CIOMS FORM SUSPECT ADVERSE REACTION REPORT DE-BFARM-17131307 I. REACTION INFORMATION 1. PATIENT INITIALS 1a. COUNTRY 2. DATE OF BIRTH 2a. AGE 3. SEX 4-6 REACTION ONSET privacy DE DA MO YR 65 DA MO YR (Year) Male 01 12 2016 [ MedDRA 19.1 LLT (10028851): Necrosis ] Vaskulitis mit zentraler Nekrose beider Unterschenkel und Füße. [ MedDRA 19.1 LLT (10047115): Vasculitis ] 8-1 CHECK ALL APPROPRIATE TO ADVERSE REACTION 7. + 13. DESCRIBE REACTION(S) (including relevant tests/lab data) (cont.) PATIENT DIED þ INVOLVED OR PROLONGED INPATIENT HOSPITALISATION Results of tests and procedures relevant to the investigation of the patient: canca neg. am 19.01.2017. Histologie am 20.01.2017: nahezu vollständige Nekrose, keine spezifische Entzündung. Reporter's comments: Maßnahme und Verlauf: UAW trat nach Gabe Forxiga auf. Nachdem die Therapie für einige Tage pausiert wurde, sei die UAW abgeklungen. Nach Wiedereinsetzen der Therapie dann erneute Entwicklung der UAW. Therapie wurde erneut abgesetzt. Aufgrund des sehr labilen BZ des Pat. wurde auf Steroidstoßtherapie verzichtet. UAW war rückläufig. Da bezüglich des sehr instabilen BZ II. SUSPECT DRUG(S) INFORMATION 14. SUSPECT DRUG(S) (include generic name) forxiga 15. DAILY DOSE(S) 16. ROUTE(S) OF ADMINISTRATION 10 Mg 17. INDICATION(S) FOR USE Diabetes mellitus 18. THERAPY DATES (from/to) 19. THERAPY DURATION from 24-NOV-2016 to 18-DEC-2016 25 Day III. CONCOMITANT DRUG(S) AND HISTORY 22. CONCOMITANT DRUG(S) AND DATES OF ADMINISTRATION (exclude those used to treat reaction) morphin sulfat daily dose: 90 Mg millgram(s) every Days ramipril daily dose: 5 Mg millgram(s) every Days (cont.) 20. 21. INVOLVED PERSISTENCE OR SIGNIFICANT DISABILITY OR INCAPACITY LIFE THREATENING CONGENITAL ANOMALY / BIRTH DEFECT OTHER MEDICALLY IMPORTANT CONDITION DID REACTION ABATE AFTER STOPPING DRUG? YES NO NA DID REACTION REAPPEAR AFTER REINTRODUCTION? þ YES NO NA (cont.) 23. OTHER RELEVANT HISTORY (e.g. diagnostics, allergics, pregnancy with last month of period, etc.) [ MedDRA 19.1 (10074572): Multiple vessel coronary artery disease ] Continuing: Unknown [ MedDRA 19.1 (10056418): Arterial bypass operation ] from 1994 Continuing: No [ MedDRA 19.1 (10002388): Angina unstable ] Continuing: Unknown (cont.) IV. SENDER INFORMATION 24a. NAME AND ADRESS OF SENDER 10623 Berlin, DE 24c. DATE RECEIVED BY MANUFACTURER 07-APR-2017 DATE OF THIS REPORT 24b. MFR CONTROL NO. DE-BFARM-17131307 24d. REPORT SOURCE þ STUDY 25a. REPORT TYPE LITERATURE HEALTH PROFESSIONAL þ INITIAL FOLLOW UP FINAL (Cont.) = Continuation on attached sheet(s)
Report Page: 2 of 10 7. + 13. Describe Reaction(s) (including relevant tests/lab data) (... continuation...) die SGLT-II-Hemmer-Therapie sehr wirksam war, wurde nach intensiver Aufklärung auf Empagliflozin gewechselt. Sender's comment: Ergänzung Reporter`s comments: Darunter bis dato keine neue Entwicklung von vaskulitistypischen Symptomatiken. Aufgrund der ausgeprägten generalisierten PAVK und Primärläsionen im peripheren Bereich der unteren Extremitäten bds,.wurde bei bekannter Wundheilungsstörungen auf eine weitergehende diagnostische Abklärung (PE) verzichtet. Am 16.1.16 bei erneutem Auftreten der UAW und dramatischer Verschlimmerung, Verlegung in eine Schwerpunktklinik. Dort nach Absetzen des Empagliflozins erneute Besserung. Reaction text as reported MedDRA coding Duration Outcome* Term highlighted Time interval 1** Time interval 2*** [MedDRA 19.1 PT (10028851): Necrosis ] recovering/resolving 01-DEC-2016 [ MedDRA 19.1 LLT (10028851): Necrosis ] Vaskulitis mit zentraler Nekrose beider Unterschenkel und Füße. [MedDRA 19.1 PT (10047115): Vasculitis ] recovering/resolving 01-DEC-2016 [ MedDRA 19.1 LLT (10047115): Vasculitis ] * Outcome of reaction/event at the time of last observation ** Time interval between beginning of suspect drug *** and start of reaction/event Results of tests Date Test Result Unit Normal low range Normal high range More inform. available 19-JAN-2017 Perinuclear antineutrophil cytoplasmic antibody negativ/negative NA 19-JAN-2017 ANA negativ/negative NA 19-JAN-2017 Antimitochondrial antibody negativ/negative NA 19-JAN-2017 Cryoglobulins negativ/negative NA 20-JAN-2017 Histology vorhanden/present NA 14. Suspect Drug(s) (including generic name) (... continuation...) Suspect Drug Duration Dose * Route(s) of forxiga 24-NOV- 18-DEC- 25 Day A: 2016 2016 C: 10Mg D: E: Diabetes mellitus
Report Page: 3 of 10 8 Day Drug withdrawn Yes Cumulative dose number (to first reaction) C: Structure dosages number dapagliflozin Causality assessment Reaction Source Method Result [ MedDRA 19.1 (10028851): Necrosis ] AkdÄ Global Introspection (WHO GI) possible [ MedDRA 19.1 (10047115): Vasculitis ] AkdÄ Global Introspection (WHO GI) possible 14. Suspect Drug(s) (including generic name) (... continuation...) Suspect Drug Duration Dose * Route(s) of jardiance 20-DEC- 2016 16-JAN- 2017 28 Day A: C: 25Mg D: E: Diabetes mellitus Drug withdrawn
Report Page: 4 of 10 Cumulative dose number (to first reaction) C: Structure dosages number empagliflozin Causality assessment Reaction Source Method Result [ MedDRA 19.1 (10028851): Necrosis ] AkdÄ Global Introspection (WHO GI) possible [ MedDRA 19.1 (10047115): Vasculitis ] AkdÄ Global Introspection (WHO GI) possible 22. (s) and Dates of (exclude those used to treat reaction) (... continuation...) morphin sulfat A: daily dose: 90 Mg millgram(s) every Days C: 30Mg D: 3 Chronic pain Cululative dose number (to first reaction) morphine sulfate 22. (s) and Dates of (exclude those used to treat reaction) (... continuation...)
Report Page: 5 of 10 ramipril A: daily dose: 5 Mg millgram(s) every Days C: 5Mg D: 1 Cardiac failure Cululative dose number (to first reaction) ramipril 22. (s) and Dates of (exclude those used to treat reaction) (... continuation...) furosemid A: daily dose: 80 Mg millgram(s) every Days C: 40Mg D: 2 Cardiac failure
Report Page: 6 of 10 Cululative dose number (to first reaction) furosemide 22. (s) and Dates of (exclude those used to treat reaction) (... continuation...) metoprolol A: daily dose: 142.5 Mg millgram(s) every Days C: 142.5Mg D: 1 Cardiac failure Cululative dose number (to first reaction) metoprolol 22. (s) and Dates of (exclude those used to treat reaction) (... continuation...)
Report Page: 7 of 10 ass A: daily dose: 100 Mg millgram(s) every Days C: 100Mg D: 1 Peripheral arterial occlusive disease Cululative dose number (to first reaction) acetylsalicylic acid 22. (s) and Dates of (exclude those used to treat reaction) (... continuation...) levemir A: daily dose: 56 Iu Subcutaneous international unit(s) every Days C: 28Iu international unit(s) D: 2 Diabetes mellitus
Report Page: 8 of 10 Cululative dose number (to first reaction) insulin detemir 22. (s) and Dates of (exclude those used to treat reaction) (... continuation...) novorapid A: C: D: E: Subcutaneous Diabetes mellitus Anwendung seit Jahren nach Bedarf. Cululative dose number (to first reaction) insulin aspart
Report Page: 9 of 10 23. Other relevant history (... continuation...) Reactions, Symptoms and Events Continuing Comments [ MedDRA 19.1 (10074572): Multiple vessel coronary artery disease ] Unknown 3-Gefäßerkrankung [ MedDRA 19.1 (10056418): Arterial bypass operation ] 1994 No Z.n. ACVB-Operation [ MedDRA 19.1 (10002388): Angina unstable ] Unknown instabile Angina Pectoris Beschwerden [ MedDRA 19.1 (10012680): Diabetic neuropathy ] Unknown [ MedDRA 19.1 (10060734): Diabetic foot ] Unknown diabetisches Fußsyndrom [ MedDRA 19.1 (10003004): Apoplexy ] 2008 No [ MedDRA 19.1 (10003004): Apoplexy ] 2009 No Report duplicates Duplicate source Duplicate number DE-DCGMA-17173345 Parent Parent identification Date of birth Age LMP Weight(kg) Height(cm) Sex Text for relevant medical history and concurrent conditions 0 ADMINISTRATIVE AND IDENTIFICATION INFORMATION Safetyreportversion 1 where the reaction/event occur Serious Date Format of receipt of the most recent information for this report Additional documents Yes 20170407 No List of documents held by sender Does this case fulfill the local criteria for an expedited report? Yes Regulatory authority's case report number Other case identifiers in previous transmissions Was the case medically confirmed, if not initially from health professional? Yes Primary source(s) of information Reporter postcode Reporter country Qualification Literature reference(s) Study name Sponsor study number Study type in which the reaction(s)/event(s) were observed 26 Physician
Report Page: 10 of 10 SENDER INFORMATION (... continuation...) Type Organisation Health professional Department Street address City Berlin Postcode 10623 Country Fax +49 / (0)30 4004 / 56555 Telephone +49 / (0)30 4004 / 56500 E-mail address phv@akdae.de PATIENT INFORMATION (... continuation...) Investigation number Gestation period Patient age group Adult >18.Lj. bis einschl. 65.Lj. Weight (kg) 105 Height (cm) 176 Last menstrual periode Text for relevant medical history and concurrent conditions