U.S. Food and Drug Administration

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 It was current when produced, but is no longer maintained and may be outdated.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. FDA/CVM/OSC/DSAdverse Drug Experience Reporting System

3. Reviewers experience • 7/7 have between 8-22 years practice experience and hold current clinical licenses • 1/7 has large animal practice experience • 6/7 have companion animal and/or exotic experience • 6/7 still practice in local practices up to 20-hrs/week

4. Adverse Drug Experiences • Any adverse reaction that occurs when using a drug product • Can be mild (itching, sneezing) to severe (death) • Include ineffectiveness product defects human safety associated with handling animal drug products

5. Components of Modified Kramer System • Previous Experience (0, -1, +1) • Alternative Etiologic Candidate (-1, 0, +2) • Timing (-2, 0, +1) • Overdose (0, +1) • Dechallenge (-1, 0, +1) • Rechallenge (–1, 0, +1)

6. Interpretation of Range • -6 to -1 Remotely drug-related • 0 to +2 Possibly drug-related • +3 to +5 Probably drug-related • +6 to +7 Definitely drug-related

7. Sources of Information • Label of approved drug • CVM database • CVM Freedom of Information Summary • Textbooks • Journal articles

8. Sample Adverse Event Report • 4 year old neutered mixed breed dog • Good health on physical exam • Negative heartworm test • Received ProHeart 6 injection, labeled dose • Vomiting 8 days later

9. Initial ProHeart 6 Label • Vomiting • Diarrhea • Listlessness • Weight loss • Seizures • Injection site reaction • Fever

10. Previous Experience • For a score of +1 • The clinical manifestation is generally recognized to occur in this species at the dosage received (from label adverse reactions, or appearing in the STARS updated database more than 10% of the time, or in published veterinary literature). • For a score of 0 • The clinical manifestation is not generally recognized to occur in this species at the dosage received but has been previously reported in veterinary and/or human medicine or: • The drug has limited accumulated clinical experience (time and/or quantity marketed) • For a score of –1 • The clinical manifestation is previously unreported and the drug has substantial accumulated clinical experience (time and/or quantity marketed)

11. Alternative Etiologic Candidate • For a Score of +2 • There is no good candidate or no change in a candidate which can explain the clinical manifestation, exclusive of drug administration • For a score of 0 • An alternative candidate(s) exists, but not a good one(s) which can well explain the clinical manifestation or: • The clinical manifestation commonly occurs spontaneously in this type of patient and situation, usually in the absence of any recognizable alternative candidate(s) • For a score of –1 • There is a good candidate or a change in a candidate which can well explain the clinical manifestation, exclusive of drug administration. (usually identified by a DDX in the comments section of the final report)

12. Possible Contributing Factors for Vomiting • Changes in diet • Intestinal parasites • Previous history of vomiting • Abnormalities in other organs (liver, kidney, pancreas)

13. Helpful Information • Physical exam by veterinarian • Medical history • Medical evaluation • Veterinarian’s opinion • Follow Up information

14. Limited information • No known dietary changes • One negative stool exam for parasites • No blood work done

15. Timing of Events • For a score of +1 • Timing was consistent and as expected for this type of clinical manifestation to this drug • For a score of 0 • Do not know what timing to expect • For a score of –2 • The timing was inconsistent for this type of clinical manifestation to this drug

16. Evidence of Overdose • For a score of +1 • The clinical manifestation is clearly a dose-related type of manifestation, and there is unequivocal evidence that the amount of drug received was an overdose for this animal • For a score of 0 • The clinical manifestation is not a dose-related type of manifestation or there is no evidence of an overdose.

17. Dechallenge • For a Score of +1 • The clinical manifestation disappeared after discontinuation of the suspect drug or administration of a specific antidote • For a Score of 0 • Dechallenge difficult, impossible, or inappropriate to assess • A non-specific agent or maneuver (non-antidotal) was administered that was directed against the clinical manifestations and that usually produces the degree and rate of improvement observed in this case • The clinical manifestation is characteristically transient and episodic, and there is no established pattern of the episodes regardless of what occurs after discontinuing the drug • The clinical manifestation is known to be dose-related and the clinical manifestation did not diminish or disappear after the dosage was reduced • For a Score of -1 • The clinical manifestation did not diminish or disappear after discontinuation of suspect drug • The clinical manifestation improved without Dechallenge and the improvement cannot be attributed to the development of tolerance

18. Rechallenge • For a score of +1 • The clinical manifestation unequivocally recurred or exacerbated after Rechallenge • For a score of 0 • There was no Rechallenge attempted • The clinical manifestation failed to recur or exacerbate on Rechallenge, but the dosage or duration of drug administration on Rechallenge was substantially less than that suspected of causing the original clinical manifestation • Recurrence or exacerbation of the clinical manifestation was impossible to assess because it was progressing or was at a level of severity that any further increase would be difficult to appreciate • For a score of –1 • The clinical manifestation failed to recur or exacerbate on Rechallenge

19. Applied Modified Kramer Algorithm (Vomiting) • Previous Experience: +1 • Alternative Etiologic Candidate: 0 • Timing: +1 • Overdose: 0 • Dechallenge: 0 • Rechallenge: 0 Total Score: +2 “Possibly Drug Related”

20. Anaphylaxis/Anaphylactoid Reactions • Sudden profuse vomiting/diarrhea • Swollen head/face • Hives • Pallor of mucous membranes • Collapse

21. Sample Adverse Event Report for Anaphylaxis • 3 year old spayed female Miniature Schnauzer • Good health on physical exam • Negative heartworm test • Received ProHeart 6 injection (labeled dose) and annual distemper vaccination • 2 hours later – hives, swollen face, collapse

22. Applied Modified Kramer Algorithm (Anaphylaxis) • Previous Experience: 0 • Alternative Etiologic Candidate: -1 • Timing: +1 • Overdose: 0 • Dechallenge: 0 • Rechallenge: 0 • Total Score: 0 “Possibly Drug Related”

23. Applied Modified Kramer Algorithm (Anaphylaxis) • Previous Experience: 0 • Alternative Etiologic Candidate: 0 • Timing: +1 • Overdose: 0 • Dechallenge: 0 • Rechallenge: 0 Total Score: +1 “Possibly Drug Related”

24. Applied Modified Kramer Algorithm (Anaphylaxis) • Previous Experience: +1 • Alternative Etiologic Candidate: +2 • Timing: +1 • Overdose: 0 • Dechallenge: 0 • Rechallenge: 0 Total Score: +4 “Probably Drug Related”

25. Causality Assessment Scores for ProHeart 6 • Overdose – seldom given, as product is injected by a health professional • Dechallenge - can’t be evaluated, as product remains in body for six months • Rechallenge - rarely given again if a reaction was recognized after first administration • Thus total score can only reach 4, rather than 6 for other drugs.