20370UMC Poster_040622_2 by liaoxiuli

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									                                              BISPHOSPHONATES AND
                                               OCULAR SIDE EFFECTS
                                                                 A K Kiuru¹, F W Fraunfelder², I R Edwards¹
                                       1. The Uppsala Monitoring Centre, Uppsala, Sweden. 2. The Casey Eye Institute, Portland, OR, USA



                        BACKGROUND                                             Table A. Vision disorder adverse reaction terms reported with bisphosphonates                                 neoplasms… 1 (8), Second malignant neoplasm of bone and
                                                                                                                       Alen    Clo     Eti     Iba      Me     Pami Rise       Tilu   Zole   bone marrow 2 (7) and single reports of Paget’s disease of bone
Pharmacovigilance, including the monitoring of benefits and                   ACCOMMODATION ABNORMAL                   2                       1                                             unspecified, Osteopenia, Osteomyelitis unspecified, Metastases to
risks of therapeutic drugs, has grown to become a field of great              BLEPHARITIS                              2                                               2
                                                                                                                                                                                             bone and Disorders resulting from impaired renal function,
importance and the WHO Programme for International Drug                       BLINDNESS                                14      1       1                       4       6
                                                                              BLINDNESS TEMPORARY                      3               1                                                     other. Time to onset varied from a couple of days to several
Monitoring provides a forum for WHO member states to                          CATARACT                                 11              4                       3       4              1      months for all the drugs.
collaborate in this field. The WHO Collaborating Centre for                   CONJUNCTIVITIS                           46      1       3       1        1      32      11             9
International Drug Monitoring (the Uppsala Monitoring Centre)                 CONJUNCTIVITIS AGGRAVATED                                                                1

holds the world’s largest database, the WHO Adverse Drug                      CORNEAL DEPOSITS                                                                         1                                                    DISCUSSION
                                                                              CORNEAL DISORDER                         1
Reaction (ADR) database, Vigibase, of spontaneously suspected                 CORNEAL OEDEMA                           1                                       1                             The WHO ADR database is not homogenous, at least with
ADRs. Vigibase contains over 3 000 000 case reports and is                    CORNEAL OPACITY                          2               1                                                     respect to origin or likelihood that the pharmaceutical product
                                                                              CORNEAL ULCERATION                       1               1                       2       1                     caused the adverse reaction, so it is difficult to get a clear picture
continuously datamined in order to detect early signals of                    DIPLOPIA                                 17              2                       5       3              2
possible ADR problems. A large number of reports accumulated                  EXOPHTHALMOS                                                                     3
                                                                                                                                                                                             of the reported truth. Many factors, such as time marketed,
in Vigibase led to the suspicion that bisphosphonates might cause             EYE ABNORMALITY                          10                                      6       2                     exposure data, different potencies, dosage and varying indications
                                                                              EYE INFECTION                            2                                       1                             can influence the reporting rates of adverse effects in spontaneous
serious visual side effects. Bisphosphonates are used in e.g.
                                                                              EYE MUSCLE PARALYSIS                                                                                    1
osteolytic bone cancer, multiple myeloma, and osteoporosis.i                  EYE PAIN                                 40              1                       7       8              3
                                                                                                                                                                                             reporting systems.
                                                                              GLAUCOMA                                 18              1                               3              1

                            METHODS                                           HYPOPYON
                                                                              IRIDOCYCLITIS
                                                                                                                       1
                                                                                                                       1
                                                                                                                                                               1
                                                                                                                                                                       1
                                                                                                                                                                                             The US National Registry database is at the Casey Eye Institute
Case reports belonging to the System Organ Class (SOC) ‘Vision                IRITIS                                   13                                      8       6
                                                                                                                                                                                             in Portland, Oregon (www.eyedrugregistry.com). The clinical
disorders’ from the WHO Adverse Reaction Terminology                          KERATITIS                                4                                               3                     review of reports in Vigibase, together with knowledge from
(WHO-ART) and the Anatomical Therapeutic Chemical (ATC)
                                                                              KERATOCONJUNCTIVITIS                                     1                                                     observational case series of collected spontaneous reports
                                                                              LACRIMAL DUCT OBSTRUCTION                1
classification code M05BA ‘Bisphosphonates’ were studied.                     LACRIMATION ABNORMAL                     14              2                       2       1
                                                                                                                                                                                             performed by the Casey Eye Institute, indicate rare but serious
Clinical review of the individual case reports was performed and              MACULA LUTEA DEGENERATION                5                                       2       1       1             ocular complications can occur with bisphosphonate treatment.iv
                                                                              MACULAR OEDEMA                           1                                       1
the issue was signalled in December 2003.ii Additional cases                  MIOSIS                                           1                               1
reported since then have also been investigated.                              MUSCAE VOLITANTES                        4                                               1
                                                                                                                                                                                             In our data, most of the clinically significant adverse ocular
                                                                              MYDRIASIS                                4       1                                                      1      reactions are ocular inflammation i.e. conjunctivitis, uveitis,
                                                                              MYOPIA                                                                                   1                     episcleritis. The first published “certain” case with rechallenge
                              RESULTS                                         PAPILLOEDEMA                             1                                               1              1
                                                                                                                                                                                             data was a patient with scleritis.v A possible mechanism behind
                                                                              PHOTOPHOBIA                              4       1                               6                      1
A compilation of terms within ‘Vision disorders’ (total number                PHOTOPSIA                                5               1                       1       1       1             these ocular problems could be the inherent chemical structure of
of reports 550) reported with bisphosphonates from 20 National                RETINAL DETACHMENT                       4               1                               1                     the different bisphosphonates.iv
Centres to Vigibase (until May 2004) can be found in table A.                 RETINAL DISORDER                         9               2                       2       1
                                                                              SCLERITIS                                4                                       9       2
Overall, most of the clinically significant reactions reported are            STRABISMUS                               1                                                                     The female predominance of the patients is expected since it is
ocular inflammation, such as conjunctivitis and uveitis,                      UVEITIS                                  20                                      21      2              3      only recently that bisphosphonates have been indicated for the
episcleritis and scleritis. Vigibase now also contains 172 case               VISION ABNORMAL                          120     6       18      2        1      24      17             4
                                                                                                                                                                                             treatment of osteoporosis in males. Fourteen of the critical term
                                                                              VITREOUS DETACHMENT                      6
reports from 15 countries on critical terms within the SOC                    VITREOUS DISORDER NOS                                         2                  1                             reports had co-suspected drugs listed, but only five of these drugs
‘Vision disorders’: blindness, blindness temporary, cataract,                 Total no. of Vision disorder reports     320 11          34   4           2      102 58    2            19     had some ocular side effects reported in literature (seriousness
cataract sub capsular, corneal opacity, corneal ulceration,                   Total no. of reports                     12244 409       1122 34          56     1363 1083 37           574
                                                                                                                                                                                             varied from blurred vision to cataract).
                                                                              % (Vision/Total)                         2.6   2.7       3.0  11.8        3.6    7.5  5.4  5.4          3.3
glaucoma, keratitis, keratoconjunctivitis, macula lutea
degeneration, papilloedema, retinal detachment, retinal disorder,                Alen = alendronic acid, Clo = clodronic acid, Eti = etidronic acid, Iba = ibandronic acid, Me = medronic
                                                                                 acid, Pami = pamidronic acid, Rise = risedronic acid, Tilu = tiludronic acid, Zole = zoledronic acid        It is difficult to determine if this is indeed a group effect, but it
retinitis, scleritis, uveitis and vitreous detachment. All results below                                                                                                                     appears ocular inflammation can occur when any member of this
                                                                                      Critical term case reports
are listed as number of critical reports and the total number of                                                                                                                             class of medicine is used. Some of these problems have already
reports, with a vision term listed, in brackets: critical (total).             Age and gender                                                                                                been recognized and published by some National Centres within
Number of critical term reports per country                                     Age                Number of patients                  Gender               Number of patients               the WHO Programme and research groupsvi, vii, viii, but it is of
                                                                                19–39              2 (13, one four year old)           Female               136 (438)                        great importance to spread the information to healthcare
(no. of reports in total)                                                       40–49              8 (25)                              Male                 28 (89)
                                                                                                                                                                                             professionals of the possibility of severe and painful vision ADRs
172 (550) originated from Australia 13 (37), Austria (3), Belgium               50–59              21 (95)                             not stated           8 (23)
                                                                                60–69              49 (147)                                                                                  to this class of drugs.
2 (4), Canada 10 (28), Czech Republic 3 (6), Germany 8 (37),                    70–79              44 (141)
Finland 1 (1), France 4 (5), Ireland 1 (1), Italy 1 (6), Japan (1),             80–89              17 (44)
Mexico (1), Netherlands (5), New Zealand 4 (10), Norway (3),                    90–95              1 (3)                                                                                                                   CONCLUSION
                                                                                not stated         30 (82)
Spain 3 (11), South Africa 2 (2), Sweden 1 (4), United Kingdom                                                                                                                               It appears ocular inflammation can occur when any member of
24 (118) and United States 95 (267).                                           Outcome and causality                                                                                         this class of medicine is used and healthcare professionals should
                                                                                Outcome                               No. of critical reports (total)
                                                                                                                                                                                             therefore be aware of this possibility. Recognition of adverse
Co-suspected drugs                                                              Recovered                             30 (134)                                                               ocular events in association with bisphosphonate therapy should
281 of the case reports in total had concomitant medications                    Recovered with sequelae               20 (32)                                                                alert clinicians to the need for ophthalmic evaluation and possibly
listed. Fourteen of the critical term reports (50 in total) had                 Not recovered                         19 (74)
                                                                                Died – unrelated to reaction          2 (3)
                                                                                                                                                                                             consideration of discontinuation of therapy.
co-suspected drugs:                                                             Unknown                               52 (157)
 Acetylsalicylic acid, Aminoglutethimide, Brimonidine*, Calcitonin,
                                                                                not stated                            49 (151)
                                                                                                                                                                                                                   Acknowledgement
 Calcium carbonate, Ergocalciferol/Hydroquinone, Fluindione, Letrozole*,        Causality                             No. of critical reports (total)
 Levothyroxine, Lovastatin*, Oxaprozin# and Simvastatin*.
                                                                                                                                                                                             We thank the National Centres for their contribution to the
                                                                                Certain                               4 (10)
                                                                                Probable                              6 (23)
                                                                                                                                                                                             WHO ADR database. The opinions and conclusions in this
* Ocular side effects reported in literature.i, iii                             Possible                              22 (60)                                                                poster are not necessarily those of the various centres or of the
# Ocular side effects reported on drugs within the ATC group.i                  Unlikely                              2 (6)                                                                  WHO.
                                                                                Not yet assessed                      4 (21)
                                                                                not stated                            148 (468)
The following drugs were additionally stated as co-suspected for
the non-critical reports:                                                      Dechallenge and rechallenge                                                                                                                 REFERENCES
 Amlodipine, Atorvastatin, Calcium, Capecitabine, Colecalciferol,               Action                                Outcome                      No. of critical (total) reports           i     Martindale Pharmacopeia on-line
 Cysteine/Aminoacetic acid/Glycyrrhizic acid ammonium salt, Digoxin,            Drug withdrawn                        Effect unknown               - (3)                                     ii    SIGNAL (Restricted document, contact the UMC for details)
 Dorzolamide, Ergocalciferol/Ascorbic acid/Folic acid/Thiamine HCl/             Drug withdrawn                        No effect observed           4 (18)
                                                                                Drug withdrawn                        Reaction abated              25 (99)                                   iii   Electronic Medicines Compendium (http://www.medicines.org.uk)
 Retinol/Riboflavin, Estrogens conjugated, Fosfomycin, Interferon,
                                                                                Dose not changed                      blank                        - (1)                                     iv    Fraunfelder, F.W.: Ocular Side Effects Associated with Bisphosphonates.
 Interferon alfa-2b, Lansoprazole, Latanoprost, Medroxyprogesterone
                                                                                Dose not changed                      Effect unknown               1 (6)                                           Drugs of Today (Barc) 2003 Nov; 39(11):829-35.
 acetate /Estrogens conjugated, Nifedipine, Omeprazole, Phenytoin,
                                                                                Dose not changed                      Not applicable               14 (39)
 Pilocarpine, Quinapril, Raloxifene HCl, Rofecoxib, Sertraline, Sultopride,     Dose not changed                      Effect unknown               91 (275                                   v     Fraunfelder, F.W., Fraunfelder, F.T: Scleritis and other ocular side
 Thalidomide, Tolterodine, Warfarin                                             not stated                            not stated                   37 (334)                                        effects associated With Pamidronate Disodium. Am. J. Ophthalmol.
                                                                                                                                                                                                   135(2):219-222, 2003.
                                                                                Action                                Outcome                      No. of critical (total) reports
Indication                                                                      Rechallenge                           No recurrence                - (3)                                     vi    Bisphosphonates and ocular disorders. Canadian Adverse Reaction
Approximately 60% of the reports with information on                            Rechallenge                           Reaction recurred            10 (38)                                         Newsletter Volume 13, Issue 4, October 2003.

indication, 25 (118), stated Osteoporosis. Other indications                    No rechallenge                        Not applicable               29 (85)                                   vii Australian Adverse drug Reactions Bulletin Volume 23, No. 2, April 2004.
                                                                                Unknown                               Effect unknown               113 (383)
included Other diseases of bone and/or cartilage 5 (16), Osteitis               Unknown                               Not stated                   - (4)                                     viii Fraunfelder, F.W., Fraunfelder, F.T. Bisphosphonates and Ocular
deformans 5 (13), Multiple myeloma 2 (10), different Malignant                  not stated                            Not stated                   20 (302)                                       Inflammation. New England Journal of Medicine 348(12):1187-1188, 2003.




                                                                                                                                   WHO Collaborating Centre for                                                                               The Uppsala Monitoring Centre
                                                                                                                                                                                                                                       Stora Torget 3, S-753 20 Uppsala, Sweden
                                                                                                                                   International Drug Monitoring                                                                       Tel +46-18-65 60 60. Fax +46-18-65 60 80
                                                                                                                                                                                                                                                    Website: www.who-umc.org

								
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