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GBCAs: regulatory update & information on Guerbet’s products

• Decisions of Healthcare Authorities: European Union, USA, Japan • Information on Guerbet’s MRI contrast products European Commission Following an in-depth review, the EMA issued its final 1 recommendations on July 21st, 2017. The EMA noted that decision “there is currently no evidence that deposition in the brain has caused any harm to patients; however EMA has recommended restrictions and suspensions for On March 17th, 2016, the European Medicines Agency some intravenous linear agents in order to prevent any (EMA) initiated a review of the risk of gadolinium risks that could potentially be associated with gadolinium deposition in brain tissue following the repeated use of brain deposition." The European Commission endorsed Gadolinium-based Contrast Agents (GBCAs) in patients EMA’s final recommendations on November 23rd, 2017, undergoing magnetic resonance imaging (MRI) scans. summarized in the table below.

Summary of the decision on non-specific GBCAs

EMA’s recommendations EMA’s explanations

Dotarem® Maintain () • Macrocyclic GBCAs “are more stable and have a lower propensity to release gadolinium than linear agents” ® Macrocyclic GBCAs Gadovist Maintain () • “These products can continue to be used in their current indications but in the lowest doses that enhance images sufficiently Prohance® and only when unenhanced body scans are not suitable” () Maintain

Optimark® () Suspend

Magnevist® • “EMA has recommended restrictions for some intravenous () Suspend linear agents in order to prevent any risk that could potentially be Linear GBCAs* associated with gadolinium brain deposition” TM Omniscan Suspend • “can continue to be used for liver scans because” () it is “taken up in the liver”

Multihance® Restrict use to liver (gadobenic acid) scans

*The table does not include the EMA recommendations for the organ-specific linear GBCAs: a formulation of gadopentetic acid injected directly into joints and for liver use. 1. Gadolinium Article-31 referral. 21/07/2017. EMA/457616/2017.

2 3 European Commission decision 1

Next step Schedule

• European Commission’s decision to endorse EMA’s recommendations is the final stage of the review procedure. Procedure starts

• This legally binding decision is applicable in all EU Member States.

• Member States are allowed to defer for up to 12 months Under evaluation the suspension of critical products on the basis of potential unmet medical need and considering the availability of suitable alternative medicinal products. Recommendations of the EMA's More information PRAC* • To find all relevant information to Healthcare Professionals and their patients, scan the QR code & access the full EMA's press release on this topic. EMA recommendations

European Commission final decision

Application in all EU member states Today

1. Gadolinium Article-31 referral. 21/07/2017. EMA/457616/2017. * Pharmacovigilance and Risk Assessment Committee

4 5 US Food and Drugs Administration (FDA) 2,3 decision

FDA’s investigation conclusion Schedule

• “There are two types of GBCAs based on their chemical structures: linear and macrocyclic […]. Linear GBCAs Investigation started 27/07/2015 result in more retention and retention for a longer time than macrocyclic GBCAs.”

• “Gadolinium levels remaining in the body are higher after Drug Safety Communication 22/05/2017 administration of OmniscanTM (gadodiamide) or Optimark® "No harmful effects identified (gadoversetamide) than after Eovist® (gadoxetate disodium), with brain retention" Magnevist® (gadopentetate dimeglumine), or Multihance® (gadobenate dimeglumine).”

• “Gadolinium levels in the body are lowest after Medical Imaging Drugs Advisory 08/09/2017 administration of Dotarem® (gadoterate ), Committee Meeting (MIDAC) Gadavist® (gadobutrol), and Prohance® (gadoteridol).”

• “Gadolinium retention has not been directly linked to adverse Drug Safety Communication: 19/12/2017 health effects in patients with normal kidney function”. GBCAs "are retained in the body" FDA requires specific changes to the labelling of all GBCAs: a Warning Recommendations and Precaution, and changes related to gadolinium retention in the Adverse • “Health care professionals should consider the retention Reactions, Pregnancy, Clinical , and Patient characteristics of each agent when choosing a GBCA Instructions Sections. for patients who may be at higher risk for gadolinium retention […]. These patients include those requiring Today multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions. Minimize Assessment continues, update repeated GBCA imaging studies when possible, public when new information particularly closely spaced MRI studies.” becomes available

• “However, do not avoid or defer necessary GBCA MRI

scans.” 2. Medical Imaging Drugs Advisory Committee Meeting. Briefing document. 08/09/2017. 3. FDA Drug Safety Communication: FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings. 19/12/2017.

6 7 Japanese Pharmaceuticals and Medical Devices Agency 4,5 (PMDA) decision

On November 28th, 2017, Japanese Health Authorities Revision of the precautions section issued their decision to restrict the use of non-specific linear GBCAs only to cases where there is no alternative, based on the “higher gadolinium accumulation in brain • “It has been reported that high signal reported with these linear agents”. Mandatory revision of intensity was observed in the cerebellar the precautions section in the package insert of GBCAs, dentate nucleus and globus pallidus on unenhanced T1-weighted MR images with immediate effect, was requested. and that gadolinium was detected in All GBCAs autopsied brain tissues in patients who received a gadolinium-based several times. In its final report on the investigation results, PMDA The necessity of MRI scan using noted "there has been no clear evidence that the gadolinium-based contrast agents should clinical symptoms that occurred in patients associated be determined carefully.” with Gd retention in the brain tissues are related to Gd retention in the brain tissues and no clinical risk has been identified". "PMDA has determined that it is appropriate to revise the package inserts of all GBCAs • “It has been reported that more approved in Japan for precaution according to the gadolinium remained in the brain with linear gadolinium-based contrast agents significance of each such risk from the perspective containing this drug than with macrocyclic of minimization of the potential risks associated with Linear GBCAs gadolinium-based contrast agents. Gd retention in the brain tissues.” This drug should be administered when macrocyclic gadolinium-based contrast agents are not appropriate.”

4. PMDA. Revisions of PRECAUTIONS (FY2017). 28/11/2017. http://www.pmda.go.jp/english/safety/info-services/drugs/revision-of-precautions/0005.html 5. Report on the investigation results. 000221379. PMDA. November 11, 2017.

8 9 DOTAREM®: Its macrocyclic and ionic structure induces a very high stability

Kinetic stability 6 Thermodynamic stability 6

• The kinetic stability represents the speed of free • The thermodynamic stability is another parameter gadolinium release from the original GBCA complex. measuring the propensity to release gadolinium.

• The lower the kinetic stability, the shorter the dissociation • The lower theLinear thermodynamic GBCAs stability,Macrocyclic the higher GBCAs the half-life, thus the faster the release of free gadolinium. quantity of free gadolinium released.

Linear GBCAs Macrocyclic GBCAs Non-ionic GBCAs Ionic GBCAs

6. Port M et al. Biometals. 2008 Aug;21(4):469-90.

10 11

Non-ionic GBCAs Ionic GBCAs DOTAREM®: No visible brain Studies comparing Dotarem® hyperintensities related to to Linear GBCAs demonstrated hyperintensities with Linear dechelated Gd following GBCAs but not with Dotarem® *7,12 repeated injections 7-11 Before After repeated administrations of GBCA

Adults ® 7 M • In a study comparing Dotarem® and Magnevist®, 6 administrations otare

"an SI [Signal Intensity] increase in the DN [Dentate D Nucleus] and GP [Globus Pallidus] on T1-weighted

images is caused by serial application of the linear ® 7 GBCA gadopentetate dimeglumine but not by the 6 administrations macrocyclic GBCA gadoterate meglumine."7

Magnevist • In a study where 33 patients received more than 20 repeated injections of macrocyclic GBCAs, ® 12 including 70% of Ionic & Macrocyclic Dotarem®, no hyperintensities were detected in the Dentate 15 administrations Nucleus (DN).10

Multihance Children DOTAREM®: No confirmed • In a study 11 assessing 41 pediatric patients (3-17 years old), “no increase of the SI in the DN was found after unconfounded cases of a mean of 8.6 serial injections of the macrocyclic ® Nephrogenic Systemic GBCA gadoterate meglumine [Dotarem ] in pediatric 13,14 patients, confirming previous studies that did not find Fibrosis (NSF) this effect after serial injections of macrocyclic GBCAs in adults.” Confirmed unconfounded cases of NSF

Today, it remains unknown if gadolinium deposition Macrocylic GBCAs Linear GBCAs could lead to potential long-term toxicity. Magnevist®: 74 15 DotareM®: 0 13,14 Ionic Multihance®: 0 16

7. Radbruch A et al. Radiology. 2015 Jun;275(3):783-91. Gadovist®: 3 17 Omniscan™: 197 15 8. Radbruch A et al. Invest Radiol. 2016 Nov;51(11):683-90. Non-ionic Prohance®: 1 18 Optimark®: 8 15 9. Eisele P et al. Medicine (Baltimore). 2016 Sep;95(39):e4624. 10. Radbruch A et al. Radiology. 2017 Mar;282(3):699-707. 11. Radbruch A et al. Radiology. 2017 Jun;283(3):828-836. * The protocols of the two studies are described page 19. 12. Weberling LD et al. Invest Radiol. 2015 Nov;50(11):743-8. 13. USA PI as of December 2017. 16. Elmhodt TR et al. PLOS ONE 2014 (The PLOS ONE Staff - correction). 14. de Kerviler E et al. Invest Radiol. 2016 Sep;51(9):544-51. 17. Endrikat J et al. Invest Radiol. 2016 Sep;51(9):537-43. 15. Edwards BJ et al. Br J Radiol. 2014 Oct;87(1042):20140307. 18. Heverhagen JT et al. Rofo. 2014 Jul;186(7):661-9.

12 13 DOTAREM®: Low rate of acute adverse events

General population

• 0.34% : adverse events (AEs) rate reported in a study conducted on over 84,000 patients.19

Children

• 0.26% : rate of AEs possibly or probably related to Ionic & Macrocyclic Dotarem® in an extensive review of 13 studies conducted on 3,810 children (0-2 years old: n=241, 2-17 years old: n=3,569).20

The article Prince et al.21 comparing acute side effects of some GBCAs does not include Dotarem®.

19. Maurer M et al. Eur J Radiol. 2012 May;81(5):885-90. 20. Balassy C et al. Pediatr Radiol. 2015 Nov;45(12):1831-41. 21. Prince MR et al. AJR Am J Roentgenol. 2011 Feb;196(2):W138-43.

14 15 DOTAREM®: Optimal Dotarem® has a concentration diagnostic performance of 0.5M and shows similar diagnostic efficacy as compared to contrast media with a higher 22-29 General population concentration ® ® In a large surveillance study with more than 84,000 • Several studies comparing Dotarem with Gadovist ® demonstrated similar efficacy in neuro imaging, breast examinations, Dotarem demonstrated optimal efficacy 22-29 in clinical practice.19 MRI, MR angiography, and cardiac MRI.

97,7% 99,7% • For example, the REMIND study, double-blind randomized controlled intraindividual crossover study, compared Dotarem® with Gadovist® in the MRI diagnosis of primary brain tumors. The noninferiority of Dotarem® versus Gadovist® for overall visualization and characterization of primary brain tumors was demonstrated. 29

Images rated Diagnostic good or excellent achieved

Children 95-100%

In an extensive review of 3 studies conducted in 1,905 children, Dotarem® demonstrated improved A B image quality & diagnostic 20 performance. A 74-year-old man with a high-grade glioma. T1 spin-echo Images rated images (1.5T) after administration of Dotarem® (A) and good or excellent Gadovist ® (B) show an approximate 30 mm mass. The mass is clearly seen on both examinations and shows no 29 difference in contrast enhancement.

19. Maurer M et al. Eur J Radiol. 2012 May;81(5):885-90. 25. Hansmann J et al. PLoS One. 2014 Jun 3;9(6):e99079. 20. Balassy C et al. Pediatr Radiol. 2015 Nov;45(12):1831-41. 26. Anzalone N et al. Eur J Radiol. 2013 Jan;82(1):139-45. 22. Szucs-Farkas Z et al. J Magn Reson Imaging. 2008 Jun;27(6):1399-405. 27. Renz DM et alInvest Radiol. 2014 Jul;49(7):474-84. 23. Loewe C et al. AJR Am J Roentgenol. 2015 Jun;204(6):1311-21. 28. Wagner M et al. Eur Radiol. 2013 Jan;23(1):108-14. 24. Haneder S et al. J Magn Reson Imaging. 2012 Nov;36(5):1213-21. 29. Maravilla K et al. Am J Neuroradiol. 2017 Sep;38(9):1681-88.

16 17 References

1. Gadolinium Article-31 referral - EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans. ® DOTAREM : Number 1 MRI 21/07/2017. EMA/457616/2017. www.ema.europa.eu. contrast agent worldwide 2. Medical Imaging Drugs Advisory Committee Meeting. 30 Gadolinium retention after gadolinium based contrast magnetic in volume resonance imaging in patients with normal renal function. Briefing document. 08/09/2017. 3. FDA Drug Safety Communication: FDA warns that gadolinium- Dotarem® was the first launched macrocylic GBCA: based contrast agents (GBCAs) are retained in the body; requires new class warnings. 19/12/2017. • Today available in more than 70 countries 4. PMDA. Revisions of PRECAUTIONS (FY2017). 28/11/2017. http://www.pmda.go.jp/english/safety/info-services/drugs/ • 29 years of clinical experience revision-of-precautions/0005.html 5. • More than 70 million doses administered 31 Report on the investigation results. 000221379. Pharmaceuticals and Medical Devices Agency (PMDA). November 11, 2017. 6. Port M et al. Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals. 2008 Aug;21(4):469- Dotarem® administered doses 90. Epub 2008 Mar 15. worldwide (cumulated) 70 7. Radbruch A et al. Gadolinium retention in the dentate nucleus 60 and globus pallidus is dependent on the class of contrast agent. Radiology. 2015 Jun;275(3):783-91. 50 Study protocol: Two groups of 50 patients who underwent at least 6 consecutive MRI examinations with the exclusive use of either Magnevist® or Dotarem® were analyzed retrospectively. The difference in mean SI ratios of DN-to-pons and GP-to-thalamus on 40 unenhanced T1w images from the last and first examinations was calculated.

30 8. Radbruch A et al. Intraindividual analysis of signal intensity changes in the dentate nucleus after consecutive serial applications

Million of doses 20 of linear and macrocyclic gadolinium-based contrast agents. Invest Radiol. 2016 Nov;51(11):683-90. 10 9. Eisele P et al. Lack of increased signal intensity in the dentate 0 nucleus after repeated administration of a macrocyclic contrast agent in multiple sclerosis: An observational study. Medicine 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 (Baltimore). 2016 Sep;95(39):e4624. 10. Radbruch A et al. No signal intensity increase in the dentate nucleus on unenhanced T1-weighted MR images after more than 20 serial injections of macrocyclic gadolinium-based contrast agents. Radiology. 2017 Mar;282(3):699-707. Epub 2016 Dec 7. 11. Radbruch A et al. Pediatric brain: no increased signal intensity in the dentate nucleus on unenhanced T1-weighted MR images after consecutive exposure to a macrocyclic gadolinium-based contrast 30. In volume: CMIG data 2016, IMS data 2016. 31. Internal data as of December 2017. agent. Radiology. 2017 Jun;283(3):828-836. Epub 2017 Mar 8.

18 19 12. Weberling LD et al. Increased signal intensity in the dentate Jun;204(6):1311-21. MR angiography at 3T of peripheral nucleus on unenhanced T1-weighted images after gadobe- arterial disease: a randomized prospective comparison of nate dimeglumine administration. Invest Radiol. 2015 gadoterate meglumine and gadobutrol. Nov;50(11):743-8. 24. Haneder S et al. Comparison of 0.5 M gadoterate and 1.0 M Study protocol: 50 patients who underwent at least 5 consecutive MRI examinations gadobutrol in peripheral MRA: a prospective, single-center, with the exclusive use of Multihance® were analyzed retrospectively. The difference of DN-to-pons and DN-to-CSF mean SI ratios was calculated on unenhanced T1w images randomized, crossover, double-blind study. J Magn Reson Imaging. between the first and last examination. Results were compared with previously 2012 Nov;36(5):1213-21. published data on Magnevist® or Dotarem®. 25. Hansmann J et al. Enhancement characteristics and impact on 13. USA PI as of December 2017. image quality of two gadolinium chelates at equimolar doses 14. de Kerviler E et al. Adverse reactions to gadoterate meglumine: for time-resolved 3-Tesla MR angiography of the calf station. review of over 25 years of clinical use and more than 50 million PLoS One. 2014 Jun 3;9(6):e99079. doses. Invest Radiol. 2016 Sep;51(9):544-51. 26. Anzalone N et al. Cerebral neoplastic enhancing lesions: 15. Edwards BJ et al. Advancing pharmacovigilance through multicenter, randomized, crossover intraindividual comparison academic-legal collaboration: the case of gadolinium-based between gadobutrol (1.0M) and gadoterate meglumine (0.5M) contrast agents and nephrogenic systemic fibrosis-a Research at 0.1 mmol Gd/kg body weight in a clinical setting. Eur J on Adverse Drug Events and Reports (RADAR) report. Radiol. 2013 Jan;82(1):139-45. Br J Radiol. 2014 Oct;87(1042):20140307. 27. Renz DM et al. Comparison of gadoteric acid and gadobutrol 16. The PLOS ONE Staff (2014) Correction: Nephrogenic Systemic for detection as well as morphologic and dynamic Fibrosis in Denmark - A nationwide investigation. PLoS ONE characterization of lesions on breast dynamic contrast-enhanced 9(6): e100407. magnetic resonance imaging. Invest Radiol. 2014 17. Endrikat J et al. Safety of gadobutrol: results from 42 clinical Jul;49(7):474-84. phase II to IV studies and postmarketing surveillance after 28. Wagner M et al. Macrocyclic contrast agents for magnetic 29 million applications. Invest Radiol. 2016 Sep;51(9):537-43. resonance imaging of chronic myocardial infarction: 18. Heverhagen JT et al. Application of extracellular gadolinium- intraindividual comparison of gadobutrol and gadoterate based MRI contrast agents and the risk of nephrogenic systemic meglumine. Eur Radiol. 2013 Jan;23(1):108-14. fibrosis. Rofo. 2014 Jul;186(7):661-9. Epub 2014 Jan 29. 29. Maravilla K et al. Comparison of gadoterate meglumine and 19. Maurer M et al. Tolerability and diagnostic value of gadoteric gadobutrol in MRI diagnosis of primary brain tumors: a double- acid in the general population and in patients with risk factors: blind randomized controlled intra-individual cross over study results in more than 84,000 patients. Eur J Radiol. 2012 (the REMIND study). Am J Neuroradiol. 2017 Sep;38(9):1681- May;81(5):885-90. 88. Epub 2017 Jun 29. 20. Balassy C et al. Safety and efficacy of gadoteric acid in 30. In volume: CMIG data 2016, IMS data 2016. pediatric magnetic resonance imaging: overview of clinical 31. Internal data as of December 2017. trials and post-marketing studies. Pediatr Radiol. 2015 Nov;45(12):1831-41. 21. Prince MR et al. Incidence of immediate gadolinium contrast media reactions. AJR Am J Roentgenol. 2011 Feb;196(2):W138-43. Dotarem®: gadoteric acid 22. Szucs-Farkas Z et al. 1.0-M gadobutrol versus 0.5 M gadoterate Gadovist®: gadobutrol for peripheral magnetic resonance angiography: a prospective Prohance®: gadoteridol randomized controlled clinical trial. J Magn Reson Imaging. Multihance®: gadobenate dimeglumine 2008 Jun;27(6):1399-405. Magnevist®: gadopentetate dimeglumine 23. Loewe C et al. MR Angiography at 3 T of Peripheral Arterial TM Disease: A Randomized Prospective Comparison of Gadoterate Omniscan : gadodiamide Meglumine and Gadobutrol. AJR Am J Roentgenol. 2015 This brochure is not intended for US/UK healthcare professionals.

20 21 DOTAREM 0.5 mmol/mL, solution for injection. Composition: For and other forms of interaction: No interactions with other 100 mL of solution: active ingredient: Gadoteric Acid 27.932 g medicinal products have been observed. Formal drug interaction corresponding to: DOTA 20.246 g corresponding to gadolinium studies have not been carried out. Fertility, pregnancy and oxide 9.062 g. Indications (*): Medicinal product for diagnostic lactation: Gadoteric acid should not be used during pregnancy use only: Magnetic Resonance Imaging for cerebral and spinal unless the clinical condition of the woman requires use of gadoteric disease, diseases of the vertebral column, and other whole-body acid. Continuing or discontinuing breast feeding for a period of pathologies (including angiography). Dotarem should be used 24 hours after administration of gadoteric acid, should be at the only when diagnostic information is essential and not available discretion of the doctor and lactating mother. Effects on ability to with unenhanced magnetic resonance imaging (MRI). Posology drive and use machines: No studies on the effects on the ability and method of administration: The recommended dose is to drive and use machines have been performed. Ambulant patients 0.1 mmol/kg, i.e. 0.2 mL/kg in adults and children. The lowest dose while driving vehicles or operating machinery should take into that provides sufficient enhancement for diagnostic purposes should account that nausea may incidentally occur. Undesirable effects: be used. The dose should be calculated based on the patient’s body Uncommon (≥1/1000 to <1/100): hypersensitivity, headache, weight, and should not exceed the recommended dose per kilogram dysgeusia, dizziness, somnolence, paraesthesia (including burning of body weight detailed in this section. In angiography, depending sensation), hypotension, hypertension, nausea, abdominal pain, on the results of the examination being performed, a second rash, feeling hot, feeling cold, asthenia, injection site reactions injection may be administered during the same session if necessary. (extravasation, pain, discomfort, oedema, inflammation, coldness). Angiography with Gadoteric acid is not recommended in children Rare (≥1/10 000 to <1/1 000): anxiety, presyncope, eyelid edema, (0-18 years). In Encephalic and spinal MRI, in some exceptional palpitations, sneezing, throat tightness, vomiting, diarrhea, salivary cases, as in the confirmation of isolated metastasis or the detection hypersecretion, Urticaria, pruritus, hyperhidrosis, chest pain, chills. of leptomeningeal tumours, a second injection of 0.2 mmol/kg Very rare (<1/10 000): anaphylactic reaction, anaphylactoid may improve tumor characterisation and facilitate therapeutic reaction, agitation, coma, convulsion, syncope, tremor, parosmia, decision making. For patients with impaired renal function and conjunctivitis, ocular hyperaemia, vision blurred, lacrimation paediatric population (0-18 years) more than one dose should not increased, tachycardia, cardiac arrest, arrhythmia, bradycardia, be used during a scan, injections should not be repeated unless flushing, pallor, vasodilatation, hot flush, cough, dyspnoea, nasal the interval between injections is at least 7 days. The product must congestion, respiratory arrest, bronchospasm, throat irritation, be administered by strict intravenous injection. Depending on the laryngospasm, pharyngeal oedema, dry throat, pulmonary amount of gadoteric acid to be given to the child, it is preferable oedema, erythema, angioedema, eczema, muscle cramps, muscular to use gadoteric acid vials with a single use syringe of a volume weakness, back pain, arthralgia, malaise, chest discomfort, pyrexia, adapted to this amount in order to have a better precision of the face oedema, injection site necrosis (in case of extravasation), injected volume. In neonates and infants the required dose should phlebitis superficial, decreased oxygen saturation, Not known : be administered by hand. Contraindications: Hypersensitivity to nephrogenic systemic fibrosis. Overdose: Gadoteric acid can gadoteric acid, to meglumine or to any medicinal products containing be removed by haemodialysis. However there is no evidence that gadolinium. Special warnings and precautions for use: haemodialysis is suitable for prevention of nephrogenic systemic Dotarem must not be administered by subarachnoid (or epidural) fibrosis. Please note: The peel-off tracking label on the vials or injection. The usual precaution measures for MRI examination syringes should be stuck onto the patient record to enable accurate should be taken such as exclusion of patients with pacemakers, recording of the gadolinium contrast agent used. The dose used ferromagnetic vascular clips, infusion pumps, nerve stimulators, should also be recorded. If electronic patient records are used, the cochlear implants or suspected intracorporal metallic foreign bodies, name of the product, the batch number and the dose should be particularly in the eye. General particulars corresponding to entered into the patient record. Pharmacological properties: all gadolinium contrast agents: All gadolinium based contrast Pharmacotherapeutic group: paramagnetic contrast media for MRI, media can cause minor or major hypersensitivity reactions that can ATC code: V08CA02. Presentation (*): 5, 10, 15, 20, 60 & be life-threatening. These can occur immediately (within 60 minutes) 100 mL in vial (glass) and 10, 15 & 20 mL in a prefilled syringe or be delayed (within 7 days) and are often unpredictable. Because (glass). Marketing authorization holder: (*) Information: of the risk of major reactions, emergency resuscitation equipment Guerbet - BP 57400 - F-95943 Roissy CdG cedex – FRANCE. Tel: should be available for immediate use. Hypersensitivity reactions 33 (0) 1 45 91 50 00. Date of revision of this document: can be aggravated in patients on betablockers and particularly February 2018 in the presence of bronchial asthma. These patients may be refractory to standard treatment of hypersensitivity reactions with beta agonists. Impaired renal function: Prior to administration of For current and complete prescribing information refer to the package gadoteric acid, it is recommended that all patients are screened insert and/or contact your local Guerbet organization. for renal dysfunction by obtaining laboratory tests. There have (*) Indications, presentations and marketing authorization holder been reports of Nephrogenic Systemic Fibrosis (NSF) associated may differ from country to country. with use of some gadolinium-containing contrast agents in patients 2 Reporting of suspected adverse reactions is important as with severe renal impairment (GFR < 30 ml/min/1.73 m ). As it helps to continuously assess the benefit-risk balance. there is a possibility that NSF may occur with Dotarem, it should Therefore, Guerbet encourages you to report any only be used in these patients after careful consideration. CNS adverse reactions to your health authorities or to our disorders: As with other contrast agents containing gadolinium, local Guerbet representative. special precautions should be taken in patients with a low seizure threshold. Precautionary measures, e.g. close monitoring, should be taken. All equipment and drugs necessary to counter any convulsions which may occur must be made ready for use beforehand. Interactions with other medicinal products

22 23 www.guerbet.com communication CM P18 042 DOT – January 2018 –