaneous mutation (  10 -9 ) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

39. Macrolide Resistance in Campylobacter MutationGene transfer (Plasmids) Comments Target site modification YesNo-- Drug inactivation No -- Drug efflux pumps YesNoRare in Campy

40. Resistance/Genetics Conclusions Three types of macrolide resistance mechanisms documented –Many of the genes are transferable –Erm genes are broadly disseminated and confer cross- resistance to MLS B Transferable macrolide resistance genes have not been documented in macrolide-resistant Campylobacter Macrolide-resistance in Campylobacter occurs via chromosomal mutation –Mutation frequency to macrolide R is very low (< 10 -9 ) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

41. Resistance Selection Pressures in the Field BRD & SRD in the US Current Macrolide Use Antibiotics Use Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

42. Bovine Respiratory Disease Normal Depressed Labored Breathing Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

43. Percent of Cattle that Developed Diseases after Arrival Feedlot 1999 – Part III, USDA/NAHMS survey, December 2000) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

44. BRD: Impact Animal welfare –31.1% of all bovine deaths –57-79% of feedlot mortality Cost to the industry –Over 23 million cattle in feedlots annually (residence time in feedlots is about 6 months) –15% (BRD) of 23M cattle = 3.45M feedlot cattle affected by BRD –Hundreds of millions of dollars lost due to BRD Release Assessment Exposure Assessment Consequence Assessment Risk Estimation Vogel 1994; Lonergan et al, 2001

45. Swine Grower/Finisher Deaths by Producer-Identified Causes Swine 2000 – Part I, USDA/NAHMS survey, August 2001 Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

46. BRD and SRD in the US Summary BRD affects approximately 15% of feedlot cattle (over 3.4M feedlot cattle affected) - morbidity SRD causes approximately 40% of deaths in swine - mortality Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

47. Macrolide Approvals in Cattle and Swine CattleSwine Erythromycin Injectable Tylosin Injectable Oral Injectable Oral Tilmicosin InjectableOral Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

48. Uses of Currently Approved Macrolides Treatment of respiratory disease Treatment of cattle at high risk of respiratory disease Control of diseases (swine dysentery caused by Brachyspira hyodysenteriae, bacterial respiratory disease) Growth promotion Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

49. Percent of Cattle that Received the Following Antimicrobials in Feed or Water Feedlot 1999 – Part III, USDA/NAHMS survey, December 2000 Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

50. Percent of Sites that Gave Antibiotics to Weaned Pigs as a Preventative Practice USDA/APHIS Veterinary Services Info Sheet, March 2002 Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

51. Five Most Common Antibiotics (by route of administration) Given to Grower/Finisher Pigs USDA/APHIS Veterinary Services Info Sheet, March 2002 Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

52. Percent of Sites that Used Antimicrobials in Feed to Grower/Finisher for any Reason Swine 2000 – Part II, USDA/NAHMS survey, August 2001 Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

53. Less than 20% of Feedlot Cattle Received an Injectable Antimicrobial Feedlot 1999 – Part II, USDA/NAHMS survey, December 2000) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

54. Major Antimicrobials Used as Primary Initial BRD Treatment Feedlot 1999 – Part III, USDA/NAHMS survey, December 2000) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

55. Approximately 10% of Cattle Are Treated on Arrival Feedlot 1999 – Part III, USDA/NAHMS survey, December 2000 Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

56. Criteria for Treatment on Arrival in Feedlot Cattle Appearance of cattle upon arrival Source of arriving cattle BRD in some of the arriving cattle Prior BRD problems from sourced cattle Known history of no vaccination for BRD Less important criteria –shipping distance –season of year Feedlot 1999 – Part III, USDA/NAHMS survey, December 2000) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

57. Swine Injectable Antimicrobials Injectable antimicrobials are a distant second to in-feed use of antimicrobials in swine Injectable penicillins command nearly 2/3 of the market (number of doses)* Other injectable antimicrobials used in swine include oxytetracycline, tylosin, lincomycin, and ceftiofur* *Doane’s Animal Health Marketing Survey Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

58. Injectable Antibiotic Use Summary Use of therapeutic antibiotics is an investment for the producer Less than 20% of all feedlot cattle receive an injectable antibiotic Slightly more than 10% of arriving cattle receive injectable antibiotic therapy when one or more “at risk” factors are present Macrolides, tetracyclines, phenicols, fluoroquinolones, and cephalosporins are used as injectables in cattle Penicillins, tetracyclines, macrolides, and cephalosporins are used as injectables in swine Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

59. Indications and Dosage Regimen for Tulathromycin For the treatment of bovine respiratory disease (BRD) associated with label pathogens, and for the control of BRD in cattle at high risk of BRD For the treatment of swine respiratory disease (SRD) associated with label pathogens Single parenteral injection (cattle and swine) Not for use in lactating dairy cows or preruminant calves Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

60. Clinical Use of Tulathromycin One dose provides full course therapy, so assurance of compliance with treatment regime Reduced stress for animals Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

61. Resistance Selection Pressures in the Field Conclusions BRD and SRD are important bacterial infections, with animal welfare and production costs Antibiotics are administered to cattle and swine by various routes and for a variety of indications –Injectable antibiotics are a small subset of the antibiotics used in livestock, and for therapeutic purposes Tulathromycin is one of several injectable antibiotic choices for the veterinarian for BRD and SRD treatment

62. Resistance Selection Pressure Conclusions Selection pressure exerted by tulathromycin will be no greater than that for macrolide products currently used in livestock –Macrolide selection pressure has existed for >30 years (multiple indications and routes of administration) –Use of tulathromycin will be by prescription parenteral injection only to individual animals Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

63. Baseline Prevalence of Resistance Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

64. Campylobacter Resistance Surveillance Programs have different sampling strategies and isolation procedures NCCLS performance standards for susceptibility testing recently issued (2003) NCCLS has not established macrolide breakpoints predictive of efficacy against Campylobacter CDC NARMS* isolates from humans has consistently used the E-test US NARMS veterinary isolate program monitors resistant Campylobacter isolates from poultry, but not cattle and swine US NARMS has recently conducted monitoring in retail beef and pork Release Assessment Exposure Assessment Consequence Assessment Risk Estimation *National Antimicrobial Resistance Monitoring System

65. US Campylobacter Macrolide Resistance Surveys (1998-2003) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation C. jejuniC. coli Poultry (NARMS)*0.2-5.1%11-23% Humans (NARMS)‡1-3%Too few Cattle (USDA/NAHMS)† 2.2% (2/92 isolates) 7.7% (2/26 isolates) * www.arru.saa.ars.usda.gov//campy.htm www.arru.saa.ars.usda.gov//campy.htm ‡ Gupta et al., 2004 † www.arru.saa.ars.usda.gov/posters.htmwww.arru.saa.ars.usda.gov/posters.htm

66. Baseline Campylobacter MIC Conclusions Prevalence of macrolide resistance 1-3% in NARMS human isolates in C. jejuni Prevalence of macrolide resistance in Campylobacter jejuni in pigs cannot be assessed due to limited isolates Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

67. Release Assessment Summary Probability is “Low” that macrolide-resistant Campylobacter will emerge or be selected as a consequence of the proposed use of tulathromycin –Tulathromycin mechanism of action, cross-resistance profile same as macrolides used in livestock –Tulathromycin activity attenuated in colonic content, feces –Macrolide resistance in Campylobacter acquired by mutation, not gene acquisition Mutation rate is at frequency of spontaneous mutation –Macrolides are currently used for SRD, BRD –Despite >30 years of macrolide use in livestock (parenteral, in-feed, water medications), baseline prevalence shows Mac R C. jejuni from humans is low (1-3%) with no trends over time

68. Qualitative Risk Estimation Exposure Assessment Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

69. Exposure Assessment Recommendation (template) Probability of human exposure to pathogen Amount of commodity contamination Amount of commodity being consumed HighMediumLow High Medium HighMediumLow MediumLow Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

70. Exposure Assessment Recommendation (template) Probability of human exposure to pathogen Amount of commodity contamination Amount of commodity being consumed HighMediumLow High Medium HighMediumLow MediumLow Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

71. Exposure Assessment Recommendation (template) Probability of human exposure to pathogen Amount of commodity contamination Amount of commodity being consumed HighMediumLow High Medium HighMediumLow MediumLow Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

72. Campylobacter in Beef Exposure Recommendation Probability of human exposure to Campylobacter Amount of beef contamination Beef Consumption HighMediumLow High Medium HighMediumLow Low (carcass)MediumLow Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

73. Campylobacter in Pork Exposure Default (Guidance #152) Probability of human exposure to Campylobacter Amount of pork contamination Pork Consumption HighMediumLow High (Carcass)High Medium HighMediumLow MediumLow Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

74. Exposure of Humans to Campylobacter Primary isolate in swine is C. coli (C. jejuni <5% of isolates from swine/carcasses) Swine contamination rates decrease substantially as swine move through the food chain (slaughter to retail) Primary risk factors –Consumption of raw/unpasteurized milk –Untreated surface water –Consumption/handling of raw/undercooked poultry –Pork, beef considered a low risk factor by all assessors C. jejuni the causative agent (90% of CDC isolates in NARMS) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

75. Campylobacter prevalence 60-100% prevalence In swine feces 0-32% prevalence In carcasses & processing 0-<5% prevalence At retail Release Assessment Exposure Assessment Consequence Assessment Risk Estimation Hedberg, 2002; Nesbakken et al., 2002; Manser & Dalziel, 1985 Oosterom et al., 1985; Nesbakken et al., 2002; Pierce et al., 2003 Duffy et al., 2001; Duffy et al., 2002; White, 2004 Zhao et al., 2001;

76. Campylobacter in Pork Exposure Recommendation Probability of human exposure to Campylobacter Amount of pork contamination Pork Consumption HighMediumLow High Medium HighMediumLow Low (retail)MediumLow Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

77. Qualitative Risk Estimation Consequence Assessment Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

78. Consequence Assessment Summary Guidance #152 defines macrolides as “Critically Important” in human medicine, namely for: –Treatment of Legionnaire’s disease: MAC/MAI prophylaxis and therapy –Treatment of campylobacteriosis in humans Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

79. Qualitative Risk Estimation Overall Risk Estimation Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

80. Qualitative Risk Assessment (Guidance #152) Release Assessment Exposure Assessment Consequence Assessment Risk Estimation Hazard Characterization Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

81. Qualitative Risk Assessment - Beef Release Assessment Exposure Assessment Consequence Assessment Risk Estimation Hazard Characterization Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

82. Qualitative Risk Assessment - Swine Release Assessment Exposure Assessment Consequence Assessment Risk Estimation Hazard Characterization Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

83. Modulations on “High” ReleaseExposureConsequenceOverall Risk Estim. Low Critically Imp. High LowMediumCritically Imp.High MediumLowCritically Imp.High Medium Critically Imp. High LowHighCritically Imp. High LowCritically Imp. High MediumHighCritically Imp. High MediumCritically Imp. High Critically Imp. High

84. Extent of Use Guidance #152 declares the extent of use is considered “Low” if: –Individual animals are injected –Duration of use is either short or medium (less than 21 days) Tulathromycin qualifies as having a “Low” extent of use Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

85. Potential Risk Management Steps (Guidance #152) Potential Approval Conditions Overall Risk Categorization 1 (High)2 (Medium)3 (Low) Marketing Status RxRx/VFDRx/VFD/OTC Extralabel drug use restrictions RestrictionsRestricted in some cases* ELDU permitted Extent of use LowLow or mediumLow, medium, or high Post-approval monitoring Yes In certain cases VMAC review YesIn certain cases*No *Category 2 drugs ranked ”critically” important and “High” for either release or exposure Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

86. Recommended Risk Management Steps ConsiderationsProposalComments Categorization1Guidance #152 default Marketing Status RxSponsor recommendation Extralabel Drug Use Restrictions No Restrictions Broad macrolide use ongoing in livestock Extent of use LowIndividual animal injection; not used in lactating cows/preruminant calves Post-approval monitoring YesNARMS Campylobacter in humans VMAC review YesCurrent Release Assessment Exposure Assessment Consequence Assessment Risk Estimation

87. Sponsor Conclusions Microbial Safety of Tulathromycin Proposed label use of tulathromycin include management considerations of: – prescription status – inherent low extent of use due to parenteral single dose administration –Advisory Committee Review Mac R is currently monitored by NARMS With these management considerations, approval of the proposed indications for injectable tulathromycin in cattle and swine poses no appreciable risk to public health with respect to microbial food safety.

88. Thank you