SUSPECT ADVERSE REACTION REPORT



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CIOMS FORM SUSPECT ADVERSE REACTION REPORT DE-BFARM-16279074 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 34 DA MO YR (Year) Female 02 2016 (10019045): Hair loss ] (10002855): Anxiety ] Verschlechterung des grauen Stars (10007742): Cataract aggravated ] (10013573): Dizziness ] (10013781): Dry mouth ] trockene Haut und Schleimhaut (10013786): Dry skin ] Energielosigkeit (10015667): Exhaustion ] schnellerer und manchmal unregelmäßiger Herzschlag (10019300): Heart rate abnormal ] veränderte Wundheilung (10048036): Wound healing delayed ] (10022437): Insomnia ] (10025482): Malaise ] (10027172): Memory disturbance ] starke Vernebelung der Gedanken (10012805): Difficulty thinking ] (10028295): Muscle cramps ] (10028322): Muscle pain ] (10028813): Nausea ] neurologische Störung des ZNS (10029298): Neurological disorder NOS ] Nervenschmerzen im Bauchraum (10029181): Nerve pain ] 8-12 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 INVOLVED PERSISTENCE OR SIGNIFICANT DISABILITY OR INCAPACITY LIFE THREATENING CONGENITAL ANOMALY / BIRTH DEFECT OTHER MEDICALLY IMPORTANT CONDITION II. SUSPECT DRUG(S) INFORMATION 14. SUSPECT DRUG(S) (include generic name) (cont.) ciprofloxacin 15. DAILY DOSE(S) 16. ROUTE(S) OF ADMINISTRATION 250 Mg milligram(s),1 Day Oral 17. INDICATION(S) FOR USE Bladder inflammation 18. THERAPY DATES (from/to) 19. THERAPY DURATION from 16-JAN-2016 to 20-JAN-2016 5 Day III. CONCOMITANT DRUG(S) AND HISTORY 22. CONCOMITANT DRUG(S) AND DATES OF ADMINISTRATION (exclude those used to treat reaction) 20. 21. DID REACTION ABATE AFTER STOPPING DRUG? YES NO NA DID REACTION REAPPEAR AFTER REINTRODUCTION? YES NO NA 23. OTHER RELEVANT HISTORY (e.g. diagnostics, allergics, pregnancy with last month of period, etc.) [ MedDRA 19.0 (10036316): Post-traumatic stress disorder ] Continuing: Unknown [ MedDRA 19.0 (10078076): Somatic symptom disorder ] Continuing: Unknown [ MedDRA 19.0 (10039809): Secondary amenorrhoea ] Continuing: Unknown (cont.) 24a. NAME AND ADRESS OF SENDER 53175 Bonn, DE IV. SENDER INFORMATION 24c. DATE RECEIVED BY MANUFACTURER 29-AUG-2016 DATE OF THIS REPORT 24b. MFR CONTROL NO. DE-BFARM-16279074 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...) (10029414): Nightmares ] (10033664): Panic attack ] Kribbeln in den Armen und Beinen, Fußsohlen (10043876): Tingling ] (10036105): Polyneuropathy ] Ausschläge besonderns an Haaransatz, Schläfen und Ohren (10015138): Eruption ] (10046996): Varicose vein ] Verschlechterung der Sehstärke um 2 Dioptrien (10047571): Visual impairment ] hormonelle Veränderungen (10020381): Hormonal imbalance ] (10016949): Food intolerance NOS ] (10066371): Tendon pain ] Medikamentenintoxikation (10013714): Drug intoxication ] Case narrative including clinical course, therapeutic measures, outcome and additional relevant information: Bericht der Meldenden: Schon während der Einnahme zeigte sich Schwindel und Unwohlsein. In der Folge kam es zu: - Kribbeln in den Armen und Beinen, Fußsohlen - Starker Vernebelung der Gedanken - Nerven-Schmerzen im Bauchraum - Verschlechterung der Sehstärke um 3 Dioptrien - Verschlechterung des grauen Stars - Muskel und Sehnenschmerzen - Ausschläge, besonders am Haaransatz, Schläfen und Ohren - Starke Angst und Panikattacken - Energielosigkeit, Schlafstörungen, Alpträume - Sehr langsame Abheilung auch von kleinen Wunden und Insektenstichen - Krampfende Muskeln - Starke Wahrnehmung des Herzschlages, schnellerer und manchmal unregelmäßiger Herzschlag Mehrere Ärzte wurden aufgesucht - Allgemeinarzt, Neurologe, Innere, Augenarzt, Endokrinologe Therapie - Infusionen und Einnahme Mg, Fe, Vitamine, Mikronährstoffe Reaction text as reported MedDRA coding Duration Outcome* Term highlighted Time interval 1** Time interval 2*** Start date End date Medikamentenintoxikation [MedDRA 19.0 PT (10070863): Toxicity to various agents ] (10013714): Drug intoxication ] [MedDRA 19.0 PT (10013573): Dizziness ] (10013573): Dizziness ] [MedDRA 19.0 PT (10025482): Malaise ] (10025482): Malaise ] Kribbeln in den Armen und Beinen, Fußsohlen [MedDRA 19.0 PT (10033775): Paraesthesia ] (10043876): Tingling ] starke Vernebelung der Gedanken [MedDRA 19.0 PT (10027374): Mental impairment ] (10012805): Difficulty thinking ]

Report Page: 3 of 10 Nervenschmerzen im Bauchraum [MedDRA 19.0 PT (10029223): Neuralgia ] (10029181): Nerve pain ] Verschlechterung der Sehstärke um 2 Dioptrien [MedDRA 19.0 PT (10047571): Visual impairment ] (10047571): Visual impairment ] Verschlechterung des grauen Stars [MedDRA 19.0 PT (10007739): Cataract ] (10007742): Cataract aggravated ] [MedDRA 19.0 PT (10028411): Myalgia ] (10028322): Muscle pain ] [MedDRA 19.0 PT (10066371): Tendon pain ] (10066371): Tendon pain ] Ausschläge besonderns an Haaransatz, Schläfen und Ohren [MedDRA 19.0 PT (10037844): Rash ] (10015138): Eruption ] [MedDRA 19.0 PT (10002855): Anxiety ] (10002855): Anxiety ] [MedDRA 19.0 PT (10033664): Panic attack ] (10033664): Panic attack ] Energielosigkeit [MedDRA 19.0 PT (10016256): Fatigue ] (10015667): Exhaustion ] [MedDRA 19.0 PT (10022437): Insomnia ] (10022437): Insomnia ] [MedDRA 19.0 PT (10029412): Nightmare ] (10029414): Nightmares ] veränderte Wundheilung

Report Page: 4 of 10 [MedDRA 19.0 PT (10021519): Impaired healing ] (10048036): Wound healing delayed ] [MedDRA 19.0 PT (10028334): Muscle spasms ] (10028295): Muscle cramps ] schnellerer und manchmal unregelmäßiger Herzschlag [MedDRA 19.0 PT (10019300): Heart rate abnormal ] (10019300): Heart rate abnormal ] 61 Day Unknown APR-2016 [MedDRA 19.0 PT (10046996): Varicose vein ] (10046996): Varicose vein ] [MedDRA 19.0 PT (10001760): Alopecia ] (10019045): Hair loss ] [MedDRA 19.0 PT (10036105): Polyneuropathy ] (10036105): Polyneuropathy ] trockene Haut und Schleimhaut [MedDRA 19.0 PT (10013786): Dry skin ] (10013786): Dry skin ] hormonelle Veränderungen [MedDRA 19.0 PT (10061210): Hormone level abnormal ] (10020381): Hormonal imbalance ] [MedDRA 19.0 PT (10027175): Memory impairment ] (10027172): Memory disturbance ] [MedDRA 19.0 PT (10013781): Dry mouth ] (10013781): Dry mouth ] neurologische Störung des ZNS [MedDRA 19.0 PT (10029202): Nervous system disorder ] (10029298): Neurological disorder NOS ]

Report Page: 5 of 10 [MedDRA 19.0 PT (10061958): Food intolerance ] (10016949): Food intolerance NOS ] [MedDRA 19.0 PT (10028813): Nausea ] (10028813): Nausea ] * Outcome of reaction/event at the time of last observation ** Time interval between beginning of suspect drug administration and start of reaction/event *** Time interval between last dose and start of reaction/event Results of tests Date Test Result Unit Normal low range Normal high range More inform. available 17-AUG-2016 Monocytes 12.7 % 4.0 11.0 17-AUG-2016 GPT 50 U/l <35 17-AUG-2016 Potassium 2.4 mmol/l 3.5 5.5 17-AUG-2016 Cholesterol 231 mg/dl 120 200 17-AUG-2016 IgA 375 mg/dl 40 350 17-AUG-2016 Uric acid 6.8 mg/dl 2.3 6.0 14. Suspect Drug(s) (including generic name) (... continuation...) Suspect Drug and batch no. Start date End date Duration Dose * Route(s) of Administration Indication(s) ciprofloxacin 16-JAN- 2016 20-JAN- 2016 5 Day A: B: C: 250Mg milligram(s) D: E: 1Day Oral Bladder inflammation Identification of the country where the drug was obtained Name of holder/applicant Authorization/Application Number Country of authorization/application Pharmaceutical form (Dosage form) Parent route of administration (in case of a parent child/fetus report) Gestation period at time of exposure Time interval between beginning of drug administration and start of reaction/event Time interval between last dose of drug and start of reaction/event Action(s) taken with drug Additional information on drug Did reaction reappear after reintroduction? * A: Dosage Text

Report Page: 6 of 10 B: Cumulative dose number (to first reaction) C: Structure dosages number D: Number of separate dosages E: Number of units in the interval Active drug substance name ciprofloxacin Causality assessment Reaction Source Method Result [ MedDRA 19.0 (10002855): Anxiety ] [ MedDRA 19.0 (10015667): Exhaustion ] [ MedDRA 19.0 (10007742): Cataract aggravated ] [ MedDRA 19.0 (10013573): Dizziness ] [ MedDRA 19.0 (10019300): Heart rate abnormal ] [ MedDRA 19.0 (10048036): Wound healing delayed ] [ MedDRA 19.0 (10025482): Malaise ] [ MedDRA 19.0 (10012805): Difficulty thinking ] [ MedDRA 19.0 (10028295): Muscle cramps ] [ MedDRA 19.0 (10028322): Muscle pain ] [ MedDRA 19.0 (10029181): Nerve pain ] [ MedDRA 19.0 (10029414): Nightmares ] [ MedDRA 19.0 (10033664): Panic attack ] [ MedDRA 19.0 (10043876): Tingling ] [ MedDRA 19.0 (10015138): Eruption ] [ MedDRA 19.0 (10022437): Insomnia ] [ MedDRA 19.0 (10047571): Visual impairment ] [ MedDRA 19.0 (10066371): Tendon pain ] [ MedDRA 19.0 (10013714): Drug intoxication ] [ MedDRA 19.0 (10046996): Varicose vein ] [ MedDRA 19.0 (10019045): Hair loss ]

Report Page: 7 of 10 [ MedDRA 19.0 (10036105): Polyneuropathy ] [ MedDRA 19.0 (10013786): Dry skin ] [ MedDRA 19.0 (10020381): Hormonal imbalance ] [ MedDRA 19.0 (10027172): Memory disturbance ] [ MedDRA 19.0 (10013781): Dry mouth ] [ MedDRA 19.0 (10029298): Neurological disorder NOS ] [ MedDRA 19.0 (10016949): Food intolerance NOS ] [ MedDRA 19.0 (10028813): Nausea ] 14. Suspect Drug(s) (including generic name) (... continuation...) Suspect Drug and batch no. Start date End date Duration Dose * Route(s) of Administration Indication(s) ciprofloxacin 14-FEB- 2016 24-FEB- 2016 11 Day A: B: C: 250Mg milligram(s) D: E: 1Day Oral Middle ear inflammation Identification of the country where the drug was obtained Name of holder/applicant Authorization/Application Number Country of authorization/application Pharmaceutical form (Dosage form) Parent route of administration (in case of a parent child/fetus report) Gestation period at time of exposure Time interval between beginning of drug administration and start of reaction/event Time interval between last dose of drug and start of reaction/event Action(s) taken with drug Additional information on drug Did reaction reappear after reintroduction? * A: Dosage Text B: Cumulative dose number (to first reaction) C: Structure dosages number D: Number of separate dosages E: Number of units in the interval Active drug substance name ciprofloxacin Causality assessment

Report Page: 8 of 10 Reaction Source Method Result [ MedDRA 19.0 (10002855): Anxiety ] [ MedDRA 19.0 (10015667): Exhaustion ] [ MedDRA 19.0 (10007742): Cataract aggravated ] [ MedDRA 19.0 (10013573): Dizziness ] [ MedDRA 19.0 (10019300): Heart rate abnormal ] [ MedDRA 19.0 (10048036): Wound healing delayed ] [ MedDRA 19.0 (10025482): Malaise ] [ MedDRA 19.0 (10012805): Difficulty thinking ] [ MedDRA 19.0 (10028295): Muscle cramps ] [ MedDRA 19.0 (10028322): Muscle pain ] [ MedDRA 19.0 (10029181): Nerve pain ] [ MedDRA 19.0 (10029414): Nightmares ] [ MedDRA 19.0 (10033664): Panic attack ] [ MedDRA 19.0 (10043876): Tingling ] [ MedDRA 19.0 (10015138): Eruption ] [ MedDRA 19.0 (10022437): Insomnia ] [ MedDRA 19.0 (10047571): Visual impairment ] [ MedDRA 19.0 (10066371): Tendon pain ] [ MedDRA 19.0 (10013714): Drug intoxication ] [ MedDRA 19.0 (10046996): Varicose vein ] [ MedDRA 19.0 (10019045): Hair loss ] [ MedDRA 19.0 (10036105): Polyneuropathy ] [ MedDRA 19.0 (10013786): Dry skin ] [ MedDRA 19.0 (10020381): Hormonal imbalance ] [ MedDRA 19.0 (10027172):

Memory disturbance ] Report Page: 9 of 10 [ MedDRA 19.0 (10013781): Dry mouth ] [ MedDRA 19.0 (10029298): Neurological disorder NOS ] [ MedDRA 19.0 (10016949): Food intolerance NOS ] [ MedDRA 19.0 (10028813): Nausea ] 23. Other relevant history (... continuation...) Reactions, Symptoms and Events Start date End date Continuing Comments [ MedDRA 19.0 (10036316): Post-traumatic stress disorder ] Unknown posttraumatische Belastungsstörung [ MedDRA 19.0 (10078076): Somatic symptom disorder ] Unknown chronische Schmerzstörung [ MedDRA 19.0 (10039809): Secondary amenorrhoea ] Unknown Zyklus jetzt unter Hormongabe [ MedDRA 19.0 (10029399): Nickel sensitivity ] Unknown [ MedDRA 19.0 (10020419): House dust mite allergy ] Unknown Report duplicates Duplicate source Paul-Ehrlich-Institut Duplicate number DE-CADRBFARM-2016013389 Parent Parent identification Date of birth Age LMP date Weight(kg) Height(cm) Sex Text for relevant medical history and concurrent conditions 0 ADMINISTRATIVE AND IDENTIFICATION INFORMATION Safetyreportversion 1 Identification of the country where the reaction/event occur Serious Date Format of receipt of the most recent information for this report Additional documents Yes 20160829 No List of documents held by sender Does this case fulfill the local criteria for an expedited report? Regulatory authority's case report number Other case identifiers in previous transmissions Was the case medically confirmed, if not initially from health professional? Yes DE-CADRBFARM-2016013389 Yes Yes

Report Page: 10 of 10 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 78 Consumer or other non health professional 78 Physician SENDER INFORMATION (... continuation...) Type Organisation Department Regulatory Authority Street address City Bonn Postcode 53175 Country Fax Telephone E-mail address uaw@bfarm.de PATIENT INFORMATION (... continuation...) Investigation number Gestation period Patient age group Adult >18.Lj. bis einschl. 65.Lj. Weight (kg) 55 Height (cm) 171 Last menstrual periode date Text for relevant medical history and concurrent conditions