Information for Healthcare Professionals and other Stakeholders

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1 Information for Healthcare Professionals and other Stakeholders NEPHROGENIC SYSTEMIC FIBROSIS: AN UNCOMMON AND DEBILITATING DISEASE POSSIBLY ASSOCIATED WITH GADOLINIUM CHELATES Villepinte, February 2014 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]. Markedly reduced renal function (egfr < 30 ml/mn/1.73 m2) is the most important patient-related risk factor for NSF and has been present in almost all reported cases of NSF, and many patients have been on haemodialysis or peritoneal dialysis [4]. NSF can occur in all age-groups and there is no predilection for a geographic region, race or gender. P DOT 1

2 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 reverse its course [2]. The mechanism of this highly debilitating disease remains unknown. Current literature suggests a multifactorial aetiology [5-7]. So far, several factors have been suggested to be frequently associated with the onset of NSF (Table 1): Table 1 Recognized or possibly associated factors for NSF Severe or end-stage renal failure [1-3] Acute kidney insufficiency [4] High cumulative dose of gadolinium chelates [8] High dose of erythropoietin [8, 9] High serum phosphate levels [8, 10, 11] High serum calcium levels [8] Coexisting pro inflammatory event (major surgery, infection, vascular event) [12-14] Iron mobilization [5, 15] Metabolic acidosis [16] (debated: [12, 17]) History of hypothyroidism [18] History of deep venous thrombosis [18-20] Younger age [18] 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) P DOT 2

3 and the occurrence of NSF in patients with renal failure [16, 17]. Numerous retrospective analyses rapidly followed and confirmed this temporal link [12, 21, 22]. The time to onset of the symptoms ranges between a few days and a few years following exposure to the gadolinium chelate [4]. The majority of published cases occurred within 2 weeks to 2 months [23]. The link between gadolinium-containing contrast media and NSF is considered probable [16, 17, 24-26]. Awareness of this potential adverse reaction to gadolinium chelates is a major requirement for radiologists and specialists in patients with stage 4 and 5 chronic kidney disease and acute kidney insufficiency who are at higher risk for NSF. In addition, patients with stage 3 chronic kidney disease are at lower risk for NSF [4]. 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 Gd 3+ 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 chelates 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 ); P DOT 3

4 Medium risk: gadofosveset (Vasovist ), gadoxetic acid (Primovist ) and gadobenic acid (MultiHance ); Low risk: gadoteric acid (Dotarem ), gadoteridol (ProHance ) and gadobutrol (Gadovist ). 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 chelates, and recommended 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 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 classification (Table 2). The CHMP recommended also that the prescribing information of all gadolinium chelates 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 have to be implemented. Finally, the CHMP advised that studies should be performed to evaluate the potential of long-term retention of gadolinium in bone. In addition, MAHs should continue to submit annual cumulative reviews of NSF cases for coordinated assessment until the final study report of the study evaluating gadolinium accumulation in bone and its long-term effect, have been submitted. The evaluation by the CHMP of the 2013 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. P DOT 4

5 Table 2 Revised contra-indications and precautions for use of gadolinium-containing contrast agents (CHMP 2010) Risk class LOW RISK: MEDIUM RISK: HIGH RISK: Dotarem, ProHance, Gadovist 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 (in consultation with the physician) Discontinuation at least 24h Renal insufficiency (RI), hepatic Precaution in severe Renal insufficiency To be avoided in severe RI and hepatic Contra-indication in severe RI and hepatic transplanted transplantation, dialysis (RI) and hepatic transplanted patients: transplanted patients patients minimum diagnostic dose and minimum 7 If used, minimum diagnostic dose and Precaution in moderate RI patients, according to days between administrations minimum 7 days between 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, may be useful in dialyzed patients Paediatric population Precaution in neonate, minimum diagnostic dose and minimum 7 days between administrations* 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**.dotarem is 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. P DOT 5

6 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 labelling of gadolinium chelates. In December 2009, the safety of gadolinium chelates was reviewed during a Joint Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committee meeting. 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 be monitored after administration. Administration of gadolinium-containing contrast agent should not be repeated in a single imaging session. Dotarem has had a Marketing Authorization in the USA since March 21, Position of the Danish Health and Medicines Authority On 18 September 2009, the Danish Health and Medicines Authority published guidelines for examination by MRI scan of kidney impaired patients using gadolinium-containing P DOT 6

7 contrast agents. On 21 November 2013, a working group established an update of these guidelines aligned with the EMA assessment (July 2010) and even reinforced some particular points listed below: The use of high risk preparations should be avoided in all contexts since usable low risk preparations are available. Medium risk preparations should be used only in case of compelling indications for patients with an egfr below 59 ml/min/1.73 m². Compelling indication means that the diagnostic information is essential and cannot be obtained by non-contrast enhanced scanning or with the use of a low risk preparation. For children 2-18 years, use of MultiHance is not recommended whatever the status of the renal function of the subject is. In contrast, low-risk products can be used without restriction if renal function exceeds 60 ml/min/1.73m². They should only be used for essential diagnostic information in case of egfr< 60 ml/min/1.73m². For children from 0 to 2 years old, the Danish guidelines recommend using Dotarem only. Although Dotarem does not have MR angiography as an approved indication for patients aged less than 18, if an MR angiography must be performed on a compelling indication, the Danish guidelines recommend to use Dotarem in a single dose not exceeding 0.1 mmol/kg. Position of the European Society of Urogenital Radiology (ESUR): Based on a review of the literature, the ESUR s Contrast Media Safety Committee published in 2013 an update of the guidelines on NSF and gadolinium chelates first established in The recommendations are summarized in the table 3: P DOT 7

8 Table 3 Recommendations for use of gadolinium-containing contrast agents (ESUR 2013) Risk class LOW RISK: MEDIUM RISK: HIGH RISK: Dotarem, ProHance, Gadovist Primovist, Vasovist, Ablavar Omniscan, Optimark, Magnevist MultiHance, Eovist Pregnancy Can be used to give essential diagnostic information Contra-indication in pregnant women Lactation Continuation or suspension 24h according to mother s decision (in consultation with the physician) Discontinuation at least 24h Renal insufficiency (RI), hepatic transplantation, dialysis Should be used with caution in patients with Chronic Kidney Disease (CDK) 4 and 5 (GFR<30mL/min), including patients on dialysis, with at least 7 days between 2 administrations. Contra-indication in patients with CDK 4 and 5 (GFR<30mL/min) and with acute renal insufficiency. Should be used with caution in patients with CDK 3 (GFR ml/min, according to benefit risk ratio, minimum diagnostic dose and minimum 7 days between administrations. No evidence supporting the use of haemodialysis for preventing or treating NSF in non-dialyzed patients, But may be useful in dialyzed patients. Paediatric population Precaution in neonate, minimum diagnostic dose and minimum 7 days between administrations Contra-indication in neonate < 4 weeks Precaution in child < 1 year, minimum diagnostic dose and minimum 7 days between administrations Patients with NSF GBCA should only be used if the indication is vital Contra-indication in patients with NSF Screening of renal function Laboratory testing of renal function (egfr) is not mandatory but renal function assessment by questionnaire should be used if serum creatinine is not measured. Mandatory laboratory test to screen all patients for renal dysfunction All patients Use the smallest amount of contrast medium necessary for a diagnostic result. Should never be given in higher doses than 0.1mmol/kg per examination Always record the name and dose of the contrast agent used in the patient records. P DOT 8

9 Guerbet Pharmacovigilance Data Guerbet markets meglumine gadoterate (Dotarem ), a macrocyclic, ionic gadolinium chelate associated with a high thermodynamic and kinetic stabilities [25-29]. 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 Guideline on Good Pharmacovigilance Practices (GVP) - European Medicines Agency and Heads of Medicines Agencies, 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 [30] 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, 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 as pro-inflammatory events. With respect to NSF, Guerbet has registered, to date, 19 medically-confirmed cases of patients who developed signs allowing this diagnosis to be considered and who received Dotarem, for more than 43 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 unlikely in all cases (Table 4). In all cases the administration of Dotarem preceded the first symptoms, except for two patients who developed NSF after injection of linear gadolinium chelates and prior to Dotarem administration. In both cases, the causality of Dotarem in the disease worsening was assessed as unlikely. P DOT 9

10 Table 4 NSF cases reported for patients having received Dotarem More than 43 million doses sold 19 reported cases of NSF (all sources i.e. health care professionals, authorities, literature) 8 confirmed or very likely cases of NSF Dia Confirmed or consistent diagnosis (Girardi score), information sufficient to rule out the differential diagnoses 11 unconfirmed or doubtful cases of NSF Due to missing information the Girardi score cannot be applied and/or the differential diagnoses cannot be ruled out 0 Single-agent case 8 Multipleagent cases 0 Non qualifiable case* 1 Singleagent case 9 Multipleagent cases 1 Non 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 Dotarem. A full collaboration in total transparency with Health Authorities for Pharmacovigilance issues and consistently acting in the best interests of the patients are fundamental principles at Guerbet. This is particularly true in the case of NSF and will remain so. P DOT 10

11 Further information about NSF and gadolinium chelates European Medicines Agency (EMA) US Food and Drug Administration (FDA) European Society of Urogenital Radiology (ESUR) International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR) (Yale University) American College of Radiology (ACR) References 1. Cowper, S.E., et al., Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet, (9234): p Cowper, S.E., P.H. Kuo, and R. Bucala, Nephrogenic systemic fibrosis and gadolinium exposure: association and lessons for idiopathic fibrosing disorders. Arthritis Rheum, (10): p Galan, A., S.E. Cowper, and R. Bucala, Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol, (6): p Thomsen, H.S., et al., Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Medium Safety Committee guidelines. Eur Radiol. 23(2): p Swaminathan, S. and S.V. Shah, New insights into nephrogenic systemic fibrosis. J Am Soc Nephrol, (10): p Nardone Beatrice, L.A.E., Bohaty Benjamin, West Dennis P., Holzem Kassandra E, Bauer Kimberly Clinical factors associated with nephrogenic systemic fibrosis (NSF): A single site academic center, 2-cohort study. Journal of the American Academy of Dermatology, (4): p. AB Chopra, T., et al., Understanding nephrogenic systemic fibrosis. Int J Nephrol. 2012: p Marckmann, P., et al., Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant, (11): p Swaminathan, S., et al., Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med, (3): p P DOT 11

12 10. Fretellier, N., et al., Hyperphosphataemia sensitizes renally impaired rats to the profibrotic effects of gadodiamide. Br J Pharmacol. 165(4b): p Frenzel, T., et al., Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Invest Radiol, (12): p Sadowski, E.A., et al., Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology, (1): p Golding, L.P. and J.M. Provenzale, Nephrogenic systemic fibrosis: possible association with a predisposing infection. AJR Am J Roentgenol, (4): p Perazella, M.A., Nephrogenic systemic fibrosis, kidney disease, and gadolinium: is there a link? Clin J Am Soc Nephrol, (2): p Miyamoto, J., et al., Detection of iron deposition in dermal fibrocytes is a useful tool for histologic diagnosis of nephrogenic systemic fibrosis. Am J Dermatopathol. 33(3): p Grobner, T., Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant, (4): p Marckmann, P., et al., Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol, (9): p Kallen, A.J., et al., Gadolinium-containing magnetic resonance imaging contrast and nephrogenic systemic fibrosis: a case-control study. Am J Kidney Dis, (6): p Introcaso, C.E., et al., Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: a case series of nine patients and review of the literature. Int J Dermatol, (5): p Cowper, S.E., Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol, (6): p Broome, D.R., et al., Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR Am J Roentgenol, (2): p Khurana, A., et al., Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (omniscan). Invest Radiol, (2): p Marckmann, P., An epidemic outbreak of nephrogenic systemic fibrosis in a Danish hospital. Eur J Radiol, (2): p Abraham, J.L. and C. Thakral, Tissue distribution and kinetics of gadolinium and nephrogenic systemic fibrosis. Eur J Radiol, (2): p Morcos, S.K., Extracellular gadolinium contrast agents: differences in stability. Eur J Radiol, (2): p Perazella, M.A. and R.A. Rodby, Gadolinium use in patients with kidney disease: a cause for concern. Semin Dial, (3): p Caravan, P., et al., Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. Chem Rev, (9): p Laurent, S., et al., Stability of MRI paramagnetic contrast media: a proton relaxometric protocol for transmetallation assessment. Invest Radiol, (2): p Wedeking, P., K. Kumar, and M.F. Tweedle, Dissociation of gadolinium chelates in mice: relationship to chemical characteristics. Magn Reson Imaging, (4): p Girardi, M., et al., Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations. J Am Acad Dermatol. 65(6): p e7. P DOT 12