Results from 42 Clinical Phase II to IV Studies and Post marketing Surveillance after 29 Million applications

1. Safety of Gadobutrol
Results from 42 Clinical Phase II to IV Studies and
Post marketing Surveillance after 29 Million applications
Jan Endrikat, MD, PhD, Kai Vogtlaender, PhD, Susan Dohanish, RA, Thomas
Balzer, MD, PhD,k and Josy Breuer, MD, PhD
Presented by Norberto Garcia MD

2. Introduction
What is Gadobutrol?
•A Gadolinium-based contrast agent (GBCA) for Magnetic Resonance Imaging (MRI)
Indications
•All body regions in adults and children including newborns

3. MRI CNS WITH AND WITHOUT
GADOBUTROL2

4. MRI ANGIOGRAPHY
Transverse section of the brain (Sbarnes)

5. Breast MRI with and without GADOLINIUM

6. Background
• Gadobutrol is a second-generation extracellular macrocyclic, nonionic GBCA 2
• Has particular physicochemical properties that enable the unique formulation of a 1 mol/L solution 2
• Other currently licensed extracellular GBCAs have 0.5 mol/L gadolinium concentration 2
• Gadobutrol binds gadolinium in a “cage” structure and therefore has lower propensity of gadolinium
release compared with linear GBCAs 2
• Gadolinium release is associated with the development of nephrogenic systemic fibrosis (NSF) 2

7. NEPHROGENIC SYSTEMIC FIBROSIS
• Nephrogenic systemic fibrosis (NSF) [1] is a rare and serious syndrome that involves fibrosis of skin,
joints, eyes, and internal organs.
• In NSF, patients develop large areas of hardened skin with fibrotic nodules and plaques. NSF may also
cause joint contractures resulting in joint pain and limitation in range of motion. In its most severe
form, NSF may cause severe systemic fibrosis affecting internal organs including the lungs, heart and
liver.
• 1. "SSA - POMS: DI 23022.835 - Nephrogenic Systemic Fibrosis - 08/10/2012". secure.ssa.gov.
Retrieved2016-01-12.

8. Materials and methods
Comprehensive retrospective safety analysis based on 2 data sets:
1.An integrated safety database based on results from 42 Clinical Studies
2.Global post marketing surveillance database based on reports obtained after 29 Million applications

9. Materials and methods (Cont.)
Integrated safety database
•42 clinical development phase II to IV studies
•Studies were conducted globally between 1993 and 2014
•Included 13 phase II studies, 27 phase III studies, and 2 phase IV studies
•Also included 2 phase I – III studies in pediatric population (0-18 years)

10. Materials and methods (Cont.)
Integrated safety database
•23 were single-arm Gadobutrol studies
•13 had a parallel group design with either different Gadobutrol doses or Gadobutrol and a comparator
contrast agent
•6 were cross-over studies with either different Gadobutrol doses or Gadobutrol and a comparator
contrast agent.
•Comparators were: Gadopentetate dimeglumine (Gd-DTPA, Magnevist), Gadodiamide (Omniscan),
Gadoversetamide (OptiMark), Gadoteridol (ProHance), or Gadoterate meglumine (Gd-DOTA, Dotarem)

11. Materials and methods (Cont.)
Global post marketing surveillance database
Run by the Bayer HealthCare Global Pharmacovigilance Department.
The department received reports and ADRs from:
•Health care professionals (physicians, pharmacists, nurses)
•Scientific publications
•Regulatory authorities
•Patients or lay persons
During the period from the first marketing authorization in Switzerland on February 26th
, 1998, through
December 31, 2015, nearly 30 million patients worldwide are estimated to have received Gadobutrol.

12. Population of the 42 clinical phase II to IV studies
• Patient of all ages (term newborns up to patients older than 90 years) with a clinical need of various
diagnostic contrast-enhanced MRI
• Patients with specific risk factors were also included (renal impairment, reduced liver function,
cardiovascular disorders, general history of allergies, and specific history of allergies to contrast agents)
• Two studies recruited children aged 0 to 18 years
• All patients (or their legal representatives) gave written informed consent before the start of the study

13. Treatments in the 42 clinical phase II to IV studies
• 6809 patients received Gadobutrol
• 2184 received one comparator
• All contrast agents were administered by a single IV bolus injection followed by a saline chaser.
• Gadobutrol was administered at a dose range from 0.01 mmol/kg to 0.51 mmol/kg bw.
• 4765 subjects received the standard dose of 0.1 mmol/kg bw
• 292 subjects received a dose between 0.01 and less than 0.09 mmol/kg
• 47 subjects received 0.31 to 0.51 mmol/kg bw (above the approved dose)
• The dose for comparators was mainly 0.1 mmol/kg bw

14. Study procedures
In all clinical studies the following were collected:
•Demographic data
•Medical history (particularly history of renal, liver, cardiovascular diseases, and allergies)
•Once contrast-enhanced MRI was performed, patients were asked about their well-being in an unsolicited way
to gather information about adverse events (AEs).
•The follow-up period lasted from just the examination day up to 72 hours.

15. Target variables
For the clinical phase II-IV studies:
•Number of patients with the characteristics of:
•AEs
•Drug related AEs
•Serious AEs
For the post marketing surveillance part:
•ADRs

16. Definitions
• Adverse event (AE): Any illness, sign or symptom, or unfavorable change in the clinical status that had
appeared or worsened after study start, whether or not it was considered to be related to contrast agent
administration.
• All AEs were evaluated for seriousness and potential relationship to contrast agent administration by
experienced healthcare professionals in each institution
Serious adverse event (SAE). Any AE that:
• Resulted in death
• Was life-threatening
• Required subject hospitalization or prolongation of existing hospitalization
• Resulted in a persistent or significant disability/incapacity
• Resulted in a congenital abnormality/birth defect
• Was considered an otherwise medically significant event

17. Statistics
• All patients who received at least one dose of Gadobutrol or comparator were included in the safety analysis.
• Subject who got multiple doses within less than one hour, the doses were summed up and counted once.
• Patients in crossover studies with different contrast agents were analyzed by period
• Analysis by age was performed looking at 3 age brackets
• Younger than 18 years
• 18 to 65 years
• 65 years or older
• All variables were analyzed by descriptive statistical methods
• AE incidence rates and ADR reporting rates were calculated

18. Results
Clinical Development Phase II to IV studies
• A total of 6809 patients were included in the database for Gadobutrol and 2184 for comparators
Gd-DTPA (n=1097), Gadodiamide (n=150), Gadoversetamide (n=227), Gadoteridol (n=555), Gd-DOTA
(n=155).
• The incidence of drug-related AEs was 3.5% in the Gadobutrol and the comparator group however, the
comparator group, consisting of 5 agents, was not as homogeneous as it appears
• A particular strength of this research is the broad age range of the population. Data were captured from
7-day old newborns to elderly up to 93 years; however, only for Gadobutrol but not for comparators.
•Patients younger than 18 years were only included in the Gadobutrol group
•Serious AEs were similarly low (<0.1%) in both groups
•Most frequent drug-related AEs were headache, nausea, and dizziness.
•Hypersensitivity reactions were less than 0.1%

19. Results (Cont.)
Clinical Development Phase II to IV studies
•There were no remarkable differences in the incidence of drug-related AEs between patients with or without
renal impairment, elevated liver enzymes, or cardiovascular diseases.
•Patients with history of allergies—or specifically allergies to contrast agents—experienced slightly more drug-related
AEs although the numbers were small.
•From the number of 25 patients with history of allergies to contrast agents, 3 (12%) showed a drug-related AE
•The incidence rates of drug-related AEs by age group were 4.9%, 4.0%, and 2.6% for the age groups younger
than 18 years, 18 to 65 years, and 65 years or older, respectively, (not statistically significantly different)

20. Results (Cont.)Post marketing Surveillance
•Patient exposure to Gadobutrol (per year) increased steadily from 416 patients in 1999, the year after
market introduction, to more than 5.7 million in 2015.
•As reporting to Pharmacovigilance departments is voluntary, databases generally yield lower ADR rates
compared with results from clinical development phase II to IV studies
•The ADR reporting rate in the post marketing surveillance was highest in the years 2001 and 2002,
reaching 0.09%. Lowest rates of 0.04% were seen in 2003, 2006, and 2013.
•The average ADR reporting rate for Gadobutrol from 1999 to 2014 was 0.05%
Gd-DTPA (first MR contrast on the market in 1988), had an average AE reporting rate of 0.0144%
Gadobenate dimeglumine (Gd- BOPTA), was introduced in 1998, approximately at the same time as
Gadobutrol (1999). It featured an overall ADR reporting rate of 0.05%.

21. Results (Cont.)
Post marketing Surveillance
•The most frequently reported ADRs in the post- marketing surveillance database were
anaphylactoid/hypersensitivity reactions featuring a reporting rate of 0.019%.
•Less frequent were nausea, vomiting, and dyspnea with rates of 0.005%, 0.004%, and 0.002%, respectively.
•All other single ADRs were 0.001% or less.
•The rate and quality of AEs, drug-related AEs, and ADRs was consistent with those of other GBCAs

22. Nephrogenic systemic fibrosis
•As of December 2015, a total of 12 reports of NSF or NSF-like symptoms in patients who reportedly were
administered Gadobutrol have been received.
•Four of these were “single-agent reports” (patients reportedly received only Gadobutrol)
•The other 8 reports are confounded by the administration of other GBCAs (“multiple-agent reports”).
•In assessing these reports, Bayer utilized a criteria previously developed by another group of researchers
and applied the criteria very conservatively.
•Bayer gave the report the highest possible score based on the information available.
•Using this conservative “worst-case scenario” approach, 3 of the 4 single-agent reports met the criteria
for being diagnostic of or consistent with NSF and a possible association with Gadobutrol could not be
excluded. The fourth single-agent report contained information that was insufficient for evaluation.

23. CONCLUSIONS
• Gadobutrol is a well-tolerated macrocyclic GBCA with higher concentration, which has a good safety
profile as shown from results of 42 clinical phase II to IV studies and post marketing surveillance over 17
years and more than 29 million applications.

24. BIBLIOGRAPHY
• 1. Safety of Gadobutrol. Results From 42 Clinical Phase II to IV Studies and Postmarketing Surveillance
After 29 Million Applications. Jan Endrikat, MD, PhD, Kai Vogtlaender, PhD, Susan Dohanish, RA,
Thomas Balzer, MD, PhD,k and Josy Breuer, MD, PhD
• 2. radiology solutions.bayer.com. Gadobutrol image library
• 3. "SSA - POMS: DI 23022.835 - Nephrogenic Systemic Fibrosis - 08/10/2012". secure.ssa.gov.
Retrieved2016-01-12.