Proheart ADE

Document Sample
Proheart ADE Powered By Docstoc
					ProHeart 6 Adverse Drug Events:
          An Overview
       VMAC ProHeart 6 Meeting
           January 31, 2005
        Lynn O. Post DVM, PhD
              FDA/CVM
Evaluation of Adverse Drug Events

   Observational Studies
       Advantages
          Larger and more diverse population

          Actual conditions of use

       Disadvantages
          Confounding  factors
          No well defined control group
                Reporting Rate
   Reporting rate
     Numerator =   total number of spontaneously reported ADEs
     Denominator            number of exposed patients
    ADE reporting rate is not an incidence
    rate
       ADEs are substantially under-reported
        (numerator).
       Accurate data on the number of exposed
        patients (denominator) is often lacking.
            Reporting Rate Cont.

    A high reporting rate compared to the
    background incidence rate may signal a
    problem with a product.
       Because of under-reporting, the fact that a
        reporting rate is less than the background
        rate does not necessarily mean that the
        product in not associated with an increased
        risk of an adverse event.
       Pre-approval History PH 6
   Approved under NADA 141-189 in June of 2001
   Laboratory Studies
      No serious adverse drug events in healthy
       dogs
     Clinical field studies
      Vomiting, diarrhea, listlessness, weight loss,
       seizures, injection site pruritus, and increased
       body temperature
Pre-approval History PH 6 Cont.

   The death of 3 dogs (2 geriatric dogs and
    1 dog with a history of health problems)
    resulted in the following PRECAUTION
    statement on the label:
       Use with caution in sick, debilitated or
        underweight animals.
     Macrocyclic Lactone Toxicity
   Macrocyclic lactone toxicity in mammals
       Ivermectin, milbemycin oxime, and selamectin
       Toxic Signs
          Dilated pupils, vomiting, diarrhea, salivation,
           disorientation, lack of coordination, muscle
           twitching, tremors, depression, coma, and
           blindness.
          Severe reactions can involve other neurologic signs
           such as seizures which have been added to the
           post-approval safety information on several
           macrocyclic lactone labels
        Post Approval History PH 6

   Three label changes
       June 13, 2002, added reported clinical
        manifestations of: anaphylaxis/anaphylactoid
        reactions, depression/lethargy, urticaria, and
        head/facial edema.
       November 5, 2002, added cardiopulmonary
        signs associated with administration of the
        product in heartworm positive dogs
    Post Approval History Cont.
   July 15, 2003, added a Client Information
    Sheet and the phrase “and rare reports of
    death”
   Two “Dear Doctor” Letters describing the
    three label changes (June 2002 and June
    2003)
Annual Number of ProHeart 6 ADE
   Reports Received by CVM
                              Initial   Follow-up    Total
         Period
                             reports     reports    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
Frequency of Initial and Follow-up
      ProHeart 6 Reports
                                          14
      Average Number of Reports per Day

                                                                                         Initial ADE Reports
                                          12                                             Follow-up ADE Reports
                                                                                         Total ADE Reports       *
                                          10

                                           8

                                           6

                                           4

                                           2

                                           0                       Manufacturing Changes             MRS Lots
                                           20 Q3

                                           20 Q4

                                           20 Q1

                                           20 Q2

                                           20 Q3

                                           20 Q4

                                           20 Q1

                                           20 Q2

                                           20 Q3

                                           20 Q4

                                           20 Q1

                                           20 Q2

                                                  3
                                                Q
                                             01

                                             01

                                             02

                                             02

                                             02

                                             02

                                             03

                                             03

                                             03

                                             03

                                             04

                                             04

                                             04
                                           20




                                                                      Calendar Year and Quarter
                                               *2004 Q3 = first 62 days of the 3rd quarter
       Causality Assessments for
       All Clinical Manifestations
        Reported as PH 6 ADE’s
Causality Assessment                      Number of Assessments
Category*
Definitely drug-related                                32**
Probably drug-related                                  4310
Possibly drug-related                                  15334
Remotely drug-related                                  2026
Information Lacking                                     183
Total                                                  21885
*possibly, probably and definitely = positive causality (19676)
**clinical manifestations that were considered definitely drug-related; all
had causality assessment scores of +6 for heartworm ineffect
PH 6 Time of Onset*: Number of
     Causality Assessments
               0
               0
               10
                0
               0
               90
                0                W on9
                                  iCi t 8
                                  t o ts 5
                                  h ca
                                     nm =6
                                  io n t t 3
                                  t u ca
                                  h
                                 Wo in6
                                    tC m  =6
                                      o s 1
               0
               80
                0                U n ca 2
                                  n C in 7
                                  k o tt
                                   n n
                                   ow o s 6
                                       m  =7
                               T ai A m1
                               o u s e 8
                               t Ct s n 9
                                as
                                l  ly s s 3
                                       s =9
                                   a e t
               0
               70
                0
               0
               60
                0
               0
               50
                0
               0
               40
                0
               0
               30
                0
CauslityAsesments

               0
               20
                0
               0
               10
                0
                0
                                      <1



                                   >90
                             1to<3
                             3to<7
                    14to<4
                         7to<1
                    30to<30
                         90
                         ie s a
                         m ey
                          o t s
                           O ( )
                         T fnD
 *For those with known time of onset; causality ≥ 0
Moxidectin Mean Serum Concentration
     Following a Single Injection
     Moxidectin Mean Serum   6
      Concentration (g/L)
                             5

                             4

                             3

                             2

                             1
                                 0   5   10   15   20   25   30
                                          Days
             Number of Dogs
           with Reported ADEs*
Monthly and 6 Month            Number of Dogs
                                                      Number of Dogs
Heartworm Preventives           Approval to
                                                      9/6/01 to 9/1/04
(Year of Initial Approval)        9/1/04
Ivermectin Products (1987)           5667                   4646

Milbemycin Products (1990)           3243                   2273

Selamectin (1999)                    9719                   7681
Moxidectin Tablets (1997)
                                      12                      1
(ProHeart)
Moxidectin Sustained
Release (2001)                       5659                   5659
(ProHeart 6)
*including “ineffect” for heartworms, hookworms, roundworms, fleas, ticks,
and mites; causality ≥ 0
      Number of Dog Deaths*
Monthly and 6 Month
                             Number of Deaths     Number of Deaths
Heartworm Preventives
                             Approval to 9/1/04    6/6/01 to 9/1/04
(Year of Initial Approval)

Ivermectin Products (1987)          133                  50

Milbemycin Products (1990)          131                  59
Selamectin (1999)                   171                 110
Moxidectin Tablets (1997)
                                     0                   0
(ProHeart)
Moxidectin Sustained
Release (2001)                      485                 485
(ProHeart 6)

*causality assessment ≥ 0

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:6
posted:11/1/2011
language:English
pages:16