1. Mitigating Pain in Livestock: What Options are Available NIAA 2014 Annual Conference Omaha, Nebraska April 2, 2014 Craig A. Lewis, DVM, MPH, DACVPM Center for Veterinary Medicine U.S. Food and Drug Administration,

2. Mitigating Pain in Livestock: What (Legal) Options are Available NIAA 2014 Annual Conference Omaha, Nebraska April 2, 2014 Craig A. Lewis, DVM, MPH, DACVPM Center for Veterinary Medicine U.S. Food and Drug Administration,

3. Outline Background Drugs (approved, unapproved, compounded) Extralabel Drug Use Pain Mitigation from the Literature (Status) Questions – Under AMDUCA is extra-label use of analgesics and anesthetics permitted? – Is extra-label use of products restricted only to those products that have been approved by FDA and have an NADA or NDA number? 2

4. Pain Mitigation Disease pain –Cutaneous –Visceral – (serosa, distention, swelling) –Musculoskeletal – (bone, joint, muscle) –(Inflammatory) Surgical pain –General –Localized 3

5. Pain Mitigation (from the literature) NSAIDs –Aspirin –Sodium salicylate –Flunixin –Ketoprofen –Diclofenac –Phenylbutazone –Meloxicam –Carprofen 4

6. Pain Mitigation (from the literature) Local anesthetics –Lidocaine –Mepivacine –Bupivacaine 5

7. Pain Mitigation (from the literature) Barbiturates –Pentobarbital –Thiopental Acepromazine Benzodiasepines –Diazepam –Midazolam Azaperone Xylazine 6

8. Pain Mitigation (from the literature) Butorphanol Medetomidine Ketamine Tiletamine-zolazepam (Telazol) Guaifenesin Tramadol Yohimbine 7

9. Pain Mitigation (from the literature) Halothane Isoflurane Propofol Guaifenesin Tramadol 8

10. Approved Animal Drugs To be legally marketed, an animal drug must be the subject of –an approved new animal drug application (NADA) –an approved generic application [abbreviated new animal drug] application] (ANADA) –a conditional approval –an index listing 9

11. Approved Human Drugs To be legally marketed, a human drug must be the subject of –an approved new drug application (NDA) –an approved generic application [abbreviated new drug application] (ANDA) –An OTC Drug Monograph 10

12. Unapproved Animal Drugs No pre-approval review No post-approval monitoring May unfairly compete against approved products Reduces the availability of legal, reviewed, tested and monitored drug products 11

13. Unapproved Animal Drugs Animal drugs illegally marketed in the United States that have not been approved by the Food and Drug Administration (FDA) Unapproved animal drugs have not been reviewed under FDA's legal review processes 12

14. Compounded Animal Drugs If compounded from approved drugs (as starting ingredients) MAY be legal under ELU regulations If compounded from bulk ingredients IS considered an unapproved animal drug Zero tolerance for compounding from bulk ingredients for food-producing animals 13

15. Compounded Animal Drugs Unknown quality control/manufacturing standards Unknown assurance of purity, potency, or stability Potential animal safety and efficacy issues Potential for unknown or unsafe residues Difficult to monitor – No reporting requirements (even less than for other unapproved animal drugs) 14

16. Extralabel Drug Use Extralabel is the use of an approved drug in a manner that is not in accordance with the approved label directions. –e.g. indication, species, dosage level, frequency, route of administration Allows veterinarians to prescribe extralabel uses of certain approved animal drugs and approved human drugs 15

17. Extralabel Drug Use “Such use is limited to treatment modalities when the health of an animal is threatened or suffering or death may result from failure to treat.” 16

18. Extralabel Drug Use Must be by or on the order of a veterinarian within the context of a “ valid veterinarian-client-patient relationship” Must not result in violative residues Must be in conformance with all other parts of extralabel drug use regulation (21 CFR Part 530) Must not use drugs prohibited from extralabel use 17

19. Extralabel Drug Use “Establish a substantially extended withdrawal period prior to marketing of milk, meat, eggs, or other edible products supported by appropriate scientific information.” 18

20. Extralabel Drug Use “Take appropriate measures to assure that assigned timeframes for withdrawal are met and no illegal drug residues occur in any food-producing animal subjected to extralabel treatment.” 19

21. Extralabel Drug Use Approved animal drugs Approved human drugs Conditionally approved animal drugs Indexed animal drugs Medicated feeds VFD drugs (veterinary feed directive) Human OTC monographed drugs Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 20

22. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs Conditionally approved animal drugs Indexed animal drugs Medicated feeds VFD drugs (veterinary feed directive) Human OTC monographed drugs Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 21

23. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs Conditionally approved animal drugs Indexed animal drugs Medicated feeds VFD drugs (veterinary feed directive) Human OTC monographed drugs Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 22

24. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs ×Conditionally approved animal drugs Indexed animal drugs Medicated feeds VFD drugs (veterinary feed directive) Human OTC monographed drugs Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 23

25. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs ×Conditionally approved animal drugs ×Indexed animal drugs Medicated feeds VFD drugs (veterinary feed directive) Human OTC monographed drugs Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 24

26. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs ×Conditionally approved animal drugs ×Indexed animal drugs ×Medicated feeds VFD drugs (veterinary feed directive) Human OTC monographed drugs Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 25

27. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs ×Conditionally approved animal drugs ×Indexed animal drugs ×Medicated feeds ×VFD drugs (veterinary feed directive) Human OTC monographed drugs Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 26

28. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs ×Conditionally approved animal drugs ×Indexed animal drugs ×Medicated feeds ×VFD drugs (veterinary feed directive) ×Human OTC monographed drugs Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 27

29. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs ×Conditionally approved animal drugs ×Indexed animal drugs ×Medicated feeds ×VFD drugs (veterinary feed directive) ×Human OTC monographed drugs ×Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 28

30. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs ×Conditionally approved animal drugs ×Indexed animal drugs ×Medicated feeds ×VFD drugs (veterinary feed directive) ×Human OTC monographed drugs ×Unapproved animal drugs Drugs compounded from approved drugs Drugs compounded from bulk ingredients 29

31. Extralabel Drug Use Approved animal drugs (Rx or OTC) Approved human drugs ×Conditionally approved animal drugs ×Indexed animal drugs ×Medicated feeds ×VFD drugs (veterinary feed directive) ×Human OTC monographed drugs ×Unapproved animal drugs Drugs compounded from approved drugs ×Drugs compounded from bulk ingredients 30

32. Pain Mitigation (from the literature) NSAIDs –Aspirin –Sodium salicylate –Flunixin –Ketoprofen –Diclofenac –Phenylbutazone –Meloxicam –Carprofen 31

33. Pain Mitigation (from the literature) NSAIDs –Aspirin Unapproved animal – cattle, swine, sheep, poultry (marketed) OTC monograph – human (marketed) –Sodium salicylate –Flunixin –Ketoprofen –Diclofenac –Phenylbutazone –Meloxicam –Carprofen 32

34. Pain Mitigation (from the literature) NSAIDs –Aspirin –Sodium salicylate Unapproved animal – cattle, swine, poultry (marketed) –Flunixin –Ketoprofen –Diclofenac –Phenylbutazone –Meloxicam –Carprofen 33

35. Pain Mitigation (from the literature) NSAIDs –Aspirin –Sodium salicylate –Flunixin Approved animal – horses, cattle, swine (marketed) –Ketoprofen –Diclofenac –Phenylbutazone –Meloxicam –Carprofen 34

36. Pain Mitigation (from the literature) NSAIDs –Aspirin –Sodium salicylate –Flunixin –Ketoprofen Approved animal – horses (marketed) –Diclofenac –Phenylbutazone –Meloxicam –Carprofen 35

37. Pain Mitigation (from the literature) NSAIDs –Aspirin –Sodium salicylate –Flunixin –Ketoprofen –Diclofenac –Phenylbutazone Approved animal – horses (marketed) –Meloxicam –Carprofen 36

38. Pain Mitigation (from the literature) Local anesthetics –Lidocaine –Mepivacine –Bupivacaine 37

39. Pain Mitigation (from the literature) Local anesthetics –Lidocaine Unapproved animal, injectable – cattle (marketed) Unapproved animal, topical (marketed) –Mepivacine –Bupivacaine 38

40. Pain Mitigation (from the literature) Barbiturates –Pentobarbital –Thiopental Acepromazine Benzodiazepines –Diazepam –Midazolam Azaperone Xylazine 39

41. Pain Mitigation (from the literature) Barbiturates –Pentobarbital –Thiopental Approved animal – dog, cats (not marketed) Acepromazine Benzodiazepines –Diazepam –Midazolam Azaperone Xylazine 40

42. Pain Mitigation (from the literature) Barbiturates –Pentobarbital –Thiopental Acepromazine Benzodiazepines –Diazepam Approved animal – dogs (not marketed) –Midazolam Azaperone Xylazine 41

43. Pain Mitigation (from the literature) Barbiturates –Pentobarbital –Thiopental Acepromazine Benzodiazepines –Diazepam –Midazolam No approved/marketed animal products Azaperone Xylazine 42

44. Pain Mitigation (from the literature) Barbiturates –Pentobarbital –Thiopental Acepromazine Benzodiazepines –Diazepam –Midazolam Azaperone –Approved animal – swine (not marketed) Xylazine 43

45. Pain Mitigation (from the literature) Barbiturates –Pentobarbital –Thiopental Acepromazine Benzodiazepines –Diazepam –Midazolam Azaperone Xylazine Approved animal drug – cats, dogs, horses, deer (marketed) 44

46. Pain Mitigation (from the literature) Butorphanol Medetomidine Ketamine Tiletamine-zolazepam (Telazol) Guaifenesin Tramadol Yohimbine 45

47. Pain Mitigation (from the literature) Butorphanol –Approved animal – dogs, cats, horses (marketed) Medetomidine Ketamine Tiletamine-zolazepam (Telazol) Guaifenesin Tramadol Yohimbine 46

48. Pain Mitigation (from the literature) Butorphanol Medetomidine Approved animal – dogs, cats (marketed) Ketamine Tiletamine-zolazepam (Telazol) Guaifenesin Tramadol Yohimbine 47

49. Pain Mitigation (from the literature) Butorphanol Medetomidine Ketamine Approved animal – cats, primates (marketed) Tiletamine-zolazepam (Telazol) Guaifenesin Tramadol Yohimbine 48

50. Pain Mitigation (from the literature) Halothane Isoflurane Propofol Guaifenesin Tramadol 49

51. Pain Mitigation (from the literature) Halothane Isoflurane –Approved animal – dogs, horses (marketed) Propofol Guaifenesin Tramadol 50

52. Under AMDUCA is extra-label use of analgesics and anesthetics permitted? 51

53. Under AMDUCA is extra-label use of analgesics and anesthetics permitted? 52 Yes

54. Is extra-label use of products restricted only to those products that have been approved by FDA and have an NADA or NDA number? 53

55. Is extra-label use of products restricted only to those products that have been approved by FDA and have an NADA or NDA number? Yes 54

56. Is extra-label use of products restricted only to those products that have been approved by FDA and have an NADA or NDA number? Yes (for the most part) 55

57. 56