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SIMW GmbH (Statistical Institute for Marketing and Sciences)

Biometrical Report

of

German study CERTUM

Code: CMEX839ADE02

Non-interventional study to evaluate

Certoparin under real-life conditions for management of deep vein thrombosis

German title Prospektive,

nicht-interventionelle Beobachtungsstudie mit Certoparin in der

Routine-Behandlung tiefer Venenthrombosen

Total number of patients: 679 Number of sites: 169

Sponsor:

Novartis Pharma GmbH Roonstraße 25

90429 Nürnberg Germany

Biometrical Evaluation: SIMW GmbH

D-41844 Wegberg Germany

Final Version

14th March 2013

Property of Novartis

Confidential May not be used, divulged, published or otherwise disclosed

without the written consent of Novartis Pharma GmbH

CERTUM: Non-interventional study with Certoparin (Mono-Embolex®)

Final Analysis; total collective: 679 patients; Final Version 14 March-2013

Table of Contents

1. Synopsis................................................................................................................................................................... 3 2. Report summary...................................................................................................................................................... 5 3. Final analysis............................................................................................................................................................ 7

3.1. Title .................................................................................................................................................................... 7 3.2. Sponsor............................................................................................................................................................. 7 3.3. Investigators of the NIS.................................................................................................................................... 7 3.4. Medium in the NIS............................................................................................................................................ 7 3.5. Surveillance Timelines..................................................................................................................................... 7 3.6. Duration of Surveillance Period per Patient, examinations: ......................................................................... 7 3.7. Collective........................................................................................................................................................... 8 3.8. Plausibility Criteria and Statistical Approach.................................................................................................. 8

4. Results....................................................................................................................................................................10 4.1. Demographic data..........................................................................................................................................10 4.2. Frequency-distribution of age and sex .........................................................................................................10 4.3. Risk factors for deep vein thrombosis (DVT)...............................................................................................10 4.4. Diagnosis of deep vein thrombosis (DVT) ...................................................................................................10 4.5. Previous and concomitant medication .........................................................................................................10 4.6. Laboratory parameters ..................................................................................................................................10 4.7. Laboratory parameters: Analysis of differences..........................................................................................10 4.8. Therapy with Mono-Embolex®.....................................................................................................................10 4.9. Therapy with vitamin-K antagonists (VKA)/oral anticoagulants (OAC).....................................................10 4.10. Result of therapy with Mono-Embolex®....................................................................................................10

5. Drug Safety (Adverse Events)..............................................................................................................................11 6. Assessment of the Non-interventional Study and Results.................................................................................12 7. Responsibility .........................................................................................................................................................12

7.1. Guidelines and Certifications.........................................................................................................................12 7.2. Reliability .........................................................................................................................................................12

8. Tables .....................................................................................................................................................................13 9. Drug Safety Tables................................................................................................................................................40 10. APPENDIX...........................................................................................................................................................49



1. SYNOPSIS Product: Certoparin-Natrium (Mono-Embolex® 8000 I.E.) Indication: Patients with deep vein thrombosis Country: Germany

Medical Director: Dr. Georg-Friedrich von Tempelhoff Title of study: Non-interventional study to evaluate Certoparin under real-life conditions for management of deep vein thrombosis Objectives: To determine the treatment duration/algorithm of routine use of certoparin as part of the time-

frame of acute DVT treatment including the following timepoints and the respective time inter-vals: first symptoms, diagnosis, onset of certoparin treatment, onset of VKA treatment, first INR result > 2, end of certoparin treatment

To determine whether the treatment duration depends on patient demography, creatinine clearance, DVT-related medical history, relevant co-medication, time to INR > 2, number/size of thrombi and D-Dimers

To determine whether the observed change in D-Dimers is related to treatment duration To determine the rate of recurrent thrombosis during the initial treatment period and its poten-

tial relation to the duration of certoparin treatment Study-Design: This study was designed as a prospective, non-interventional study. Patients were recruited for the study, multicentrically throughout the Federal Republic of Germany. The study includes a repre-sentative number of 169 centers which perform routine DVT treatment in Germany. Inclusion criteria were that - patient had been informed about the objectives of this study and had given a written consent to participation in this study - patient is at least 18 years of age - patients with diagnostically confirmed DVT - the attending physician had already decided on patient́ s treatment of DVT with certoparin All occurring adverse events (AE) were registered in conventional CIOMS II line listings and peri-odically sent to the drug safety department of NOVARTIS for further processing. Design and duration of the study: Prospective, observational study including the documentation of 2 routine visits; visit 1 (day 1): start of certoparin therapy visit 2 (day 30-45): ca. two weeks after end of therapy with certoparin. This collective contains completed baseline-documentations of 679 patients.



Evaluation criteria: Demography Age, Sex, Size, Weight Medical History VTE Surgery Acute illness leading to immobilization Infection Inflammatory disease Exsiccosis Stroke Myocardial infarction Other risk factor for DVT Lab parameters (if available) Thrombocyte, INR, creatinine, D-Dimer, aXa Indication Onset of symptoms, Wells criteria, diagnostic method, number location and size of thrombi Therapy Ambulant vs. hospitalized Onset, dose and end of certoparin treatment Reason for treatment duration Type, onset and dose of VKA Other Timelines Date of first documentation February 9th 2012 Date of last documentation January 27th 2013 Drug and dosage: Mono-Embolex® 8000 I.E. solution for injection (8000 I.E. anti-Xa Certoparin-Natrium) is a low molecular weight heparin (LMWH) for treatment of deep vein thrombosis. It is administered by free medical therapy decision according to dosage instruction in the Mono-Embolex® 8000 I.E. SmPC. Statistical methodology: The statistical analysis followed a standardized operating procedure of SIMW GmbH and included all case report forms received, irrespective of any possible inconsistencies, incompleteness or im-plausibilities (intent-to-treat-collective). For the analysis of this unadjusted intent-to-treat-collective, descriptive statistical methods were applied. Presentation of table numbering and language within this document: The format of this report and the numbering of tables follows the standard operating procedures of SIMW. Due to German language of the study and questionnaires: For exact translation of the very few free-text answers to correspondent English wording a certified translator would be necessary.



2. REPORT SUMMARY Objective of this non-interventional study was to evaluate Certoparin under real-life conditions for management of deep vein thrombosis. Data about treatment duration/algorithm of routine use were recorded and documented by 169 sites from 2012 to 2013 covering a total of 679 patients. 51.5% of patients were female, 48.5% male. The mean age of all patients was 59.97 (± 15.16; median 61.00) years. 634 patients (93%) showed at least one risk factor for deep vein thrombosis (DVT): Mostly con-firmed were highly developed varicosis (230), nicotine abuse (203), obesity (152), earlier DVT / pulmonary embolism (137) and infection or acute flammable, not bedridden disease (131). Most diagnosed localizations of DVT at both sides of the body were lower legs (298 right side / 276 left side), lower legs with v. poplitea (185 right side / 174 left side) and upper legs (107 right side / 104 left side). 98% of diagnosed DVT were symptomatic, 48% completely occludent, 30% multi-opening. For 55 patients Wells-Score was documented (mean 3.75 points ± 1.79; median 3.00 points). Most often applied objectivisation methods were duplex sonography (67%) and color duplex sonography (20%). 61% of patients got previous and concomitant medication before / during treatment with Mono-Embolex®. Mostly named were Ramipril (12%), Simvastatin (8%), ASS, Bisoprolol and Metoprolol (6% each). Most common cause for previous and concomitant medication was hypertension (47%), followed by diabetes mellitus (7%), pain therapy (6%), coronary heart disease (5%) and hyperlipidemia (4%). First treatment with Mono-Embolex® began averaged 5.9 (± 28.03; median 2.00) days after first occurrence of DVT symptoms. At 48% of patients therapy duration was planned by physicians ac-cording to guideline (“Leitlinie der Deutsche Gesellschaft für Angiologie”: at least 5 days of treat-ment). At another 48% of patients therapy duration was planned according to product characteris-tics Mono-Embolex® (“Fachinformation Mono-Embolex® 8000 I.E. Therapie Sicherheitsspritze”: ca. 10-14 days of treatment). In reality duration of therapy from enrolment to final examination stood at averaged 23.62 (± 23.53; median 17.00) days. The mean duration of treatment with Mono-Embolex® was 12.93 (± 10.97; median 11.00) days. 99% of patients got 8000 I.E. as first dosage of Mono-Embolex®. 91% of patients got a continu-ous treatment with dosage of 8000 I.E. twice a day. Mostly mentioned other dosage of Mono-Embolex® was 8000 I.E. once a day at 5% of patients. At 11% of patients therapy duration was changed compared to standard, mostly because patients did not reappear or because targeted INR value was prematurely achieved. 80% of patients were treated with vitamin-K antagonists (VKA)/oral anticoagulants (OAC), mostly Marcumar (39%) and Falithrom (28%). On average first treatment with VKA took place 5.94 (± 6.17; median 5.00) days after first treatment with Mono-Embolex®. At 43% of patients dosage of VKA was changed during treatment. Result of therapy with Mono-Embolex® concerning thrombosis was good: At 85% of finally as-sessed patients DVT was classified as “completely or partially dissolved” at the end of treatment.



85% of finally assessed patients had no post-thrombotic changes. Neither heparin induced throm-bocytopenia nor rethrombosis occurred during treatment with Mono-Embolex®. There were 68 patients (10.01% of total collective) with Adverse Advents (AE): 43 of them with one Adverse Event, 16 of them with two, 9 of them with 3 Adverse Events. In total 102 Adverse Events were reported: 64 were Serious Adverse Events (SAE), 23 of them suspected, 41 of them not suspected. 38 were non serious Adverse Events, 35 of them suspected, 3 of them not sus-pected.



3. FINAL ANALYSIS

3.1. Title

Non-interventional study to evaluate Certoparin under real-life conditions for management of deep vein thrombosis Project: CERTUM (CMEX839ADE02)

3.2. Sponsor

Novartis Pharma GmbH Roonstraße 25 90429 Nürnberg

3.3. Investigators of the NIS

169 sites in Germany

3.4. Medium in the NIS

Conventional written paper documentation

3.5. Surveillance Timelines

Start of NIS November 2011 Date of first documentation February 9th 2012 Date of last documentation January 27th 2013

3.6. Duration of Surveillance Period per Patient, examinations:

Patients were observed over a period of ca. 30-45 days under therapy with Mono-Embolex®. This collective contains completed baseline-documentations of 679 patients. Measures, collectives at first examination and at final examination: First examination: - Admission of the patient after obtaining written consent in accordance with medical decisions - Demographic data: Age, sex, size, weight - Risk factors for DVT: VTE Surgery Acute illness leading to immobilization Infection Inflammatory disease Exsiccosis Stroke Myocardial infarction Other risk factors for DVT - Laboratory parameters (if available): Thrombocyte, INR, creatinine, creatinine clearance, D-dimer, aXa



- Indication: Onset of symptoms, diagnostic method, number, location and size of thrombi - Therapy with Mono-Embolex®: Start of treatment, dose Final examination ca. 14 days after end of treatment with Mono-Embolex®: - Duration of treatment with Mono-Embolex® - Reason for selected therapy duration - Therapy with vitamin-K antagonists (VKA) - Laboratory parameters (if available): Thrombocyte, INR, creatinine, creatinine clearance, D-dimer, aXa - Report on adverse drug reactions (ADR) and adverse events (AE) - Additional documentation of certain adverse events

3.7. Collective

679 patients

3.8. Plausibility Criteria and Statistical Approach

An examination of the integrity of all target parameters in the input control of the documentation was carried out by the record management staff of SIMW GmbH. Obvious input mistakes or lack of information was noted and the original documentation was returned to the treating physician for correction / completion. Furthermore, qualified monitors from SIMW GmbH contacted selected sites randomly by telephone or onsite and, using an interview process, a comparison was made of the documented data with the patient file (source data verification; SDV). In the SDV, however, only those parameters that were normally noted in the patient records were queried. All documents received were immediately archived and all data were entered into a database. The documentation forms used were designed for scanning systems. The process of data capturing was supplemented by visual / manual controls, performed by skilled medical specialists. Additional plausibility checks were performed by software, to discover, on the one hand, any implausible or incomplete records in the physician´s report, and on the other hand, to prevent any mistakes re-sulting from the data capture process. Where it was clear that there was implausible or incomplete data in the documentation, the relevant documentation was returned to the treating physician for clarification (query management). This final analysis was conducted in the form of an “intention-to-treat” analysis on all documenta-tion submitted. Interval scaled parameters were listed by number, mean value, median, minimum, maximum, lower quartile, upper quartile, lower 5% percentile, upper 95% percentile and standard deviation. In the case of ordinal scaled parameters, the absolute frequencies of the different re-sponses have been listed as a proportional percentage of the participating cohort i.e., the adjusted relative frequency according to the number of valid entries. Full-text answers were left “as re-ported”. A homologation of terms was carried out in accordance with SIMW SOPs (because this study was carried out in Germany, german texts reported by the physicians and patients were translated). All reports of side effects have been coded in accordance with MedDRA (V 13.0) and compiled into a line-listing (CIOMS II). All reports on SAE / AE / ADR have been notified to the pharmacovigilance department of Novartis Pharma GmbH, Nürnberg within the approved time-lines.



General Note: Any differences to 100% in the frequency distributions are always conditional on a lack of detailed data in the documentation.



4. RESULTS

4.1. Demographic data

TTaabbllee 11

4.2. Frequency-distribution of age and sex

TTaabbllee 22 aanndd ffiigguurree 11

4.3. Risk factors for deep vein thrombosis (DVT)

TTaabblleess 33 -- 77

4.4. Diagnosis of deep vein thrombosis (DVT)

TTaabblleess 88 -- 1122

4.5. Previous and concomitant medication

TTaabblleess 1133 aanndd 1144

4.6. Laboratory parameters


4.7. Laboratory parameters: Analysis of differences


4.8. Therapy with Mono-Embolex®

TTaabblleess 1199 --2211

4.9. Therapy with vitamin-K antagonists (VKA)/oral anticoagulants (OAC)

TTaabbllee 2222 -- 2244

4.10. Result of therapy with Mono-Embolex®

TTaabbllee 2255



5. DRUG SAFETY (ADVERSE EVENTS) SSeeee TTaabblleess 2266 -- 3333 aanndd AAppppeennddiixx ((LLiinnee--lliissttiinngg)) This non-interventional study was monitored throughout its entire duration for reports of adverse events (including suspected cases). All document records were checked on receipt for complete-ness and plausibility of "safety" areas. Where there was a lack of clarity and / or an omission in the answers, contact was made with the treating physician. In cases of serious adverse events (re-gardless of a possible causes), reports were submitted within 24 hours to the sponsor for medical evaluation, classification and registration. All documents have been subjected to an independent evaluation by SIMW regardless of the physician’s opinion. All reported adverse events were made in English and encoded with the corresponding numbers in accordance with MedDRA (LLT; HLT; SOC). During the project, a database comparison with the sponsor’s registrations was continu-ously performed. In accordance with SOPs, evaluation of all case documents, where the treating physician reported adverse events, shows that out of a total of 68 patients (10.01% of total collective) at least one ad-verse event was registered. Overall, within this non-interventional study of Mono-Embolex® 102 single adverse events were recorded (58 “suspected”, 44 “not suspected”). In 38 patients (5.60% of total collective; 55.88% of patients with AE total), 64 adverse events were considered "serious”. In all the other 30 patients with 38 adverse events, these were considered "non serious" (table 26). The number of AE per patient sums up to 3 adverse events in 9 patients throughout the whole course of treatment. Tables 27 and 28 show an overview of the serious (table 27) and non serious adverse events (table 28) sorted by frequency of occurrence (coded by MedDRA). Table 29 shows the frequency of the respective system organ classes (SOC) of all AE, sorted by frequency of occurrence. Tables 30 and 31 show the frequency of the respective system organ classes (SOC) of the serious (table 30) and the non serious adverse events (table 31), sorted by frequency of occurrence. The causal relationship between each AE and Mono-Embolex® (causality) was assessed by the investigator. Following investigator’s assessment a causal relationship with Mono-Embolex® was not excluded in 58 AE (56.86% of all AE: Suspect / not assessable). In 44 AE cases (43.14%) there was no relationship to Mono-Embolex® (not suspected). Table 33 shows an overview of all AE coded by SOC1 (short), causality and seriousness. In 36 AE-cases (35.29%) the outcome was "complete recovery". In 8 AE-cases (7.84%) the out-come was “condition improving”. In 6 patients the outcome of the AE was “condition unchanged“. In 50 patients the outcome of the AE was not known ("unknown", 9 patients) or “not reported” (41 patients). In 2 patients the outcome was “fatal/death”, but with no causal relationship to treatment with Mono-Embolex® (“not suspected”). A detailed overview on all registered AE-cases is shown in the line-listing in the appendix.



6. ASSESSMENT OF THE NON-INTERVENTIONAL STUDY AND RESULTS In this non-interventional study conducted with Mono-Embolex® on a total of 679 patients, good data quality was achieved. No abnormalities were noted which extend beyond the normal level of a properly conducted non-interventional study.

7. RESPONSIBILITY

7.1. Guidelines and Certifications

This statistical assessment was carried out by the contract research organization: SIMW GmbH, (Statistical Institute for Marketing and Sciences), D-41844 Wegberg, Heuchterstrasse 68, Ger-many. Descriptive and inferential statistics, if applicable, have been carried out by the means of a certified statistical program (STATISTICA™) on a validated computer system by newest stan-dards.

7.2. Reliability

According to the contract closed the data were entered into the database by “single data entry”. Additionally all manually written items have been examined and verified in comparison to the origi-nal documentations in a second course. However, errors or missing data in the documents could not be recovered by this second validation procedure. In general the reliability for the reflection of the documentations in the database is better than 95%. For the dignity of the medical documenta-tions no liability is assumed by SIMW.



8. TABLES

Note: Mono-Embolex® is a registered trademark. In the following tables, for technical reasons, the nomenclature “Mono-Embolex” is used without adding the symbol ®.

Tab

les



Table 1

Demographic data

total male femalepatients valid n % ¹ valid n % ² valid n % ³

total 679 100.00%male 329 48.45% 329 100.00%female 349 51.40% 349 100.00%missing 1 0.15%

age [years] value % ¹ value % ² value % ³

number of calculable entries 672 98.97% 323 98.18% 348 99.71%mean 59.97 60.37 59.54median 61.00 62.00 60.50lower 25% quartile 49.00 51.00 47.00upper 75% quartile 72.50 72.00 73.005% percentile 34.00 38.00 29.0095% percentile 82.00 79.00 84.00minimum 18.00 18.00 19.00maximum 93.00 89.00 93.00standard deviation 15.16 13.58 16.46

height [cm] value % ¹ value % ² value % ³


weight [kg] value % ¹ value % ² value % ³


¹ : percentual reference to number total collective n = 679² : percentual reference to number of male patients n = 329



Table 2

Frequency-distribution of age and sex

categories of age [years] valid n % ¹ valid n % ² valid n % ³

0,00000<=x<10,00000 0 0.00% 0 0.00% 0 0.00%10,00000<=x<20,00000 3 0.44% 1 0.30% 2 0.57%20,00000<=x<30,00000 22 3.24% 6 1.82% 16 4.58%30,00000<=x<40,00000 32 4.71% 15 4.56% 17 4.87%40,00000<=x<50,00000 123 18.11% 55 16.72% 68 19.48%50,00000<=x<60,00000 133 19.59% 65 19.76% 68 19.48%60,00000<=x<70,00000 139 20.47% 80 24.32% 59 16.91%70,00000<=x<80,00000 169 24.89% 88 26.75% 81 23.21%80,00000<=x<90,00000 45 6.63% 13 3.95% 31 8.88%90,00000<=x<100,0000 6 0.88% 0 0.00% 6 1.72%no entries of age or sex 7 1.03% 6 1.82% 1 0.29%entries total 679 100.00% 329 100.00% 349 100.00%

¹ : percentual reference to number total collective n = 679² : percentual reference to number of male patients n = 329³ : percentual reference to number of female patients n = 349

total male female



Figure 1

Frequency-distribution of age

0

10

20

30

40

50

60

70

80

90

100

20 30 40 50 60 70 80 90 100 missing

Age [years] (upper limits)

num

ber

of p

atie

nts

male female

n = 679



Table 3

Risk factors for deep vein thrombosis (DVT) Part I

infection or acute flammable, not bedridden disease valid n² % ¹ % ³

yes 131 19.29% 19.88%no 528 77.76% 80.12%number of valid entries 659 97.05% 100.00%

infection or acute flammable, bedridden disease valid n² % ¹ % ³


centrally placed catheter / port catheter valid n² % ¹ % ³


acute heart failure valid n² % ¹ % ³


acute decompensated COPD without ventilation valid n² % ¹ % ³


stroke with leg paresis valid n² % ¹ % ³


acute decompensated COPD with ventilation valid n² % ¹ % ³


sepsis valid n² % ¹ % ³


¹ : percentual reference to number total collective n = 679² : multiple entries per patient possible³ : adjusted relative frequency to number of valid entries



Table 4

Risk factors for deep vein thrombosis (DVT) Part II

earlier DVT / pulmonary embolism valid n² % ¹ % ³


thrombophilic hemostasis defects valid n² % ¹ % ³


malignant disease valid n² % ¹ % ³


VTD at relations in first degree valid n² % ¹ % ³


chronic heart failure valid n² % ¹ % ³


status post heart attack valid n² % ¹ % ³


obesity (BMI > 30 kg/m²) valid n² % ¹ % ³


endocrine chemotherapy valid n² % ¹ % ³





Table 5

Risk factors for deep vein thrombosis (DVT) Part III

chemotherapy valid n² % ¹ % ³


treatment with estrogen with/without progestin valid n² % ¹ % ³


nicotine abuse valid n² % ¹ % ³


nephrotic syndrome valid n² % ¹ % ³


highly developed varicosis valid n² % ¹ % ³


exsiccosis or hyperviscosity syndrome valid n² % ¹ % ³


postthrombotic syndrome valid n² % ¹ % ³


minor surgical procedure valid n² % ¹ % ³





Table 6

Risk factors for deep vein thrombosis (DVT) Part IV

injury with/without less soft tissue trauma valid n² % ¹ % ³


longer-lasting operation (> 2 hours) valid n² % ¹ % ³


cross joint immobilisation of lower extremity valid n² % ¹ % ³


arthroscopically assisted joint surgery at lower extrem. valid n² % ¹ % ³


major procedures in stomach and pelvic area valid n² % ¹ % ³


polytrauma, injuries vertical column, pelvis, lower extr. valid n² % ¹ % ³


major procedures vertical column, pelvis, hip, knee valid n² % ¹ % ³


major surgical procedures in body cavities valid n² % ¹ % ³





Table 7

Risk factors for deep vein thrombosis (DVT) Part V

major reoperations within 2 weeks valid n² % ¹ % ³


frequent air-trips / bus-trips valid n² % ¹ % ³


standing activity valid n² % ¹ % ³


restricted sitting for a longer time valid n² % ¹ % ³


further relevant risk factors (as reported) valid n² % ¹ % ³

immobilisation 8 1.18% 27.59%carcinoma 3 0.44% 10.34%diabetes mellitus 2 0.29% 6.90%phlebitis 2 0.29% 6.90%arthritis 1 0.15% 3.45%ablatio mammae 1 0.15% 3.45%body building 1 0.15% 3.45%coronary angiography 1 0.15% 3.45%depression 1 0.15% 3.45%dermatitis 1 0.15% 3.45%gastrointestinal disease 1 0.15% 3.45%hyperlipidemia 1 0.15% 3.45%hypertension 1 0.15% 3.45%lung fibrosis 1 0.15% 3.45%Parkinson´s disease 1 0.15% 3.45%playing soccer 1 0.15% 3.45%positive family anamnesis 1 0.15% 3.45%splenectomy 1 0.15% 3.45%number of valid entries 29 4.27% 100.00%




Table 8

Diagnosis of deep vein thrombosis (DVT) Part I

Localization / affected vein - Right side

lower leg valid n² % ¹ % ³


lower leg with v. poplitea valid n² % ¹ % ³


upper leg valid n² % ¹ % ³


pelvis valid n² % ¹ % ³


pelvis with v. iliaca externa valid n² % ¹ % ³


pelvis with v. iliaca communis valid n² % ¹ % ³


pelvis with v. cava inferior valid n² % ¹ % ³





Table 9

Diagnosis of deep vein thrombosis (DVT) Part II

Localization / affected vein - Left side

lower leg valid n² % ¹ % ³


lower leg with v. poplitea valid n² % ¹ % ³


upper leg valid n² % ¹ % ³


pelvis valid n² % ¹ % ³


pelvis with v. iliaca externa valid n² % ¹ % ³


pelvis with v. iliaca communis valid n² % ¹ % ³


pelvis with v. cava inferior valid n² % ¹ % ³





Table 10

Diagnosis of deep vein thrombosis (DVT) Part III

Localization / affected vein

atypical vein localization (as reported) valid n² % ¹ % ³

arm (left) 2 0.29% 25.00%cubital (right) 1 0.15% 12.50%gastrocnemius muscle 1 0.15% 12.50%sinus 1 0.15% 12.50%soleus 1 0.15% 12.50%tibialis (left) 1 0.15% 12.50%subclavian vein (right) 1 0.15% 12.50%number of valid entries 8 1.18% 100.00%




Table 11

Diagnosis of deep vein thrombosis (DVT) Part IV

Kind of thrombosis

symptomatic valid n² % ¹ % ³


occlusion in imaging valid n² % ¹ % ³

partially occludent 276 40.65% 51.78%completely occludent 257 37.85% 48.22%number of valid entries 533 78.50% 100.00%

multi-opening thrombosis valid n² % ¹ % ³


port thrombosis valid n² % ¹ % ³


port thrombosis with pulmonary embolism valid n² % ¹ % ³





Table 12

Diagnosis of deep vein thrombosis (DVT) Part V

first occurence of DVT symptoms value % ¹ % ³[days before first treatment with Mono-Embolex]

number of calculable entries 627 92.34% - / -mean 5.90median 2.00lower 25% quartile 1.00upper 75% quartile 4.005% percentile 0.0095% percentile 15.00minimum 0.00maximum 589.00standard deviation 28.03

Wells-Score (if documented) [points] value % ¹ % ³


objectivisation method (as reported) valid n % ¹ % ³

duplex sonography 203 29.90% 67.44%color duplex sonography 61 8.98% 20.27%compression sonography 14 2.06% 4.65%clinical examination 12 1.77% 3.99%phlebography 11 1.62% 3.65%number of valid entries 301 44.33% 100.00%




Table 13

Previous and concomitant medication Part I

medication (most frequent) ATC valid n² % ¹ % ³

Ramipril C09AA05 80 11.78% 8.57%Simvastatin C10AA01 51 7.51% 5.46%Metoprolol C07AB02 44 6.48% 4.71%ASS (acetylsalicylic acid) N02BA01 43 6.33% 4.60%Bisoprolol C07AB07 39 5.74% 4.18%L-Thyroxin H03AA01 29 4.27% 3.10%Amlodipin C08CA01 28 4.12% 3.00%Torasemid C03CA04 25 3.68% 2.68%Pantoprazol A02BC02 25 3.68% 2.68%Ibuprofen C01EB16 23 3.39% 2.46%Candesartan C09CA06 20 2.95% 2.14%Omeprazol A02BC01 18 2.65% 1.93%Metformin A10BA02 18 2.65% 1.93%Allopurinol M04AA01 18 2.65% 1.93%Valsartan C09CA03 16 2.36% 1.71%Vocado HCT C09DX03 12 1.77% 1.28%Enalapril C09AA02 12 1.77% 1.28%Diclofenac S01BC03 12 1.77% 1.28%Beloc zok C07CB02 11 1.62% 1.18%Micardis C09CA07 9 1.33% 0.96%Lisinopril C09AA03 9 1.33% 0.96%Furosemid C03CA01 8 1.18% 0.86%Euthyrox H03AA01 8 1.18% 0.86%Votum C09CA08 7 1.03% 0.75%Prednisolon A01AC04 7 1.03% 0.75%Novaminsulfon N02BB02 7 1.03% 0.75%Falithrom M03BA01 7 1.03% 0.75%Codiovan C09DA03 6 0.88% 0.64%Targin N02AA05 5 0.74% 0.54%Spiriva C03DA01 5 0.74% 0.54%Marcumar B01AA04 5 0.74% 0.54%Losartan C09CA01 5 0.74% 0.54%Carvedilol C07AG02 5 0.74% 0.54% less frequent entries (<0.5%) 317 46.69% 33.94% number of valid entries 934 137.56% 100.00%

n = 679¹ : percentual reference to number total collective² : multiple entries per patient possible³ : adjusted relative frequency to number of valid entries



Table 14

Previous and concomitant medication Part II

reason for treatment (most frequent) valid n² % ¹ % ³

Hypertension 316 46.54% 38.77%Diabetes mellitus 48 7.07% 5.89%Pain therapy 42 6.19% 5.15%Coronary heart disease 31 4.57% 3.80%Hyperlipidemia 30 4.42% 3.68%Prophylaxis 29 4.27% 3.56%Heart insufficiency 25 3.68% 3.07%Hypothyreosis 18 2.65% 2.21%Hypercholesterimenia 17 2.50% 2.09%Hyperuricemia 12 1.77% 1.47%Depression 12 1.77% 1.47%COPD 12 1.77% 1.47%Edema 11 1.62% 1.35%Gastroesophageal reflux disease 9 1.33% 1.10%Contraception 9 1.33% 1.10%Arthrosis 7 1.03% 0.86%Gastritis 7 1.03% 0.86%Atrial fillibration 6 0.88% 0.74%Hyperthyreosis 6 0.88% 0.74%Osteoporosis 5 0.74% 0.61%Metabolc disorder 5 0.74% 0.61% less frequent entries (<0.5%) 158 23.27% 19.39% number of valid entries 815 120.03% 100.00%




Table 15

Laboratory parameters Part I

before treatment´s start after treatment´s endLaboratory parameters value % ¹ % ³ value % ¹ % ³

Platelet count [109/l]

number of calculable entries 417 61.41% - / - 279 41.09% - / -mean 258.30 258.08median 249.00 256.00lower 25% quartile 199.00 200.00upper 75% quartile 308.00 310.005% percentile 141.00 153.0095% percentile 410.00 389.00minimum 94.00 84.00maximum 595.00 480.00standard deviation 83.46 72.99

Blood creatinine [mg/dl]


Creatinine clearance [ml/min]


¹ : percentual reference to number total collective n = 679³ : adjusted relative frequency to number of valid entries



Table 16

Laboratory parameters Part II

before treatment´s start after treatment´s endLaboratory parameters value % ¹ % ³ value % ¹ % ³

aXa value [IE/ml]


D-dimers [mg/l]





Table 17

Laboratory parameters: Analysis of differences* Part IPre-/post comparison

Laboratory parameters value % ¹ % ³

Platelet count [109/l]

number of calculable entries 228 33.58% - / -mean -6.86median -3.00lower 25% quartile -29.00upper 75% quartile 14.505% percentile -89.0095% percentile 76.00minimum -252.00maximum 196.00standard deviation 53.78

Blood creatinine [mg/dl]

number of calculable entries 190 27.98% - / -mean -0.01median -0.01lower 25% quartile -0.06upper 75% quartile 0.035% percentile -0.1895% percentile 0.20minimum -0.40maximum 0.32standard deviation 0.11

Creatinine clearance [ml/min]

number of calculable entries 58 8.54% - / -mean 0.21median 0.00lower 25% quartile -2.00upper 75% quartile 3.005% percentile -15.4095% percentile 25.00minimum -31.20maximum 25.40standard deviation 9.73

¹ : percentual reference to number total collective n= 679³ : adjusted relative frequency to number of valid entries* : positive values indicate an increase, negative values a reduction of each parameter value during course of treatment with Mono-Embolex



Table 18

Laboratory parameters: Analysis of differences* Part IIPre-/post comparison

Laboratory parameters value % ¹ % ³

aXa value [IE/ml]

number of calculable entries 13 1.91% - / -mean -0.02median 0.00lower 25% quartile -0.02upper 75% quartile 0.005% percentile -0.2095% percentile 0.11minimum -0.20maximum 0.11standard deviation 0.07

D-dimers [mg/l]

number of calculable entries 68 10.01% - / -mean -0.96median -0.59lower 25% quartile -1.19upper 75% quartile -0.155% percentile -6.7195% percentile 2.28minimum -7.72maximum 3.41standard deviation 1.95

¹ : percentual reference to number total collective n= 679³ : adjusted relative frequency to number of valid entries* : positive values indicate an increase, negative values a reduction of each parameter value during course of treatment with Mono-Embolex



Table 19

Therapy with Mono-Embolex Part I

planned duration of therapy valid n % ¹ % ³

according to guideline (at least 5 days) 328 48.31% 48.38%according product characteristics Mono-Emb. (10-14 days) 327 48.16% 48.23%according other standard 23 3.39% 3.39%number of valid entries 678 99.85% 100.00%

if other standard, which one: valid n % ¹ % ³

switch to Xarelto 11 1.62% 47.83%Monoembolex therapy for more than 15 days 9 1.33% 39.13%individual therapy 2 0.29% 8.70%switch to Fraxiparin 1 0.15% 4.35%number of valid entries 23 3.39% 100.00%

real duration of therapy (enrolment to final examin.) [days] value % ¹ % ³


duration of treatment with Mono-Embolex [days] value % ¹ % ³


¹ : percentual reference to number total collective n = 679² : multiple entries per patient possible³ : adjusted relative frequency to number of valid entries*: ULN = upper limit of normal



Table 20

Therapy with Mono-Embolex Part II

first dosage of Mono-Embolex [I.E.] valid n % ¹ % ³

8000 669 98.53% 99.11%3000 6 0.88% 0.89%number of valid entries 675 99.41% 100.00%

last dosage of Mono-Embolex [I.E.] valid n % ¹ % ³

8000 642 94.55% 98.77%3000 6 0.88% 0.92%4000 1 0.15% 0.15%5000 1 0.15% 0.15%number of valid entries 650 95.73% 100.00%

continuous treatment with dosage of 8000 I.E. twice a day valid n % ¹ % ³

yes 619 91.16% 93.93%no (other dosage regimen) 40 5.89% 6.07%number of valid entries 659 97.05% 100.00%

if no, which dosage regimen: 1x1 31 4.57% 86.11% 1x1 from day 6 3 0.44% 8.33% 1x1 from day 7 1 0.15% 2.78% 1x1 (4000 I.E.) 1 0.15% 2.78% number of valid entries 36 5.30% 100.00%

dosages omitted during treatment with Mono-Embolex valid n % ¹ % ³


if yes, reason: non-compliance 1 0.15% 33.33% rethrombosis 1 0.15% 33.33% dose missed 1 0.15% 33.33% number of valid entries 3 0.44% 100.00%

¹ : percentual reference to number total collective n = 679² : multiple entries per patient possible³ : adjusted relative frequency to number of valid entries*: ULN = upper limit of normal



Table 21

Therapy with Mono-Embolex Part III

reasons for change of therapy duration comp. to standards valid n % ¹ % ³

patient did not reappear 29 4.27% 40.28%allergic reaction to Mono-Embolex 1 0.15% 1.39%bleeding occurred 1 0.15% 1.39%rethrombosis 1 0.15% 1.39%increased risk of bleeding 2 0.29% 2.78%non-compliance of Mono-Embolex 0 0.00% 0.00%non-compliance of oral anticoagulants 6 0.88% 8.33%other reason 32 4.71% 44.44%number of valid entries 72 10.60% 100.00%

if other reason, which:achievement of target INR value 8 1.18% 25.00%tumor 5 0.74% 15.63%switch to other medication 4 0.59% 12.50%hospitalization 3 0.44% 9.38%patient´s wish 2 0.29% 6.25%only symptomes of thrombosis 2 0.29% 6.25%necessary travelling after diagnosis 2 0.29% 6.25%increase in transaminases 1 0.15% 3.13%pulmonary embolism 1 0.15% 3.13%stroke 1 0.15% 3.13%hepatic dysfunction 1 0.15% 3.13%switch to other physician 1 0.15% 3.13%thrombocytopenia 1 0.15% 3.13%number of valid entries 32 4.71% 100.00%

first treatment with vitamin-K antagonists (VKA) value % ¹ % ³[days after first treatment with Mono-Embolex]





Table 22

Therapy with vitamin-K antagonists (VKA)/oral anticoagulants (OAC) Part I

therapy with VKA/OAC valid n % ¹ % ³


therapy with VKA/OAC (medication, as reported) valid n % ¹ % ³

Marcumar 264 38.88% 48.44%Falithrom 187 27.54% 34.31%Xarelto 49 7.22% 8.99%Phenprocoumon 33 4.86% 6.06%Pradaxa 9 1.33% 1.65%ASS 2 0.29% 0.37%Rivaroxaban 1 0.15% 0.18%number of valid entries 545 80.27% 100.00%

dosage of VKA/OAC [mg] value % ¹ % ³


dosage of VKA/OAC changed during treatment valid n % ¹ % ³

no 333 49.04% 53.37%yes 291 42.86% 46.63%number of valid entries 624 91.90% 100.00%

applied VKA/OAC during changed treatment (as rep) valid n % ¹ % ³

Marcumar 185 27.25% 47.31%Falithrom 151 22.24% 38.62%Phenprocoumon 28 4.12% 7.16%Xarelto 26 3.83% 6.65%Pradaxa 1 0.15% 0.26%number of valid entries 391 57.58% 100.00%




Table 23

Therapy with vitamin-K antagonists (VKA)/oral anticoagulants (OAC) Part II

initial dosage of VKA/OAC at changed treatment [mg] value % ¹ % ³


targeted INR value (minimum) value % ¹ % ³


targeted INR value (maximum) value % ¹ % ³





Table 24

Therapy with vitamin-K antagonists (VKA)/oral anticoagulants (OAC) Part III

dosage after change INR value at this timechanges of dosage of VKA/OAC value % ¹ % ³ value % ¹ % ³

first changenumber of calculable entries 326 48.01% - / - 183 26.95% - / -mean 5.61 1.88median 6.00 1.70lower 25% quartile 3.00 1.30upper 75% quartile 6.00 2.205% percentile 1.00 1.0095% percentile 16.00 3.40minimum 1.00 0.80maximum 20.00 5.70standard deviation 4.05 0.79

second changenumber of calculable entries 254 37.41% - / - 143 21.06% - / -mean 3.38 2.18median 3.00 2.10lower 25% quartile 3.00 1.70upper 75% quartile 3.00 2.605% percentile 1.50 1.2095% percentile 6.00 3.50minimum 0.75 0.90maximum 22.00 4.60standard deviation 2.52 0.68

third changenumber of calculable entries 151 22.24% - / - 133 19.59% - / -mean 2.85 2.24median 1.50 2.20lower 25% quartile 1.50 1.80upper 75% quartile 3.00 2.605% percentile 1.00 1.3095% percentile 6.00 3.30minimum 0.50 0.90maximum 21.00 4.40standard deviation 2.37 0.61

fourth changenumber of calculable entries 52 7.66% - / - 52 7.66% - / -mean 2.56 2.19median 3.00 2.20lower 25% quartile 1.50 1.85upper 75% quartile 3.00 2.505% percentile 0.50 1.3095% percentile 4.50 2.80minimum 0.00 1.00maximum 6.00 4.00standard deviation 1.26 0.53




Table 25

Result of therapy with Mono-Embolex

result concerning thrombosis valid n % ¹ % ³

unchanged 59 8.69% 15.40%partial dissolution 169 24.89% 44.13%complete dissolution 155 22.83% 40.47%number of valid entries 383 56.41% 100.00%

post-thrombotic changes valid n % ¹ % ³

no changes 359 52.87% 84.87%reflux 20 2.95% 4.73%valve insufficiency 24 3.53% 5.67%gap in diameter 15 2.21% 3.55%other 5 0.74% 1.18%if other, which change (as reported): edema 2 0.29% 0.47% varicosis 1 0.15% 0.24% partial recanalization 1 0.15% 0.24% compression 1 0.15% 0.24%number of valid entries 423 62.30% 100.00%

bleedings occurred during treatment valid n % ¹ % ³

no 669 98.53% 99.85%yes 1 0.15% 0.15%if yes, which localization (as reported): colon diverticulum (minor bleeding) 1 0.15% 0.15%number of valid entries 670 98.67% 100.00%

heparin induced thrombocytopenia occurred valid n % ¹ % ³


rethromboses occurred during treatment valid n % ¹ % ³


pulmomary embolism occurred during treatment valid n % ¹ % ³

no 666 98.09% 99.25%yes 5 0.74% 0.75%if yes, diagnostic method (as reported): computer tomography (CT) 4 0.59% 0.60% echocardiogram 1 0.15% 0.15%number of valid entries 671 98.82% 100.00%




9. DRUG SAFETY TABLES



Table 26

Evaluation of registered AE PART I

patients with AE valid n² % ¹ % °

patients with AE total 68 10.01% 100.00% 1÷ 11patients with serious adverse events 38 5.60% 55.88% 1÷ 19patients with non serious adverse events 30 4.42% 44.12% 1÷ 24

kind of adverse events n ² % *

Serious adverse events 64 62.75%suspected 23not suspected 41

Non serious adverse events 38 37.25%suspected 35not suspected 3

number of AE total 102 100.00%

patients with... valid n % ¹

1 adverse event 43 6.33% 1÷ 172 adverse events 16 2.36% 1÷ 453 adverse events 9 1.33% 1÷ 79

number of AE total 102 - / -

¹ : percentual reference to number of total collective n = 679² : multiple entries per patient possible³ : occurence of AE per treated patient (95% probability of occurence)°: adjusted percentual reference to number of patients with AE*: adjusted percentual reference to number of all AE

95%-incidence ³

95%-incidence ³

95%-incidence ³



Table 27

Evaluation of registered AE PART IISerious AE

Serious adverse events coded by MedDRA LLT * valid n² % ¹

MedDRA termPost thrombotic syndrome 40 5.89% 1÷ 18Pulmonary embolism 6 0.88% 1÷ 119Transaminases increased 3 0.44% 1÷ 238Cerebrovascular accident 2 0.29% 1÷ 357Rethrombosis 1 0.15% 1÷ 715Venous recanalisation 1 0.15% 1÷ 715Dyspnoea 1 0.15% 1÷ 715Fibrin D dimer increased 1 0.15% 1÷ 715Diverticulum intestinal haemorrhagic 1 0.15% 1÷ 715International normalised ratio increased 1 0.15% 1÷ 715Metastatic bronchial carcinoma 1 0.15% 1÷ 715Pancreatic carcinoma 1 0.15% 1÷ 715Pneumonia 1 0.15% 1÷ 715Blood creatinine increased 1 0.15% 1÷ 715Renal failure 1 0.15% 1÷ 715Breast cancer 1 0.15% 1÷ 715Brain neoplasm 1 0.15% 1÷ 715

serious AE total 64 - / -

¹ : percentual reference to number of total collective n = 679² : multiple entries per patient possible³ : occurence of AE per treated patient (95% probability of occurence)°: adjusted percentual reference to number of patients with AE* : seriousness assessed by physicians information

95%-incidence ³



Table 28

Evaluation of registered AE PART IIINon serious AE

non serious adverse events coded by MedDRA LLT * valid n² % ¹

MedDRA termPlatelet count decreased 11 1.62% 1÷ 65Creatinine renal clearance decreased 10 1.47% 1÷ 71Blood creatinine increased 6 0.88% 1÷ 119Fibrin D dimer increased 5 0.74% 1÷ 143International normalised ratio increased 3 0.44% 1÷ 238Thrombocytopenia 1 0.15% 1÷ 715Oedema 1 0.15% 1÷ 715Post thrombotic syndrome 1 0.15% 1÷ 715

non serious AE total 38 - / -

¹ : percentual reference to number total collective n = 679² : multiple entries per patient possible³ : occurence of AE per treated patient (95% probability of occurence)°: adjusted percentual reference to number of patients with AE* : seriousness assessed by physicians information

95%-incidence ³



Table 29

Analysis of AE by System Organ Classes [SOC]All AE

Adverse events [SOC1] MedDRA valid n² % ¹

SOC organ class short term / long term

VASC VASCULAR DISORDERS 41 40.20% 1÷ 17INV INVESTIGATIONS 41 40.20% 1÷ 17RESP RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 7 6.86% 1÷ 102NEOP NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED 4 3.92% 1÷ 179NERV NERVOUS SYSTEM DISORDERS 2 1.96% 1÷ 357CARD CARDIAC DISORDERS 2 1.96% 1÷ 357BLOOD BLOOD AND LYMPHATIC SYSTEM DISORDERS 1 0.98% 1÷ 715GENRL GENERAL DISORDERS AND ADMINISTRATION SITE COND. 1 0.98% 1÷ 715INF INFECTIONS AND INFESTATIONS 1 0.98% 1÷ 715RENAL RENAL AND URINARY DISORDERS 1 0.98% 1÷ 715GASTR GASTROINTESTINAL DISORDERS 1 0.98% 1÷ 715

TOTAL all adverse events 102

¹ : percentual reference to number of adverse events total n = 102² : multiple entries per patient possible³ : occurence of AE per treated patient (95% probability of occurence) patients n = 679* : sorted by frequency

95%-incidence ³

AE entries*



Table 30

Analysis of SAE by System Organ Classes [SOC]Serious AE

Serious adverse events [SOC1] MedDRA valid n² % ¹


VASC VASCULAR DISORDERS 40 39.22% 1÷ 18RESP RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 7 6.86% 1÷ 102INV INVESTIGATIONS 6 5.88% 1÷ 119NEOP NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED 4 3.92% 1÷ 179CARD CARDIAC DISORDERS 2 1.96% 1÷ 357INF INFECTIONS AND INFESTATIONS 2 1.96% 1÷ 357RENAL RENAL AND URINARY DISORDERS 1 0.98% 1÷ 715IMMUN IMMUNE SYSTEM DISORDERS 1 0.98% 1÷ 715GASTR GASTROINTESTINAL DISORDERS 1 0.98% 1÷ 715

TOTAL serious adverse events 64


95%-incidence ³

SAE entries*



Table 31

Analysis of SAE by System Organ Classes [SOC]Non serious AE

Non serious adverse events [SOC1] MedDRA valid n² % ¹


INV INVESTIGATIONS 35 34.31% 1÷ 20VASC VASCULAR DISORDERS 1 0.98% 1÷ 715GENRL GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIO 1 0.98% 1÷ 715BLOOD BLOOD AND LYMPHATIC SYSTEM DISORDERS 1 0.98% 1÷ 715

TOTAL non serious adverse events 38


95%-incidence ³

AE entries*



Table 32

General Assessment of Adverse Events

SAE non SAE All AE

causality investigator events events events % ²

Suspect 23 5 28 27.45%Not assessable 0 30 30 29.41%Not suspected 41 3 44 43.14%Not assessed 0 0 0 0.00%

outcome events events events % ²

Complete Recovery 20 16 36 35.29%Condition Improving 8 0 8 7.84%Condition Unchanged 6 0 6 5.88%Fatal/Death 2 0 2 1.96%Unknown 5 4 9 8.82%Not reported 23 18 41 40.20%

² : adjusted percentual reference to number of AE total n = 102



Table 33

Causality and seriousness of Adverse Events, overviewAll AE

AE SOC1 short Causality non serious serious total

VASC Suspect 0 7 7Not assessable 0 4 4Not suspected 1 29 30

INV Suspect 5 3 8Not assessable 28 1 29Not suspected 2 2 4

RESP Suspect 0 1 1Not assessable 0 3 3Not suspected 0 3 3

NEOP Suspect 0 0 0Not assessable 0 2 2Not suspected 0 2 2

NERV Suspect 0 0 0Not assessable 0 0 0Not suspected 0 2 2

CARD Suspect 0 1 1Not assessable 0 0 0Not suspected 0 1 1

BLOOD Suspect 0 0 0Not assessable 1 0 1Not suspected 0 0 0

GENRL Suspect 0 0 0Not assessable 1 0 1Not suspected 0 0 0

INF Suspect 0 0 0Not assessable 0 1 1Not suspected 0 0 0

RENAL Suspect 0 0 0Not assessable 0 0 0Not suspected 0 1 1

GASTR Suspect 0 1 1Not assessable 0 0 0

Not suspected 0 0 0

results total 38 64 102

Seriousness



10. APPENDIX Line-Listing: 102 Adverse Events from 68 patients

Ap

pen

dix

Event Seriousness

Event Causality

Center-/ Pat.-Nr.

Age [Y]

Gender

AE onset Action taken Outcome Causality Event VerbatimMedDRA Preferred

Term

Not serious Not assessable 450/3 69 f 23.02.2012 00:00 Treatment Discontinued Not Reported Not assessable Re-increased of D-Dimer Fibrin D dimer increasedNot serious Not assessable 450/2 81 m 31.01.2012 00:00 Treatment Discontinued Complete Recovery Not assessable Increased D-Dimer Fibrin D dimer increased

Not serious Not assessable 450/1 55 m 10.02.2012 00:00 Treatment Discontinued Not Reported Not assessableRe-increase of D-Dimer/ D-Dimer was at 564 mcg/l Fibrin D dimer increased

Not serious Not assessable 195/4 46 m 25.05.2012 00:00 Unknown Not Reported Not assessable Platelets decreased Platelet count decreased

Not serious Not assessable 166/2 76 f 31.05.2012 00:00 Treatment Discontinued Complete Recovery Not assessable Creatinine renal clearance decreasedCreatinine renal clearance decreased

Not serious Not assessable 423/1 69 m 16.02.2012 00:00 Treatment Discontinued Not Reported Not assessable Platelets decreased Platelet count decreased

Not serious Not assessable 190/1 71 f 01.10.2012 00:00 Treatment Discontinued Complete Recovery Not assessableCreatinine renal clearance decreased 57 ml/min, 55 ml/min

Creatinine renal clearance decreased

Not serious Not assessable 190/2 73 m 01.10.2012 00:00 Treatment Discontinued Complete Recovery Not assessable Creatinine renal clearance decreasedCreatinine renal clearance decreased

Not serious Not assessable 070/4 41 f 28.08.2012 00:00 Treatment Discontinued Unknown Not assessable Fibrin D dimer increased Fibrin D dimer increasedNot serious Not assessable 301/2 79 m 18.06.2012 00:00 Treatment Discontinued Complete Recovery Not assessable Thrombocytopenia Thrombocytopenia

Not serious Not assessable 301/2 79 m 21.06.2012 00:00 Treatment Discontinued Complete Recovery Not assessable Serum creatinine increasedBlood creatinine increased

Not serious Not assessable 301/2 79 m 21.06.2012 00:00 Treatment Discontinued Complete Recovery Not assessable Creatinine renal clearance decreasedCreatinine renal clearance decreased

Not serious Not assessable 301/3 76 f 28.06.2012 00:00 Treatment Discontinued Complete Recovery Not assessable Creatinine renal clearance decreasedCreatinine renal clearance decreased

Not serious Not assessable 076/1 66 m 02.07.2012 00:00 Treatment Discontinued Unknown Not assessable Creatinine renal clearance decreasedCreatinine renal clearance decreased

Not serious Not assessable 463/1 58 m 02.05.2012 00:00 Treatment Discontinued Not Reported Not assessable Creatinine renal clearance decreasedCreatinine renal clearance decreased

Not serious Suspect 037/4 64 f 29-Mai-2012 Unknown Complete Recovery Suspect Platelets decreased Platelet count decreasedNot serious Not assessable 328/1 41 f 17-Aug-2012 Treatment Discontinued Not Reported Not assessable Fibrin D dimer increased Fibrin D dimer increased

Not serious Suspect 101/4 62 m 24-Jul-2012 Treatment Discontinued Complete Recovery Suspect INR increasedInternational normalised ratio increased

Not serious Suspect 101/3 45 m 20-Jul-2012 Treatment Discontinued Complete Recovery Suspect INR increasedInternational normalised ratio increased

Not serious Not assessable 373/1 80 f Treatment Discontinued Complete Recovery Not assessable Oedema Oedema

Not serious Suspect 477/3 39 f 11-Jun-2012 Treatment Discontinued Complete Recovery Suspect Serum creatinine increasedBlood creatinine increased

Not serious Not assessable 366/4 84 f 25-Okt-2012 Treatment Discontinued Not Reported Not assessable Serum creatinine increasedBlood creatinine increased

Not serious Not assessable 092/1 71 m 18-Jun-2012 Treatment Discontinued Not Reported Not assessable Platelet count decreased Platelet count decreased

Not serious Not assessable 168/1 71 m 23-Mai-2012 Treatment Discontinued Not Reported Not assessable Platelet count decreased Platelet count decreased

Not serious Not assessable 366/5 77 m 13-Jul-2012 Treatment Discontinued Not Reported Not assessable Serum creatinine increasedBlood creatinine increased

Not serious Not assessable 386/4 49 f Unknown Not Reported Not assessable Reduced creatinine clearanceCreatinine renal clearance decreased

CERTUM NIS Database nsADR

Not serious Not assessable 398/2 62 m 9-Okt-2012 Treatment Discontinued Complete Recovery Not assessablePlatelet count decreased to 84 x 10x9/L Platelet count decreased

Not serious Not assessable 079/2 78 f 15-Jun-2012 Treatment Discontinued Not Reported Not assessablePlatelet count decreased to 145 x 10x9/L Platelet count decreased

Not serious Not assessable 133/3 59 m 7-Jun-2012 Treatment Discontinued Unknown Not assessablePlatelet count decreased to 94 x 10x9/L Platelet count decreased

Not serious Suspect 267/1 77 m 25-Jan-2012 Treatment Discontinued Unknown SuspectPlatelet count decreased to 132 x 10x9/L Platelet count decreased

Not serious Not assessable 267/3 77 m 20-Feb-2012 Treatment Discontinued Not Reported Not assessableCreatinine renal clearance decreased to 68 ml/min


Not serious Not assessable 267/4 73 m 13-Mrz-2012 Treatment Discontinued Not Reported Not assessableCreatinine renal clearance decreased to 30 ml/min


Not serious Not assessable 004/2 78 m 14-Mai-2012 Treatment Discontinued Not Reported Not assessableSerum creatinine increased to 1.3 mg/dl

Blood creatinine increased

Not serious Not assessable 371/1 70 m 19-Nov-2012 Treatment Discontinued Not Reported Not assessableSerum creatinine increased to 1.46 mg/dl

Blood creatinine increased

Not serious Not assessable 519/3 28 f 14-Sep-2012 Treatment Discontinued Not Reported Not assessable Platelet count decreased to 98 x10x9/L Platelet count decreased

CERTUM NIS Database nsADR

Event Seriousness

Event Causality

Center-/ Pat.-

Nr.

Age [Y]

Gender AE onset Action taken Outcome Causality Event VerbatimMedDRA Preferred

Term

Not serious Not Suspected 498/4 43 m 6-Sep-2012 Treatment Discontinued Complete Recovery Not Suspected Reduced platelet count Platelet count decreased

Not serious Not Suspected 088/5 65 m 14-Sep-2012 Treatment Discontinued Complete Recovery Not Suspected Post thrombotic syndromePost thrombotic syndrome

Not serious Not Suspected 322/1 74 f 26-Jul-2012 Treatment Discontinued Not Reported Not Suspected Increased INRInternational normalised ratio increased

CERTUM NIS Database nsAEnr

Event Seriousness

Event Causality

Center-/ Pat.-

Nr.

Age [Y]

Gender


Term

Serious Suspect 344/1 f 20-Jan-2012 Treatment Discontinued Complete Recovery Suspect Pulmonary embolism Pulmonary embolism

Serious Suspect 481/1 40 m Treatment Discontinued Complete Recovery Suspect ALT increasedAlanine aminotransferase increased

Serious Suspect 481/1 40 m Treatment Discontinued Complete Recovery Suspect Elevated transaminases Transaminases increased

Serious Suspect 481/1 40 m Treatment Discontinued Complete Recovery Suspect AST increased

Aspartate aminotransferase increased

Serious Suspect 450/3 69 f 23.02.2012 00:00 Treatment Discontinued Not Reported Suspect Post thrombotic change like reflux Post thrombotic syndrome

Serious Suspect 450/2 81 m 07.02.2012 00:00 Treatment Discontinued Complete Recovery Suspect Bleeding in colon diverticulumDiverticulum intestinal haemorrhagic

Serious Suspect 450/2 81 m 24.02.2012 00:00 Treatment Discontinued Not Reported Suspect Postthrombotic changes Post thrombotic syndrome

Serious Suspect 450/1 55 m 21.02.2012 00:00 Treatment Discontinued Not Reported Suspect Valve incompetence Heart valve incompetence

Serious Suspect 450/1 55 m 21.02.2012 00:00 Treatment Discontinued Not Reported Suspect Post thrombotic changes Post thrombotic syndromeSerious Suspect 450/4 50 f 03.05.2012 00:00 Treatment Discontinued Not Reported Suspect Partielle recanalisation Venous recanalisation

Serious Suspect 450/4 50 f 03.05.2012 00:00 Treatment Discontinued Not Reported SuspectPostthrombotic changes like change of the calibre Post thrombotic syndrome

Serious Suspect 450/4 50 f 03.05.2012 00:00 Treatment Discontinued Not Reported SuspectPostthrombotic changes like change of the calibre Vasodilatation

Serious Suspect 133/1 47 m 28.06.2012 00:00 No Change Condition Improving Suspect Pulmonary embolism both sides Pulmonary embolismSerious Suspect 328/4 73 m 13-Nov-2012 Treatment Discontinued Unknown Suspect Brain tumor Brain neoplasmSerious Suspect 075/5 52 f Treatment Discontinued Not Reported Suspect Postthrombotic change: reflux Venous insufficiency

Serious Suspect 075/5 52 f 14-Dez-2012 Treatment Discontinued Not Reported Suspect Postthrombotic change: reflux Post thrombotic syndrome

Serious Suspect 079/3 74 m Treatment Discontinued Not Reported SuspectIncreased D-Dimer (3303 Ng/ml, 6161 Ng/ml) Fibrin D dimer increased

Serious Suspect 079/3 74 m Okt-2012 Treatment Discontinued Not Reported Suspect Pneumonia PneumoniaSerious Suspect 527/1 40 m Treatment Discontinued Not Reported Suspect Change of a caliber of vein Vein disorderSerious Suspect 527/1 40 m Treatment Discontinued Not Reported Suspect Rethrombosis Thrombosis

Serious Suspect 527/1 40 m Treatment Discontinued Not Reported Suspect Postthorombotic changes Post thrombotic syndromeSerious Suspect 386/4 49 f Unknown Not Reported Suspect Suspicion of mamma carcinoma Breast cancerSerious Suspect 49/1 75 m Treatment Discontinued Unknown Suspect Pulmonary embolism Pulmonary embolism

CERTUM NIS Database SADR

Event Seriousness

Event Causality

Center-/ Pat.-

Nr.

Age [Y]

Gender


Term

Serious Not Suspected 084/1 53 m 17.07.2012 00:00 Treatment Discontinued Condition Improving Not Suspected Post-thrombotic changes Post thrombotic syndromeSerious Not Suspected 084/1 53 m 17.07.2012 00:00 Treatment Discontinued Condition Improving Not Suspected Reflux Venous insufficiencySerious Not Suspected 084/2 70 f Jul-2012 Treatment Discontinued Condition Improving Not Suspected Dyspnoea/ aggravation of dyspnoea Dyspnoea

Serious Not Suspected 031/1 56 m 23.05.2012 00:00 Treatment Discontinued Complete Recovery Not Suspected Increased INR value up to 5.4International normalised ratio increased

Serious Not Suspected 031/5 81 m Treatment Discontinued Condition Unchanged Not SuspectedPost thrombotic change venous valve insufficiency Venous insufficiency

Serious Not Suspected 048/1 m 05.10.2012 00:00 Treatment Discontinued Condition Unchanged Not Suspected Postthrombotic changes Post thrombotic syndromeSerious Not Suspected 048/1 m 05.10.2012 00:00 Treatment Discontinued Condition Unchanged Not Suspected Gap in diameter of deep vein Vein disorderSerious Not Suspected 498/4 43 m 4-Okt-2012 Treatment Discontinued Unknown Not Suspected Post thrombotic changes ThrombosisSerious Not Suspected 498/4 43 m 4-Okt-2012 Treatment Discontinued Unknown Not Suspected Valve insufficiency/ Reflux Venous insufficiencySerious Not Suspected 498/1 45 f 08.08.2012 00:00 Treatment Discontinued Unknown Not Suspected Reflux/ valve insufficiency Venous insufficiencySerious Not Suspected 498/1 45 f 08.08.2012 00:00 Treatment Discontinued Not Reported Not Suspected Post-thrombotic changes Thrombosis

Serious Not Suspected 231/2 63 m 29-Mai-2012 Treatment Discontinued Complete Recovery Not Suspected Mild stroke Cerebrovascular accident

Serious Not Suspected 231/2 63 m 29-Mai-2012 No Change Complete Recovery Not Suspected Mild stroke Cerebrovascular accidentSerious Not Suspected 314/2 m 25-Okt-2012 Treatment Discontinued Complete Recovery Not Suspected Pulmonary embolism Pulmonary embolismSerious Not Suspected 424/1 70 m 25-Jun-2012 Unknown Complete Recovery Not Suspected Pulmonary embolism Pulmonary embolismSerious Not Suspected 218/3 29 f 25-Okt-2012 Treatment Discontinued Complete Recovery Not Suspected Pulmonary embolism Pulmonary embolismSerious Not Suspected 312/2 74 f 8-Aug-2012 Treatment Discontinued Complete Recovery Not Suspected Compensated renal insufficiency Renal failure

Serious Not Suspected 213/2 74 f Aug-2012 Treatment Discontinued Complete Recovery Not Suspected Increased creatinineBlood creatinine increased

Serious Not Suspected 062/3 68 m Treatment Discontinued Condition Improving Not Suspected Post-thrombotic changes Post thrombotic syndromeSerious Not Suspected 062/3 68 m Treatment Discontinued Condition Improving Not Suspected Vascular reflux Venous insufficiency

Serious Not Suspected 336/1 72 m 17-Jul-2012 Treatment Discontinued Not Reported Not Suspected 1xvalve insufficiency Heart valve incompetence

Serious Not Suspected 336/1 72 m 17-Jul-2012 Treatment Discontinued Not Reported Not Suspected Postthrombotic changes Post thrombotic syndrome

Serious Not Suspected 336/1 72 m 17-Jul-2012 Treatment Discontinued Not Reported Not Suspected 1xchange of the caliber of affected vein Vein disorder

Serious Not Suspected 62/1 57 5-Jun-2012 Treatment Discontinued Not Reported Not Suspected Post thrombotic changes Post thrombotic syndromeSerious Not Suspected 62/1 57 5-Jun-2012 Treatment Discontinued Not Reported Not Suspected Reflux Venous insufficiencySerious Not Suspected 62/2 28-Jun-2012 Treatment Discontinued Condition Improving Not Suspected valvular reflux Venous insufficiency

Serious Not Suspected 62/2 28-Jun-2012 Treatment Discontinued Condition Improving Not Suspected Postthrombotic changes Post thrombotic syndrome

Serious Not Suspected 519/1 27 f 5-Aug-2012 Treatment Discontinued Condition Unchanged Not SuspectedPostthrombotic changes defined as valve insufficiency Venous insufficiency

Serious Not Suspected 425/1 52 f Treatment Discontinued Complete Recovery Not SuspectedPost thrombotic changes / Valve insuficiency Post thrombotic syndrome

Serious Not Suspected 425/1 52 f Treatment Discontinued Complete Recovery Not SuspectedPost thrombotic changes / Valve insuficiency Venous insufficiency

CERTUM NIS Database SAEnr without cases of death

Serious Not Suspected 322/1 74 f 5-Okt-2012 Treatment Discontinued Complete Recovery Not Suspected Postthrombotic changes Post thrombotic syndromeSerious Not Suspected 322/1 74 f 15-Okt-2012 Treatment Discontinued Not Reported Not Suspected Change of the caliber of vein Venous insufficiency

Serious Not Suspected 322/4 60 m 15-Okt-2012 Treatment Discontinued Complete Recovery Not Suspected Postthrombotic changes Post thrombotic syndromeSerious Not Suspected 322/4 60 m 15-Okt-2012 Treatment Discontinued Complete Recovery Not Suspected Change of the caliber of vein Venous insufficiency

Serious Not Suspected 322/5 74 f 1-Nov-2012 Treatment Discontinued Complete Recovery Not Suspected Postthrombotic changes Post thrombotic syndromeSerious Not Suspected 322/5 74 f 1-Nov-2012 Treatment Discontinued Complete Recovery Not Suspected Change of the caliber of vein Venous insufficiency

Serious Not Suspected 107/1 39 m 2-Mai-2012 Treatment Discontinued Condition Unchanged Not Suspected

Post thrombotic changes like change of caliber of vein, valvular reflux, valve insufficiency Post thrombotic syndrome

Serious Not Suspected 107/2 61 f 31-Mai-2012 Treatment Discontinued Condition Unchanged Not Suspected

Post thrombotic changes like as change of the caliber of vein, valvular reflux, valve insufficiency Post thrombotic syndrome

Serious Not Suspected 476/3 51 m Treatment Discontinued Not Reported Not SuspectedPostthrombotic changes defined as valve insufficiency Venous insufficiency

CERTUM NIS Database SAEnr without cases of death

Event Seriousness

Event Causality

Center-/ Pat.-

Nr.

Age [Y]

Gender


TermDeath Date Death Cause

Serious Not Suspected 302/5 56 m Treatment Discontinued Fatal/Death Not Suspected Aggravated metastatic bronchial carcinoma

Metastatic bronchial carcinoma

12-Sep-2012 Metastatic bronchial carcinoma

Serious Not Suspected 424/1 70 m Okt-2012 Unknown Fatal/Death Not Suspected Aggravation of pancreas carcinoma

Pancreatic carcinoma 15-Okt-2012 Neoplasm

CERTUM NIS Database SAEnr (cases of death)

certum ea01 130314 - vfa.de€¦ · mono-embolex® 8000 i.e. solution for injection (8000 i.e....

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