TABLE OF CONTENTS
NAPHYLAXIS/ANAPHYLACTOID REACTIONS................................................................ 22
C
ONVULSIONS................................................................................................................ 24
L
IVER SIGNS................................................................................................................... 26
H
EMATOLOGIC SIGNS.................. endobj
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Table 1. Number of dogs with reported ADEs* that are possibly, probably, or definitely
related to the use of marketed monthly or 6-month heartworm preventives.
Heartworm Preventive
Year of Initial Approval
Number of Dogs, Approval to September 1, 2004 Number of Dogs,
June 1, 2001 to September 1, 2004
Ivermectin and
Ivermectin/Pyrantel
(all products)
1987 5667 4646
Milbemycin and
Milbemycin/Lufenuron 1990 3243 2273
Selamectin
1999 9719 7681
Moxidectin Tablets
(ProHeart) 1997 12 1
Moxidectin Sustained
Release (ProHeart 6) 2001 5659 5659
*including ineffect for heartworms, hookworms, roundworms, fleas, ticks, and
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(thrombocytopenia), and immune-mediated hemolytic anemia (IMHA) were considerably higher for ProHeart 6 than for other heartworm preventives. The number of convulsions in dogs receiving selemectin was high between 2001 and 2002 but has been declining
since the warning not to use this product in sick, debilitated or underweight animals was placed on the label in 2002. The numbers of hematologic and liver signs also decreased for selamectin.
Table 4. Number of causality assessments for certain reported clinical manifestations that are possibly, probably, or definitely related to the use of marketed monthly or 6-month heartworm preventives, from approval to September 1, 2004.
Heartworm Preventive
(year of initial approval)
Anaphylaxis/
Anaphylactoid Reactions Convulsions SGPT/ALT Elevations Liver Lesions Low Platelets IMHA
Ivermectin and
Ivermectin/Pyrantel (all products) (1987) 16 131 38 9 10 20
Milbemycin and
Milbemycin/Lufenuron
(1990) 36 194 38 8 26 16
Selamectin (1999) 45 304 69 13 50 15
Moxidectin Tablets
(Proheart) (1997) 0 1 0 0 0 0
Moxidectin Sustained
Release (ProHeart 6) (2001) 1820 378 192 65 124 67
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Table 5. Number of causality assessments for certain reported clinical manifestations that are possibly, probably, or definitely related to the use of marketed monthly or 6-month heartworm preventives, June 1, 2001 to September 1, 2004.
Heartworm
Preventive
Anaphylaxis/
Anaphylactoid Reactions Convulsions SGPT/ALT elevations Liver lesions Low Platelets IMHA
Ivermectin and
Ivermectin/Pyrantel (all products) 13 69 10 2 5 8
Milbemycin and
Milbemycin/Lufenuron
20 107 26 5 10 9
Selamectin 37 234 45 8 30 8
Moxidectin Tablets
(ProHeart) 0 0 0 0 0 0
Moxidectin Sustained
Release (ProHeart 6) 1820 378 192 65 124 67
ProHeart 6 ADEs Between June 6, 2001 and September 1, 2004, ProHeart 6 ADEs were reported for 6015 dogs (all causality assessment categories). There were 21,885 causality assessments conducted for clinical manifestations reported among these dogs. Table 6 shows the number of assessments by causality assessment category. There were 19,676 assessments for clinical manifestations determined by CVM to be possibly, probably, or definitely related to the administration of ProHeart 6 (Table 6). These assessments were for clinical manifestations in 5659 dogs (Table 1).
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Table 7. Number of causality assessments by time of onset* and concomitant drug/vaccine status for reported clinical manifestations that are possibly, probably or definitely related to the use of ProHeart 6, June 6, 2001 to September 1, 2004.
Time of Onset
Total
Causality
Assessments
Assessments with
Concomitant Drugs and/or Vaccines
Assessments without
Concomitant Drugs or Vaccines
<3 hours 6613 (34.9%) 2710 (27.5%) 3043 (48.2%)
3 to < 24 hours 2546 (13.4%) 1291 (13.1%) 877 (13.9%)
1 to <3 days 2296 (12.1%) 1279 (13.0%) 660 (10.4%)
3 to <7 days 2178 (11.5%) 1399 (14.2%) 515 (8.2%)
7 to <14 days 1962 (10.4%) 1301 (12.2%) 370 (5.9%)
14 to <30 days 1395 (7.4%) 839 (8.5%) 332 (5.3%)
1 to <3 months 1291 (6.8%) 715 (7.3%) 354 (5.6%)
>3 months 658 (3.5%) 322 (3.3%) 165 (2.6%)
Total* 18939 9856 6316
*For those with known time of onset
Includes causality assessments for dogs that had concomitant drugs and/or vaccines, dogs that did not have concomitant drugs or vaccines, and dogs with unknown concomitant drug/vaccine status
The majority of clinical manifestations occurred between 0 and 14 days, when there were rising or peak serum moxidectin levels. Some dogs had no adverse events on initial dosing but did after subsequent doses. CVM encouraged the sponsor to investigate whether the drug could be causing hypersensitivity reactions. Hypersensitivity reactions occur when there is an exaggerated immune response to a foreign substance. Anaphylaxis is one type of hypersensitivity reaction. Preliminary results from studies investigating the possible association between ProHeart 6 and hypersensitivity reactions wer endobj
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Trends in ProHeart 6 ADE Reporting
CVM tracks the number of incoming original and follow-up ADE reports as well as severity of reported ADE s. Often, severe ADE s will have follow-up reports. Figure 2 shows the mean number of initial and follow-up ProHeart 6 ADE reports received per day at CVM by calendar quarter (90 to 92 day quarter).
Data for the third quarter of
2004 represents the mean number of ADE reports per day across the first 62 days of the quarter. The reporting pattern has remained similar each year, with a peak in the second quarter, coinciding with start of heartworm prevention season (Figure 2).
Figure 2.
Mean number of initial and follow-up ProHeart 6 reports received by CVM day,
by calendar quarter*.
*Data for the third quarter of 2004 represents the mean number of reports per day across the first 62 days of the quarter
The annual reporting period for a product is based on its approval date, not the calendar year. Table 8 shows the annual number of initial and follow-up ProHeart 6
ADE reports received by CVM from July 1, 2001 to June 30, 2004. The table shows that the annual number of initial ProHeart 6 ADE reports has not decreased over time.
Calendar Year and Quarter
2001 Q3
2001 Q42002 Q12002 Q22002 Q32002 Q42003 Q12003 Q22003 Q32003 Q42004 Q12004 Q22004 Q3
Average Number of Reports per Day
0
24
6
810
12
14
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Table 8. Number of ProHeart 6 ADE reports received by CVM, by year (July 1, 2001 to June 30, 2004). Period Initial reports Follow-up reports Total reports
July 1, 2001-June 30, 2002 1719 546 2265
July 1, 2002-June 30, 2003 1905 838 2743
July 1, 2003-June 30, 2004 1763 1076 2839
Table 9 shows the number of assessments over time for anaphylaxis/anaphylactoid reactions, convulsions, elevated SGPT/ALT, liver lesions, low platelets, and immune-mediated hemolytic anemias (IMHA) that were possibly or probably related to ProHeart 6 administration. The annual number of assessments for anaphylaxis/anaphylactoid reactions decreased, but still remained relatively high in 2003-2004. The number of assessments for convulsions ranged between 110 and 126 annually.
Assessments for the other clinical manifestations shown in Table 10 have increased over time. The clinical manifestations shown in Table 9 are described in more detail in the next section.
Table 9. Number of causality assessments for certain reported clinical manifestations that are possibly or probably related to the use of ProHeart 6, by year (July 1, 2001 to June 30, 2004).
Period
Anaphylaxis/
Anaphylactoid Reactions Convulsions SGPT/ALT Elevation Liver Lesions Low Platelets IMHA
July 1, 2001 -
June 30, 2002 704 110 34 9 26 14
July 1, 2002 -
June 30, 2003 544 126 52 15 28 24
July 1, 2003 -
June 30, 2004
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Table
10 shows by year the number of dogs with ADEs that were possibly,
probably, or definitely related to ProHeart 6 and the number of dog deaths that were possibly or probably related to ProHeart 6 by year. A label revision, which was approved on July 15, 2003, required the sponsor to add and rare reports of death to the post approval experience section of the product label and to send a Dear Doctor Letter. Despite these changes, the number of reported deaths, possibly or probably related to ProHeart, 6 increased each year since the product was marketed (Table 10). In addition, the number of dogs with heartworm infections that were possibly, probably, or definitely related to the ineffectiveness of ProHeart 6 also increased (Table 11).
Table 10. Number of dogs with reported ADEs that are possibly, probably, or definitely
related to ProHeart 6 and number of reported dog deaths that are possibly or probably
related to ProHeart 6, by year (July 1, 2001 to June 30, 2004).
Period Number of Dogs Number of Deaths
July 1, 2001 - June 30, 2002 1896 112
July 1 2002 - June 30, 2003 1814 148
July 1 2003 - June 30, 2004 1640 185
Table 11. Number of dogs with reported heartworm infections that are possibly, probably,
or definitely related to the ineffectiveness of ProHeart 6, by year (July 1, 2001 to June 30, 2004).
Period Number of Dogs
July 1, 2001 - June 30, 2002 8
J endobj
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poor (3). The health status of dogs in the remaining 7 episodes is not known. In 816 episodes, dogs did not have concomitant drugs or vaccines and in 731 episodes, dogs had
concomitant drugs and/or vaccines. The concomitant status for dogs in 273 episodes is not known.
Table
13 shows the number of anaphylaxis/anaphylactoid reaction assessments by time of onset. Eighty (80) percent of the episodes occurred within 3 hours of ProHeart 6 administration. Among the 1837 dogs involved in the 1820 episodes, there were at least 54 deaths that were possibly or probably related to ProHeart 6.
Table 13. Number of assessments by time of onset for anaphylaxis/ anaphylactoid reactions possibly or probably related to ProHeart 6 administration, June 6, 2001 to September 1,
2004.
Time of Onset Number of Assessments
< 15 minutes 374 (20.5%)
15 minutes to <1 hour 575 (31.6%)
1 to <3 hours 508 (27.9%)
3 to < 24 hours 296 (16.3%)
1 to <3 days 37 (2.0%)
3 to <7 days 8 (0.4%)
7 to <14 days 14 (0.8%)
14 to <30 days 3 (0.2%)
>1 month 1 (0.1%)
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Table 15. Number of assessments by time of onset for convulsions possibly or probably related to ProHeart 6 administration, June 6, 2001 to September 1, 2004.
Time of Onset Number of Assessments
<3 hours 62 (16.4%)
3 to <24 hours 51 (13.5%)
1 to <3 days 74 (19.6%)
3 to <7 days 66 (17.5%)
7 to <14 days 43 (11.4%)
14 to <30 days 31 (8.2%)
1 to <3 months 29 (7.7%)
>3 months 13 (3.4%)
Unknown 9 (2.4%)
Total 378
There were more episodes with convulsions during the period of June 1, 2001 to September 1, 2004 for ProHeart 6 (Table 5) than for ivermectin products, for milbemycin products, or for selamectin products since their approvals (Table 4). The clinical manifestation convulsions was the most commonly reported neurologic sign among dogs treated with ProHeart 6. However, there were an additional 484 dogs with other types of neurologic signs that were possibly or probably related to ProHeart 6. Other neurologic signs reported include, but are not limited to ataxia, trembling, nervousness, confusion, and paresis.
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in 192 dogs. There were at least 38 deaths among the dogs that were possibly or probably related to ProHeart 6.
Table 17. Number of assessments by time of onset for SGPT/ALT elevations possibly or
probably related to ProHeart 6 administration, June 6, 2001 to September 1, 2004.
Time of Onset Number of Assessments
<3 hours 11 (5.7%)
3 to <24 hours 11 (5.7%)
1 to <3 days 31 (16.1%)
3 to <7 days 40 (20.8%)
7 to <14 days 41 (21.4%)
14 to <30 days 26 (13.5%)
1 to <3 months 16 (8.3%)
>3 months 13 (6.8%)
Unknown 3 (1.6%)
Total 192
Liver Lesions Table 18 shows the number of assessments, by causality assessment category, for
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Table 19. Number of assessments by time of onset for liver lesions possibly related to ProHeart 6 administration, June 6, 2001 to September 1, 2004.
Time of Onset Number of Assessments
<3 hours 2 (3.1%)
3 to <24 hours 7 (10.8%)
1 to <3 days 8 (12.3%)
3 to <7 days 5 (7.7%)
7 to <14 days 10 (15.4%)
14 to <30 days 9 (13.8%)
1 to <3 months 15 (23.1%)
>3 months 8 (12.3%)
Unknown 1 (1.5%)
Total 65
There were more assessments for SGPT/ALT elevations and liver lesions for
ProHeart 6 in the period June 1, 2001 to September 1, 2004 (Table 5) than there were for all monthly heartworm preventives combined for all marketing years (Table 4).
Furthermore, Table 9 shows that the number of assessments for these two signs have increased over time for ProHeart 6. Hematologic Signs
Several hematologic signs (clinical manifestations) were reported as ADEs for ProHeart 6. There were 551 dogs with hematologic signs possibly or probably related to ProHeart 6. An endobj
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Time of Onset Number of Assessments
<24 hours 2 (3.0%)
1 to <3 days 2 (3.0%)
3 to <7 days 6 (9.0%)
7 to <14 days 15 (22.4%)
14 to <30 days 18 (26.9%)
1 to <3 months 18 (26.9%)
>3 months 6 (9.0%)
Unknown 0
Total 67
Thrombocytopenia Thrombocytopenia refers to a low platelet count. In dogs, thrombocytopenia is frequently caused by the destruction of platelets by an immune response (immune-mediated thrombocytopenia).
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Table 22 shows the number of assessments, by causality assessment category, for thrombocytopenia reported in dogs following the administration of ProHeart 6. There were 135 reported episodes with thrombocytopenia following ProHeart 6 administration.
CVM determined that the majority were possi
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Table 23. Number of assessments by time of onset for thrombocytopenia possibly or probably related to ProHeart 6 administration, June 6, 2001 to September 1, 2004.
Time of Onset Number of Assessments
<24 hours 2 (1.6%)
1 to <3 days 11 (8.9%)
3 to <7 days 25 (20.2%)
7 to <14 days 29 (23.4%)
14 to <30 days 24 (19.4%)
1 to <3 months 23 (18.5%)
>3 months 8 (6.5%)
Unknown 2 (1.6%)
Total 124
There were more assessments for IMHA and thrombocytopenia for ProHeart 6 in the period June 1, 2001 to September 1, 2004 (Table 6) than there were for all monthly heartworm preventives combined for all marketing years (Table 5).
Table 9 shows that
the number of assessments for low platelets has increased over time for ProHeart 6. Conclusions CVM has the responsibility for ensuring the safety of animal drugs. The sponsor of an animal drug product has the responsibility to demonstrate that the product is safe and effective prior to approval. Prior to their approval, new animal drugs are subject to studies to establish their safety and effectiveness under the labeled conditions of use. Most of the common adverse events may become known prior to approval. CVM has a post-approval monitoring system to detect adverse drug events that occur after marketing, i.e., when an animal drug is used in a larger and more diverse population. If CVM determines that a marketed anim
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15.
NADA 141189 Freedom of Information Summary, Center for Veterinary Medicine 7915 Standish Pl., Rockville, MD 20855. 16. Label File; NADA 141-189, CVM DS/ FDA/CVM 7519 Standish Pl., 20855. 17. Warning Letter from Charles Sedgwick, Kansas City District FDA Office to Tom Corcoran March 31, 2004. Web version at:
http://www.fda.gov/foi/warning_letters/g4602d.pdf. Accession date 10/31/04
18. Recall Enforcement Report 6/9/04. http://www.fda.gov/bbs/topics/enforce/2004/ENF00851.html. Accession date 10/31/-
4
19. Recall Enforcement Report 7/21/04. http://www.fda.gov/bbs/topics/enforce/2004/ENF00857.html. Accession date
10/31/04
20. Keck G and Ibrahim C. Veterinary Pharmacovigilance: between regulation and science. J Vet Pharmacol and Therapeutics 2001;24:369-373. 21. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA 1999;281(9): 824-829. 22. Telememo in CVM records from Martine Hartogensis to Fort Dodge Animal Health. April 10, 2003. 23. Telememo in CVM records from Martine Hartogensis to Fort Dodge Animal Health March 13 &14, 2002. 24. Telememo in CVM records from Martine Hartogensis to Fort Dodge Animal Health. April 24 & 30, 2002. 25. Hutchinson TA, Leventhal JM, Kramer MS, et al. An algorithm for the operational assessment of adverse drug reactions. I. Background, description and instructions for use. JAMA1979;242(7):623-632. 26. Hutchinson TA, Leventhal JM, Kramer MS, et al. An algorithm for the operational assessment of adverse drug reactions. II. Demonstration of reproducibility and validity. JAMA 1979;242(7):633-638.
27. World Health Organization. The importance of pharmacovigilance: safety monitoring of medicinal products. 2002.
http://www.who.int/medicines/library/qsm/ip_booklet.pdf
28. Rodriquez EM, Staffa JA, Graham DJ.
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Appendix B. Approved Monthly and 6-Month Heartworm Preventives
Product
Name Active Ingredient(s) Route of Administration Indications for Dogs NADA/ANADA Approval Date
Heartgard Ivermectin Oral
For use in dogs to prevent canine heartworm disease. Heartgard prevents heartworm disease by eliminating the tissue stage of heartworm larvae (Dirofilaria immitis) for a month (30 days) after infection. 138-412 4/7/1987
Heartgard
Chewables Ivermectin Oral For use in dogs to prevent canine heartworm disease by eliminating the tissue stage of heartworm larvae (Dirofilaria immits) for one month (30 days) after infection . 140-886 8/9/1989
Heartgard
Plus Ivermectin and Pyrantel Pamoate Oral For use in dogs to prevent canine heartworm disease by eliminating the tissue stage of heartworm larvae (Dirofilaria immits) for one month (30 days) after infection andfor the treatment and control of ascarids (Toxocara canis, Toxascaris leonina) and hookworms (Ancylostoma caninum, Uncinaria stenocephala, Ancylostoma braziliense). 140-971 1/15/1993
Advantage
Duo Ivermectin and Imidacloprid Oral Advantage DUO (imidacloprid/ivermectin) is indicated for the prevention of heartworm disease caused by Dirofilaria immitis, kills adult fleas and is indicated for the treatment of flea infestations (Ctenocephalides felis). Advantqge DUO is recommended for dogs eight weeks of age or older. 141-208 9/27/2002
Iverhart Ivermectin
Oral For use in dogs to prevent canine heartworm disease. IVERHART tablets prevent heartworm disease by eliminating the tissue stage of
heartworm larvae (Dirofilaria immitis) for one month (30 days) after infection. 200-270 11/30/2001
Ivermectin
Chewable Tablet endobj
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Product
Name Active Ingredient(s) Route of AdministrationIndications for Dogs NADA/ANADA Approval Date
Iverhart
Plus Ivermectin and Pyrantel Pamoate Oral For use in dogs to prevent canine heartworm diseases by eliminating the tissue stage of heartworm larvae (Dirofilaria immitis) for a month (30 days) after infection and for the treatment and control of ascarids
(Toxocara canis, Toxascaris leonina) and hookworms (Ancylostoma caninum, Uncinaria stenocephala Ancylostoma braziliense). 200-302 5/30/2001
Tri-Heart
Plus Ivermectin and Pyrantel Pamoate Oral For use in dogs to prevent canine heartworm diseases by eliminating the tissue stage of heartworm larvae (Dirofilaria immitis) for a month (30 days) after infection and for the treatment and control of ascarids
(Toxocara canis, Toxascaris leonine) and hookworms (Ancylostoma caninum, Uncinaria stenocephala, Ancylostoma brazilense). 200-338 8/13/2003
Interceptor
Milbemycin Oxime Oral INTERCEPTOR Flavor Tabs are indicated for use in the prevention
of heartworm disease caused by Dirofilaria immitis, the control of adult Ancylostoma caninum (hookworm), and the removal and control of adult Toxocara canis and Toxascaris leonina (roundworms) and Trichuris vulpis (whilpworm) infections in dogs and puppies four weeks of age or greater and two pounds of body
weight or greater.
140-915 6/14/1990
Sentinel
Milbemycin Oxime and Lufenuron Oral
SENTINEL Flavor Tabs are indicated for use in dogs and puppies,
four weeks of age or older, and two pounds of body weight or greater for the prevention of heartworm disease caused by Dirofilaria immitis, for the prevention and control of flea populations, the control of adult Ancylostoma caninum (hookworm), and the removal and control of adult Toxocara canis, and
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Appendix C. ProHeart 6 Label, May 2003
(note, if difficulty viewing click view on the tools menu and then click print layout .
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