Information for Healthcare Professionals and other Stakeholders NEPHROGENIC SYSTEMIC FIBROSIS: AN UNCOMMON AND DEBILITATING DISEASE POSSIBLY ASSOCIATED WITH GADOLINIUM CHELATES Any significant information (eg publication of results of a new study, results of the investigation of a pharmacovigilance case) may cause the issue of a new version of this document. What is Nephrogenic Systemic Fibrosis (NSF)?
NSF was first recognized in 1997 in 15 dialyzed patients and described in 2000 (1). This
rare and highly debilitating disorder is characterized by extensive thickening and hardening
of the skin associated with skin-colored to erythematous papules that coalesce into
erythematous to brawny plaques with a “peau d’orange” appearance. Nodules are
sometimes also described. Joint contractures may develop, with patients progressively
becoming wheelchair-dependent. Patients often complain of pruritus, causalgia and sharp
pains (2). The distal extremities are the most common area of involvement (with a
distribution from ankles to mid-thighs and from wrists to mid-upper arms), followed by the
trunk. The lesions are typically symmetrical. It is worth noting that the face and neck are
virtually never involved (3). NSF always occurs in patients with severe or end-stage
chronic kidney disease (CKD) (eGFR < 30 ml/mn/1.73 m2) (1-3), usually in those requiring
NSF can occur in all age-groups and there is no predilection for a geographic region, race
So far, there is no recognized treatment for NSF. It has been suggested that improving
renal function may slow down the development of the disease and, in some cases, may
The mechanism of this highly debilitating disease remains unknown. Current literature
suggests a multifactorial aetiology (4).
So far, several factors have been suggested to be frequently associated with the onset of
Recognized or possibly associated factors for NSF
• Severe or end-stage renal failure (1-3)
• High cumulative dose of gadolinium chelate (5)
• Coexisting pro inflammatory event (major surgery, infection, vascular event) (7)
• Metabolic acidosis (8) (debated: 7,9)
• History of deep venous thrombosis (10)
In 2006, two European teams independently suggested a link between the administration
of gadolinium (Gd) chelates used as contrast media for magnetic resonance imaging (MRI)
and the occurrence of NSF in patients with renal failure (8,9). Numerous retrospective
analyses rapidly followed and confirmed this temporal link (7,11-13).
The time to onset of the symptoms ranges between a few days and a few years following
exposure to the gadolinium chelate. The majority of published cases occurred within 3
The link between gadolinium-containing contrast media and NSF is considered probable
(8, 9, 14, 15, 16) and awareness of this potential adverse reaction to gadolinium chelates
is a major requirement for radiologists and specialists in patients with stage 4 and 5
Current Position of European Health Authorities
In February 2007, the European Pharmacovigilance Working Party (PhVWP) of the
European Medicines Agency (EMA) initially advised all contrast media marketing
authorization holders to add warnings about the possibility that NSF may occur with
gadolinium chelates to section 4.4 of the Summary of Product Characteristics (SPC).
There are two generally recognized categories of gadolinium chelates: macrocyclic
molecules where Gd3+ is caged in the pre-organised cavity of the ligand (15), and the
linear open chain molecules (15). Gadolinium chelates differ in their thermodynamic
stability constants and in their kinetic stability. In general, pre-clinical and ex vivo studies
have suggested that macrocyclic molecules are more stable than linear molecules (17-21).
In December 2007, the Scientific Advisory Group (SAG) for Diagnostics of the CHMP
(Committee for Medicinal Products for Human Use) agreed with the PhVWP that the risk of
developing NSF depends on the type of gadolinium-containing contrast agent used, and
advised that these agents should be categorized into three groups:
• High risk: gadoversetamide (OptiMARK), gadodiamide (Omniscan) and gadopentetic
acid (Magnevist, Magnegita, and Gado-MRT-ratiopharm);
• Medium risk: gadofosveset (Vasovist), gadoxetic acid (Primovist) and gadobenic acid
• Low risk: gadoteric acid (Dotarem), gadoteridol (ProHance) and gadobutrol
In November 2008 a referral procedure was triggered in order for the CHMP to carry out
an assessment of the risk of NSF for the authorized gadolinium-containing contrast
agents, and recommend measures that could be taken to reduce this risk.
The final CHMP opinion was issued in November 2009, and was ratified by an European
Commission decision in July 2010. The conclusions confirmed the classification of the
active substances into the three categories of risk, and the CHMP emitted
recommendations for the labelling of the different agents to vary according to their risk
The CHMP recommended also that the prescribing information of all gadolinium-containing
contrast agents should include a statement that the type and dose of contrast agent used
should be recorded; in that view, “sticky labels” removable from the vials and syringes
Finally, the CHMP advised that studies should be performed to evaluate the potential of
long-term retention of gadolinium in bone. In addition, a cumulative review of NSF cases
should be submitted annually for 3 years.
The evaluation by the CHMP of the 2012 new cumulative review of the cases regarding
gadoteric acid (Dotarem) maintained the classification of the product in the low risk class,
and endorsed the causality assessment of the reported cases as provided by Guerbet.
Revised contra-indications and precautions for use of gadolinium-containing contrast agents (CHMP 2010) Risk class MEDIUM RISK: HIGH RISK: Primovist, Vasovist, MultiHance Omniscan, Optimark, Magnevist Pregnancy
Not recommended, unless benefit risk ratio assessed as favorable
Lactation
Continuation or suspension 24h according to mother’s decision
Discontinuation at least 24h Renal insufficiency (RI), hepatic To be avoided in severe RI and hepatic Contra-indication in severe RI and hepatic transplanted transplantation, dialysis
transplanted patients: minimum diagnostic
transplanted patients patients If used, minimum diagnostic dose and Precaution in moderate RI patients, according to benefit risk ratio, minimum diagnostic dose and administrations minimum 7 days between administrations
No evidence supporting the use of haemodialysis for preventing or treating NSF in non-dialyzed patients,
Paediatric population
Precaution in neonate, minimum diagnostic dose and minimum 7 days between
Contra-indication in neonate < 4 weeks
Precaution in child < 1 year, minimum diagnostic dose and minimum 7 days between administrations
Elderly patient
Important to screen patients > 65 years for renal dysfunction
Screening of renal function
Recommended laboratory test to screen patients for renal dysfunction
Mandatory laboratory test to screen all patients for renal dysfunction *In the low and medium risk categories of NSF, DOTAREM provides the largest range of indications for newborns and infants ranging from 0 to 2 years old, for MRI of whole body pathologies as well as for MRI of the brain and spinal
diseases and diseases of the vertebral column**.DOTAREMis not recommended for MR angiography in children under 18 years of age due to insufficient data on the efficacy and safety in this indication.
**For more information and because indications may vary from country to country, please refer to your mandatory local SPC. Current Position of US Health Authorities (FDA)
In 2006, the Food and Drug Administration (FDA) alerted the public about cases of NSF
reported in patients who received gadolinium chelates.
In 2007, the FDA required the addition of a boxed warning about the risk of NSF to the
In December 2009, the safety of gadolinium chelates was reviewed during a Joint
Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory
Following that, in September 2010, the FDA made a Safety Announcement, requiring new
changes in the labelling of gadolinium chelates, falling more closely into line with those
requested by European Health Authorities.
High-risk gadolinium chelates (Optimark, Omniscan, Magnevist) are contraindicated in
patients with acute kidney injury (AKI) or with chronic severe kidney disease.
In addition, the FDA recommended a screening of patients for kidney problems using
clinical history and laboratory testing.
The use of gadolinium chelates should be avoided in patients having impaired drug
elimination, unless this use is necessary; in that case, signs and symptoms of NSF should
Administration of gadolinium chelates should not be repeated in a single imaging session.
Dotarem has a Marketing Authorization in the USA since March 21, 2013.
Guerbet Pharmacovigilance Data
Guerbet markets meglumine gadoterate (Dotarem), a macrocyclic, ionic gadolinium chelate
associated with a high thermodynamic and kinetic stability (15-19).
The Department of International Pharmacovigilance of Guerbet manages the Adverse Events
reported in a context of Dotarem administration in accordance with the regulatory
Pharmacovigilance reporting standards; in particular Volume 9A of the Rules Governing Medicinal
Products in the European Union - Guidelines on Pharmacovigilance for Medicinal Products for
For each case reported as NSF and based on the available information, Guerbet has assessed the
strength of the diagnosis of NSF and the causality of Dotarem :
the strength of the diagnosis of NSF using the clinicopathological score developed by Yale
University (USA) and published by Girardi et al (22) on the basis of their registry of more than
250 cases, and discussing the differential diagnoses of the disease ;
Dotarem causality considering the available and missing information regarding the medical
history of the patient, in particular renal function, the injection of the sole Dotarem (single-
agent case) or other gadolinium chelates (multiple-agent case), the chronology of both the
injections and the clinical, biological and imaging events, other possible causative factors such
With respect to NSF, Guerbet has registered, to date, 16 medically-confirmed cases of patients
who developed signs allowing this diagnosis to be considered and who received Dotarem, for
more than 37 million of patients who received the product, and more than 850 cases of NSF
reported worldwide (source European Medicines Agency, 2010).
On the basis of the available information, the diagnosis of NSF is confirmed or consistent
according to the Girardi score in only 1/3 of the reported cases, and the causality of Dotarem is
In all cases the administration of Dotarem preceded the first symptoms, except for one patient
who developed NSF after injection of linear gadolinium chelates, the disease worsening after she
had undergone several Dotarem-enhanced MRA, in a context of degradation of the renal function
NSF cases reported for patients having received Dotarem®
(all sources i.e. health care professionals , authorities, literature)
Due to missing information the Girardi score
score), information sufficient to rule out the
cannot be applied and/or the differential
0 Single-agent 5 Multiple- 1 Single- 9 Multiple- agent cases qualifiable case* agent case agent cases qualifiable case*
Non qualifiable = unspecified agent received in addition to Dotarem
Position Statement
At Guerbet, we significantly contribute to improving diagnosis for major disease areas
(cardiovascular diseases, cancer, inflammatory and neurodegenerative diseases).
We are strongly committed to providing radiologists, cardiologists and healthcare
professionals with a comprehensive range of innovative and effective contrast media to
achieve their aim to provide optimum diagnosis for their patients.
A complete research programme is in progress at Guerbet and in cooperation with
recognized academic centres to better understand the mechanism of NSF and thoroughly
study the role of physicochemical properties of gadolinium chelates in its pathogenesis.
The research programme includes a prospective clinical analysis of the safety of
We are in full collaboration with Health Authorities for Pharmacovigilance issues with total
transparency and consistently acting in the best interests of the patients is a fundamental
principle at Guerbet. This is particularly true in the case of NSF and will remain so.
Further information about NSF and gadolinium chelates European Medicines Agency (EMA)
European Society of Urogenital Radiology (ESUR)
http://www.esur.org/Nephrogenic_Fibrosis.39.0.html
International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR) (Yale
www.acr.org/./quality_safety/contrast_manual/NephrogenicSystemicFibrosis.asp
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Information for Healthcare Professionals and other Stakeholders