Application for Inclusion of Gadolinium-Based Contrast Agents to the WHO

Home , Gadobenic acid, Gadobutrol, Gadodiamide, Gadofosveset, Gadopentetic acid, Gadoteric acid

Application for inclusion of Gadolinium‐based contrast agents to the WHO Essential List of Medicines

Submitted by

Daniel Patiño, PhD (McMaster)

Faculty of Medicine

University of Antioquia, Medellin, Colombia

Holger J. Schünemann, MD, PhD

Chair and Professor, Departments of Clinical Epidemiology and Biostatistics

Co‐Director, WHO Collaborating Center for Evidence Informed Policy, McMaster University

Potential conflicts of interest

Dr. Patiño and Dr. Schünemann declare that they have no COI.

Date: Dec 15, 2014

Application to add Gadolinium‐based contrast agents to the WHO Essential List of Medicines

1. Summary statement of the proposal for inclusion, change or deletion

Currently the 18th edition of WHO Model List of Essential Medicines does not include gadolinium‐based contrast agents (Gd‐CAs) under 14.2 radio contrast media classification. Since the introduction of gadopentate dimeglumine in 1988, gadolinium‐based contrast agents have significantly improved the diagnostic efficacy of Magnetic Resonance Image (MRI) (1). Gadolinium‐based contrast agents are intravenous agents used for contrast enhancement with magnetic resonance imaging (MRI) and with magnetic resonance angiography (MRA). The Gd‐CAs are available for different types of MR scan varying from product to product, including liver, brain and whole body scan.

This application proposes to add Gd‐CAs for the complementary list of WHO Essential List of Medicines to be used in the detection of lymph node metastases. It will focus on the following ‘general purpose’ Gd‐CAs: gaodopentate dimeglumine, gadodiamide, gadoversetamide, gadobenate dimeglumine, gadoteridol, gadoteric acid, gadobutrol. We will not include the ‘newer’ Gd‐CAs that are organ specific like the hepatobiliary‐specific contrast agents that are available for imaging the liver (e.g., gadoxetic acid).

We do not propose Gd‐CAs for the core list of essential medicine but as a complementary medicine to be used only by health specialists.

2. Name of the focal point in WHO submitting or supporting the application (where relevant)

Nicola Magrini, MD

3. Name of the organization(s) consulted and/or supporting the application

Daniel Patiño, PhD Faculty of Medicine University of Antioquia, Medellin, Colombia [email protected]

Holger Schünemann, MD, PhD Department of Medicine and of Clinical Epidemiology and Biostatistics & WHO Collaborating Center for Evidence Informed Policy McMaster University, Hamilton, Ontario, Canada [email protected]

4. International Nonproprietary Name (INN, generic name) of the medicine

Gadopentate dimeglumine

5. Formulation proposed for inclusion; including adult and paediatric (if appropriate)

Solution for intravenous injection Gaodopentate dimeglumine 0.5mmol/ml Available in vials and prefilled syringes

6. International availability ‐ sources, of possible manufacturers and trade names

Gadopentate dimeglumine is manufacture by Bayer Health Care Pharmaceutical under the brand name Magnevist and it is available worldwide.

Other gadolinium‐based contrast agents are available worldwide and manufactured by multiple companies (Table 1). Although, these agents can be differentiated in terms of their stability and physiochemical properties (e.g., viscosity, and osmolality) they cannot be differentiated on the basis of efficacy (1,2).

Table 1 Name Brand name Manufacture EMA or FDA approved Gaodopentate Magnevist® Bayer HealthCare EMEA and FDA dimeglumine Pharmaceuticals Gadodiamide Omniscan® GE Healthcare EMEA and FDA Gadoversetamide OptiMARK® Covidien EMEA and FDA Gadobenate MultiHance® Bracco Diagnostics EMEA and FDA dimeglumine Gadoteridol ProHance® Bracco Diagnostics EMEA and FDA Gadoteric acid Dotarem® Guerbet EMEA and FDA Gadobutrol Gadavist® Bayer HealthCare EMEA and FDA Pharmaceuticals EMA: European Medicines Agency FDA: Food and Drug Administration

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group

(□) Gadopentate dimeglumine

We request to include gadopentate dimeglumine with a square box symbol as an example of a therapeutic group that includes the other Gd‐CAs listed in table 1. Gadopentate dimeglumine was the first Gd‐CAs that was licensed for marketing (3) and it is often used to assess the comparative effectiveness of other Gd‐CAs.

8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)

In most malignancies (e.g., breast cancer), the presence of lymph node metastases and the extent of their spread are important prognostic factors for staging disease and planning treatment. Accurate preoperative assessment of lymph node metastasis is an important first step in assigning patients to one of the available management strategies. One method for staging lymph node metastases is histopathologic examination. However, this is an invasive surgical procedure in which complications and morbidity may occur. Contrast‐enhanced MRI may provide information on whether a lesion is suspicious for metastasis, based on criteria such as size, morphology and enhancement characteristics following administration of a contrast agent. The administration of an intravenous contrast agent, such as gadolinium, can reveal the surrounding blood vessels and demonstrate additional morphological characteristics of tumor tissue leading to more accurate diagnosis (4,5). Although in suspected neurological disease, e.g. cerebrovascular accidents or multiple sclerosis, the use of contrast‐enhanced MRI supports establishing diagnosis, we will focus on the use of Gd‐ CAs in cancer as an example.

9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills)

The following information is based on the FDA recommendations for prescribing MAGNEVIST (gadopentetate dimeglumine) (6).

Indications and usage Magnevist is a gadolinium‐based contrast agent for intravenous use in diagnostic MRI in adults and children (2 years of age and older) to facilitate the visualization of lesions and abnormal vascularity in: ‐ Central Nervous System: brain, spine and associated tissues ‐ Extracranial/Extraspinal Tissues: head and neck ‐ Body

Dosage and administration Magnevist is administered intravenously, 0.2 mL/kg (0.1 mmol/kg), at a rate not to exceed 10 mL per 15 seconds. The version 9 of the manual on contras media developed by the American College of Radiologist considers 0.1 to 0.3 mmol per kg of body weight as de usual dose.

Dosage forms and strengths Magnevist contains 0.5 mmol gadopentetate dimeglumine/mL (equivalent to 469.01 mg gadopentetate dimeglumine/mL) and is available in vials and prefilled syringes.

Contraindications Magnevist is contraindicated in patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) or acute kidney injury, or history of severe hypersensitivity reactions to Magnevist.

Warnings and precautions ‐ Nephrogenic Systemic Fibrosis (NSF) has occurred in patients with impaired elimination of Gd‐GAs. Higher than recommended dosing or repeat dosing appears to increase the risk. ‐ Hypersensitivity: Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, and/or cutaneous manifestations rarely resulting in death have occurred. ‐ Monitor patients closely for need of emergency cardiorespiratory support. ‐ Renal Failure: In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of Magnevist injection.

Adverse reactions The most common adverse reactions (≥1%) are headache, nausea, injection site coldness/localized coldness, and dizziness.

Drug interactions There are no known drug interactions. Magnevist does not interfere with serum and plasma calcium measurements determined by colorimetric assays.

Special populations Children ‐ Neonates may have eGFR values < 30 ml/min/1.73 m2 due to immature renal function. The ACR Committee on Drugs and Contrast Media calls for caution when administering Gd‐CAs in this population (2). However, the European Medicine agency describes a contraindication for the use of the high‐risk category of Gd‐CAs in neonates up to 4 weeks of age. The use of medium and low risk Gd‐CAs in neonates should only be considered after careful consideration and subject to dose and interval administration restrictions (7). ‐ In infants below 1 year of age the use of all Gd‐ CAs should be subject to careful consideration and to dose and interval administration restrictions to not more than one injection of the minimum dose during a scan with a minimum seven‐day interval between dose administrations (7).

Pregnant woman Gd‐CAs should not be used in pregnant patients unless exceptional circumstances demand it. The manual of the ACR states (2): “Because it is unclear how GBCAs will affect the fetus, these agents should be administered only with caution. They should only be used if their usage is considered critical and the potential benefits justify the potential risk to the unborn fetus. If a GBCA is to be used in a pregnant patient, one of the agents believed to be at low risk for the development of nephrogenic systemic fibrosis (NSF) should be used at the lowest possible dose to achieve diagnostic results. In pregnant patients with severely impaired renal function, the same precautions should be observed as in non‐pregnant patients”

Breast‐feeding Discontinuation of breastfeeding for at least 24 h is recommended for all patients receiving high‐risk Gd‐CAs.

Need for special diagnostics, treatment or monitoring facilities and skills

Given the need of a radiologist in the assessment of patients that would benefit from a gadolinium‐enhances MRI, we are proposing to list Gd‐CAs in the complementary list.

Public health need and evidence appraisal and synthesis 10. Summary of comparative effectiveness in a variety of clinical settings: A literature search was performed in PubMed and Cochrane dating up to Dec 4, 2014 for systematic reviews and meta‐analyses on the use of gadolinium‐enhanced magnetic resonance imaging in the detection of lymph node metastases. The search was limited to publications over the last 5 years, humans and English language. The search strategy was as follows: #1 MeSH descriptor: [Contrast Media] explode all trees #2 contrast agent #3 gadolinium contrast #4 gadolinium enhancement #5 gadolinium contrast agent #6 gadolinium #7 Gadodiamide #8 gadopentetate dimeglumine #9 gadoversetamide #10 Gadoteridol #11 gadoteric acid #12 gadobutrol #13 Gadofosveset #14 Gadoxetic acid #15 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 #16 enhanced MRI #17 MeSH descriptor: [Magnetic Resonance Imaging] explode all trees #18 #16 or #17 #19 MeSH descriptor: [Lymphatic Metastasis/diagnosis*] #20 #15 AND #18 AND #19

We identified one protocol of a Cochrane systematic review and two completed systematic reviews.

1. Sun Y‐S, Li X‐T, Tang L, Zhang X‐Y, Zhang X‐P, Yong Cui JL, et al. Magnetic resonance imaging (MRI ) versus computed tomography (CT ) for the diagnosis of lymph node metastasis in preoperative rectal cancer (Protocol). Cochrane Database Syst Rev. 2012;(5). (8)

2. Klerkx WM, Bax L, Veldhuis WB, Heintz APM, Mali WP, Peeters PHM, et al. Detection of lymph node metastases by gadolinium‐enhanced magnetic resonance imaging: systematic review and meta‐analysis. J Natl Cancer Inst. United States; 2010 Feb;102(4):244–53. (9)

3. Cooper KL, Meng Y, Harnan S, Ward SE, Fitzgerald P, Papaioannou D, et al. Positron emission tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary lymph node metastases in early breast cancer: systematic review and economic evaluation. Health Technol Assess. England; 2011 Jan;15(4):iii – iv, 1–134.

The review developed by Klerkx et al. included 32 studies that evaluated gadolinium‐ enhanced MRI compared with histopathology of lymph nodes obtained by surgery, autopsy, or biopsy as the reference standard. The total number of patients was 1402 and the studies included patients with colon, cervical, breast, lung, head and neck, esophageal, pancreatic, renal cell, endometrial, urinary bladder and gall bladder cancers (9).

According to the meta‐analysis, the overall sensitivity of all 32 studies was 0.72 (95% CI = 0.66 to 0.79), and the specificity was 0.87 (95% CI = 0.82 to 0.91) (Table 2). In addition, the sensitivity of the test increased in a subgroup analysis that included nine studies (306 patients) that evaluated lymph node metastases by multiple malignancy criteria including gadolinium enhancement. The sensitivity in this subgroup was 0.84 (95% CI = 0.70 to 0.92) and the specificity was 0.82 (95% CI = 0.72 to 0.89) (Table 3). The quality of the evidence was moderate given that many of the included studies did not report several items of the QUADAS list (9).

Table 2 ‐ Summary of findings

Table 3 ‐ Summary of findings: Subgroup analysis with studies that included gadolinium enhancement as a criterion of malignancy

The review by Copper et al., compared positron emission tomography (PET) and magnetic resonance imaging (MRI) in the assessment of axillary lymph node metastases in early breast cancer (10). The study included nine contrast‐enhanced MRI studies. Three of these studies (n = 187) used gadolinium‐based contrast agents and the other used ultrasmall super‐paramagnetic iron oxide (USPIO) contrast agent. The mean sensitivity and specificity across the studies that used gadolinium were 88% (95% CI 78% to 94%) and 73% (95% CI 63% to 81%) respectively. The sensitivity and specificity of MRI based on all identified studies were 93% and 89.7% respectively. It is also important to notice that the use of contrast uptake pattern as the main criterion for defining a node as metastatic appeared to give better combined sensitivity and specificity than size and morphology. The authors concluded that the studies in this review demonstrated a significantly higher sensitivity for MRI than for PET. However, since none of the included studies directly compared PET and MRI, caution should be taken when comparing these estimates. In addition, as in the review by Klerkx et al., the authors found that the use of contrast uptake pattern as the main criterion for defining a node as metastatic appeared to give better combined sensitivity and specificity than size and morphology.

11. Summary of comparative evidence on safety:

The meta‐analysis about the use of gadolinium‐enhanced MRI for the detection of lymph nodes metastasis developed by Klerkx et al., did not report any adverse events. The review developed by Cooper et al., reported that non of the gadolinium‐based MRI studies reported any adverse event. In addition, we identified a systematic review about the effects of imaging tests for the staging of colorectal cancer which systematically searched for

8 information on harms related to MRI and other imaging test regardless of condition or disease state (11). In the appendix we present the search strategies and summary tables of the studies that were included in that review.

The largest study (n=84,621) of gadolinium‐enhanced MRI adverse events that was identified in the aforementioned systematic review included 19,354 (22.9%) patients with renal and liver dysfunctions, history of allergies, hypertension, chronic heart disease, and central nervous system disorders. The study reported four hundred twenty‐one adverse events (65 different types) in 285 out of the 84,621 patients (0.34%). Only eight serious (3 life‐threatening) adverse events (less than 0.01%) were reported (12).

Furthermore, the American College of Radiology’s (ACR) “ACR Manual on Contrast Media” (2013) states that acute adverse reactions to Gd‐CAs are encountered with a lower frequency than is observed after administration of iodinated contrast media (2). The ACR manual indicates the following frequencies of acute adverse events:

‐ After an injection of 0.1 or 0.2 mmol/kg of gadolinium‐based contrast agent the frequency of acute adverse events ranges from 0.07% to 2.4%. ‐ The majority of these reactions are mild and include coldness at the injection site, nausea with or without vomiting, headache, warmth or pain at the injection site, paraesthesia’s, dizziness, and itching. ‐ Reactions resembling an “allergic” response are very unusual and vary in frequency from 0.004% to ¬0.7%. A rash hives or urticaria are the most frequent of this group, and very rarely there may be bronchospasm. ‐ Severe, life‐threatening anaphylactoid or nonallergic anaphylactic reactions are rare (0.001% to 0.01%). In an accumulated series of 687,000 doses there were only 5 severe reactions. In another survey based on 20 million administered doses there were 55 cases of severe reactions. ‐ Fatal reactions to gadolinium agents occur but are extremely rare. ‐ As we will discuss below, gadolinium‐based contras media administered to patients with acute renal failure or severe chronic kidney disease can result in a syndrome of nephrogenic systemic fibrosis (NSF).

The patients that are a greater risk of presenting adverse events are those that presented previous reactions to gadolinium‐based contrast media and those with asthma and various allergies, including to other medications or foods and those that had previous allergic‐like reactions to iodinated contrast media (2).

Finally, given the risk of NSF following gadolinium‐based contrast material administration, especially in patients with acute renal failure or severe chronic kidney disease, and because of the nephrotoxicity of high doses of gadolinium agent, Gd‐CAs should not be used for angiography or Computer tomography (2,13).

Nephrogenic systemic fibrosis (NFS)

Definition

“Nephrogenic systemic fibrosis (NSF) is a fibrosing disease, primarily involving the skin and subcutaneous tissues but also known to involve other organs, such as the lungs, esophagus, heart, and skeletal muscles. Initial symptoms typically include skin thickening and/or pruritis. Symptoms and signs may develop and progress rapidly, with some affected patients developing contractures and joint immobility. In some patients, the disease may be fatal” (2).

Gd‐CAs and NFS association In 2006 a strong association between gadolinium‐based contrast agent (Gd‐CA) administration in patients with advanced renal disease and the development of nephrogenic systemic fibrosis (NSF) was noted (14,15). This association has been confirmed by several studies including a systematic review that conducted a meta‐analysis of six controlled trials demonstrated a significant association between Gd‐CA exposure and NSF [odds ratio (OR) 26.7; 95% confidence interval (CI) 10.3–69.4] and between gadodiamide (Omniscan®), which was used in four of the six studies, and NSF (OR 20.0; 95% CI 3.7–107.8) (16).

Estimate of total patient exposure to Gd‐CA and cases of NFS Table 4 presents an overview of worldwide unconfounded (i.e., cases which exhibit a definite association with a specific gadolinium‐based contrast medium) NSF cases for the various gadolinium‐based contrast agents.

Table 4‐ NFS cases and relative frequency. Adapted from Heverhagen et.al., 2014 (17) Contrast media NSF Contrast media NSF relative cases examinations frequency (cases/1 global global million applications) Gadodiamide (Omniscan®) 438 47 million 9.3 Gadopentetate dimeglumine 135 115 million 1.2 (Magnevist®) and generics Gadoversetamide (Optimark®) 7 >9 million 0.8 Gadobutrol (Gadavist®) 1 >6 million 0.7 Gadoteridol (ProHance®) 1 >14 million <0.1 Gadoteric acid (Dotarem®) 1 >21 million <0.1 Gadobenate dimeglumine 0 >11 million <0.1 (MultiHance®)

Classification of Gd‐CAs in different risk groups Given this association, the European Medicines Agency (EMA), the American College of Radiology (ACR), the Food and Drug administration (FDA) and the European Society for Urogenital Radiology (ESUR) have classified Gd‐CAs into different groups based on reported associations with NSF in vulnerable patients (2,7,18,19).

Table 5‐ Classification of Gd‐CAs according to the risk of NFS Name Brand name EMA1 ACR2 FDA3 ESUR4 Gaodopentate Magnevist® High‐risk Group I Avoid use in AKI or High‐risk dimeglumine chronic, severe kidney disease Gadodiamide Omniscan® High‐risk Group I Avoid use in AKI or High‐risk

chronic, severe kidney disease Gadoversetamide OptiMARK® High‐risk Group I Avoid use in AKI or High‐risk chronic, severe kidney disease Gadobenate MultiHance® Medium‐ Group Medium‐risk dimeglumine risk II Gadoteridol ProHance® Low ‐risk Group Low ‐risk II Gadoteric acid Dotarem® Low‐risk Group Low‐risk II Gadobutrol Gadavist® Low‐risk Group Low‐risk II 1 The European Medicines Agency uses a classification based on the characteristics of the contrast media. The calcification also includes Gadofosveset (Ablavar) and gadoxetic acid (Primovist) as medium risk agents. 2 The American College of Radiology uses Classification based on the number of NSF cases in relation to the frequency of agent administration. Group I: Agents associated with the greatest number of NSF cases. Group II: Agents associated with few, if any, unconfounded cases of NSF. Group III: agents that recently appeared on the market, Gadofosveset (Ablavar® – Lantheus Medical Imaging) and Gadoxetic acid (Eovist® – Bayer HealthCare Pharmaceuticals). 3 The Food and Drug administration issued warning and contraindications for the high‐risk agents. Patients with Acute kidney injury (AKI) or chronic, severe kidney disease (with a glomerular filtration rate or GFR < 30 mL/min/1.73m2) should not be exposed to the high‐risk agents 4 The European Society for Urogenital Radiology uses the same calcification as EMA

Patients at risk of NSF (2,7,18,20) ‐ Patients with renal impairment ‐ Patients in the perioperative liver transplantation period ‐ Infants, neonates ‐ Women who are pregnant or breastfeeding

Contraindications and recommendations Renal monitoring: ‐ Renal function should be verified in all patients getting high‐risk agents (i.e., gaodopentate, gadodiamide and gadoversetamide), and is generally advisable for patients receiving medium‐risk agents. This is particularly important in patients aged 65 years or older or patients with chronic diseases such as diabetes, which are associated with renal failure (2,7,20).

Renal impairment: ‐ If the estimated glomerular filtration rate (eGFR) value for a patient is below 30ml/min/ 1.73m2, no high‐risk contrast medium may be used (18,20). If use of a low‐risk agent cannot be avoided, a single lowest possible dose should be used and should not be repeated for at least seven days (2,20).

‐ For patients with moderate renal impairment (eGFR <60ml/ min/1.73m2), a contrast medium in the high‐risk group should be avoided. If, after clinical review, it is necessary to use a high‐risk agent, a single lowest dose possible can be used with a minimum seven day interval between administrations (19,20).

Perioperative liver transplantation period:

‐ Patients undergoing liver transplantation are at particular risk of NSF if exposed to Gd‐CAs particularly to the high‐risk Gd‐CAs. Therefore, the use of a high‐risk agent in this population is contraindicated. If the use of a low‐risk agent cannot be avoided or if it is necessary to use a medium‐risk agent, a single lowest dose possible can be used and should not be repeated for at least seven days (7,20).

Pediatric patients: ‐ Neonates may have eGFR values < 30 ml/min/1.73 m2 due to immature renal function. The ACR Committee on Drugs and Contrast Media calls for caution when administering Gd‐CAs in this population (2). In addition, the European Medicine Agency listed a contraindication for the use of the high‐risk category of Gd‐CAs in neonates up to 4 weeks of age. The use of medium and low risk Gd‐CAs in neonates should only be considered after careful consideration and subject to dose and interval administration restrictions (7). ‐ In infants below 1 year of age the use of all Gd‐ CAs should be subject to careful consideration and to dose and interval administration restrictions to not more than one injection of the minimum dose during a scan with a minimum seven day interval between dose administrations (7).

Pregnancy: ‐ Gadolinium‐containing contrast agent should not be used unless absolutely necessary.

Breastfeeding: ‐ Discontinuation of breastfeeding for at least 24 h is recommended for all patients receiving high‐risk Gd‐CAs.

12. Summary of available data on comparative cost and cost‐effectiveness within the pharmacological class or therapeutic group:

Range of costs of the proposed medicine The International Drug Price Indicator Guide, Management Sciences for Health (MSH) (http://erc.msh.org/mainpage.cfm?file=1.0.htm&module=dmp&language=english) does not provide price for any of the Gd‐CAs.

However, we found an economic evaluation study that compared the cost‐effectiveness of gadoxetic acid (i.e., Gd‐CA specific for detecting liver lesions) vs. some of the Gd‐CA that we included in this application (21). The prices of the contrast agents in Germany were obtained from current sales prices to hospitals according to the pharmaceutical database Ifap index, in Italy from current sales prices to hospitals according to Italian National Drug Agency product list and in Sweden from the national Swedish pharmaceutical reference book (Table 6).

Table 6 – 2009 sale prices of Gd‐CA in Germany, Italy and Sweden (€)

Resource use and comparative cost‐effectiveness presented as range of cost per routine outcome

We performed a literature search of economic evaluations in the NHS Economic Evaluation Database (NHS EED), the Health Technology Assessments (HTA) database (using the Cochrane library) and Pubmed.

Search strategy in NHS EED and HTA through the Cochrane library

ID Search Hits #1 MeSH descriptor: [Magnetic Resonance Imaging] explode all trees #2 MeSH descriptor: [Gadolinium DTPA] explode all trees #3 MeSH descriptor: [Costs and Cost Analysis] explode all trees #4 Cost effectiveness #5 Cost benefit analysis #6 MeSH descriptor: [Contrast Media] explode all trees #7 Gadodiamide #8 Gadopentetate #9 Gadoversetamide #10 Gadobutrol #11 Gadoteridol #12 Gadoteric acid #13 Gadobenate dimeglumine #14 Omniscan #15 Magnevist #16 Optimark #17 Gadavist #18 ProHance #19 Dotarem #20 MultiHance #21 #2 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 #22 #1 and #21 #23 #3 or #4 or #5 #24 #22 and #23

The search yielded 35 studies.

The search strategy for Pubmed was: (((((Cost effectivness) OR cost effectiveness) OR Cost benefit) OR ("Costs and Cost Analysis"[Mesh]))) AND ((((((((Gadobenate dimeglumine) OR Gadoteric acid) OR Gadoteridol) OR Gadobutrol) OR Gadoversetamide) OR Gadopentetate) OR Gadodiamide) OR Contrast‐ enhanced MRI)

The search yielded 94 studies. After screening all titles and abstracts and excluding those that focus on magnetic resonance angiography or those that used Gd‐CAs that are specific for detecting liver lesions (e.g., gadoxetic acid), we found two economic evaluations that compared positron emission tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary lymph node metastases in early breast cancer (10,22). Both studies were based on the same data, therefore we will report only the results of the study produced by Cooper et al., 2011 (10).

The effectiveness data of the study came from a systematic review of nine contrast‐ enhanced MRI studies. Three of these studies used gadolinium‐based contrast agents and the other used ultrasmall super‐paramagnetic iron oxide (USPIO) contras agent. The sensitivity and specificity values of MRI that were used as an input in the cost‐effectiveness model, were based on all identified studies and were 93% and 89.7% respectively. The costs were obtained from UK NHS reference costs (23).

The study compared PET and MRI strategies with two baseline techniques baseline 4‐node sampling (4‐NS) and sentinel lymph node biopsy (SLNB), which are both used in the UK. The MRI replacement strategy was the most cost‐effective strategy and dominated the two baseline strategies. The higher QALYs of the MRI replacement strategy were driven by fewer cases of lymphoedema, which has a lifelong impact on quality of life (Table 7 taken from the study) (10).

According to the authors, these results show that, on the population level, it is beneficial to replace invasive sampling methods with the non‐invasive imaging techniques of MRI or PET. Nevertheless, the MRI replacement strategy may be considered unacceptable on clinical grounds, due to higher numbers of false positive and false negative cases. In that case, the most cost‐effective strategy is the 4‐NS strategy (if 4‐NS is used as the baseline) or the addition of MRI before SLNB (if SLNB is used as the baseline) (10).

Table 7‐ taken from Cooper et.al., 2011 .

Regulatory information 13. Summary of regulatory status of the medicine (in various countries)

European Medicine Agency (EMA): In 2010 EMA reviewed the information about gadolinium containing contrast agents. The revision included nine different active substances: gadoversetamide (OptiMARK), gadodiamide (Omniscan), gadopentetic acid (Magnevist, Magnegita, and Gado‐MRT‐ ratiopharm), gadofosveset (Vasovist), gadoxetic acid (Primovist), gadobenic acid (MultiHance), gadoteric acid (Dotarem), gadoteridol (ProHance) and gadobutrol (Gadovist).

According to EMA “most of these medicines are authorized nationally. Two of these products – OptiMARK (gadoversetamide) and Vasovist (gadofosveset) – have received a marketing authorization that is valid throughout the European Union (EU)” (24).

Food and drug administration:

The FDA has approved the following Gd‐CAs (18): Ablavar (gadofosveset trisodium) Eovist (gadoxetate disodium) Magnevist (gadopentetate dimeglumine) Multihance (gadobenate dimeglumine) Omniscan (gadodiamide) Optimark (gadoversetamide injection) Prohance (gadoteridol)

The information about these products can be access in: http://www.fda.gov/Drugs/DrugSafety/ucm223966.htm

In 2013 the FDA also approved the Gd‐CA Dotarem (25).

Australian Government, Department of Health and Ageing, Therapeutic Goods Administration All the products listed in this application are also approved by the Australian government Magnevist https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=pi&q=Mag nevist Omniscan https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=pi&q=Om niscan OptiMARK https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=PI&q=Opti MARK&r=https://www.ebs.tga.gov.au/ MultiHance https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=PI&q=Mul tiHance&r=https://www.ebs.tga.gov.au/ ProHance https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=PI&q=Pro Hance&r=https://www.ebs.tga.gov.au/ Dotarem https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=PI&q=Dot arem&r=https://www.ebs.tga.gov.au/ Gadovist https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=PI&q=Gad obutrol%20&r=https://www.ebs.tga.gov.au/

Health Canada The following products are in the Drug Product Database Magnevist Omniscan OptiMARK MultiHance ProHance Gadovist

The following product is not in the Drug Product Database Dotarem

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia) Magnevist British Pharmacopoeia: No access International Pharmacopoeia: No United States Pharmacopoeia: No European Pharmacopeia: No access Omniscan British Pharmacopoeia: No access International Pharmacopoeia: No United States Pharmacopoeia: Yes European Pharmacopeia: No access

OptiMARK British Pharmacopoeia: Restricted access International Pharmacopoeia: No United States Pharmacopoeia: Yes European Pharmacopeia: No access

MultiHance British Pharmacopoeia: No access International Pharmacopoeia: No United States Pharmacopoeia: No European Pharmacopeia: No access

ProHance British Pharmacopoeia: No access International Pharmacopoeia: No United States Pharmacopoeia: Yes European Pharmacopeia: No access

Dotarem British Pharmacopoeia: No access International Pharmacopoeia: No United States Pharmacopoeia: No European Pharmacopeia: No access

Gadovist British Pharmacopoeia: No access International Pharmacopoeia: No United States Pharmacopoeia: No European Pharmacopeia: No access

15. Proposed (new/adapted) text that could be included in a revised WHO Model Formulary The following exhibit provides an example of the information that could be included in the WHO Model Formulary.

References

1. Van der Molen AJ, Bellin M‐F. Extracellular gadolinium‐based contrast media: differences in diagnostic efficacy. Eur J Radiol [Internet]. 2008 May [cited 2014 Nov 30];66(2):168–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18372137

2. ACR Committee on Drugs and Contrast Media. ACR Manual on Contrast Media Version 9. 2013.

3. De Haën C. Conception of the first magnetic resonance imaging contrast agents: a brief history. Top Magn Reson Imaging. 2001;12:221–30.

4. Lin S, Brown J. MR contrast agents: physical and pharmacologic basics. J Magn Reson Imaging. 2007;25(5):884–99.

5. Degani H, Chetrit‐Dadiani M, Bogin L, Furman‐Haran E. Magnetic resonance imaging of tumor vasculature. Thromb Haemost. 2003;89(1):25–33.

6. Federal Drug Administration. HIGHLIGHTS OF PRESCRIBING INFORMATION: MAGNEVIST (gadopentetate dimeglumine) [Internet]. 2014. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019596s057,021037s03 0lbl.pdf

7. European Medicines Agency. Assessment report for Gadolinium‐containing contrast agents [Internet]. London; 2010 p. 13. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/gad olinium_31/WC500099538.pdf

8. Sun Y‐S, Li X‐T, Tang L, Zhang X‐Y, Zhang X‐P, Yong Cui JL, et al. Magnetic resonance imaging (MRI ) versus computed tomography (CT ) for the diagnosis of lymph node metastasis in preoperative rectal cancer (Protocol). Cochrane Database Syst Rev. 2012;(5).

9. Klerkx WM, Bax L, Veldhuis WB, Heintz APM, Mali WP, Peeters PHM, et al. Detection of lymph node metastases by gadolinium‐enhanced magnetic resonance imaging: systematic review and meta‐analysis. J Natl Cancer Inst. United States; 2010 Feb;102(4):244–53.

10. Cooper KL, Meng Y, Harnan S, Ward SE, Fitzgerald P, Papaioannou D, et al. Positron emission tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary lymph node metastases in early breast cancer: systematic review and economic evaluation. Health Technol Assess. England; 2011 Jan;15(4):iii – iv, 1–134.

11. Bruening W, Sullivan N, Paulson E, Zafar H, Mitchell M, Treadwell J, et al. Imaging Tests for the Staging of Colorectal Cancer. Comparative Effectiveness Review No. 142. (Prepared by the ECRI Institute‐Penn Medicine Evidence‐based Practice Center under

Contract No. 290‐2012‐00011‐I.) [Internet]. Rockville; 2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK248261/

12. Maurer M, Heine O, Wolf M. Tolerability and diagnostic value of Gadoteric Acid in the general population and in patients with risk factors: results in more than 84,000 patient. Eur J Radiol. 2012;81(5):885–90.

13. Stacul F, van der Molen AJ, Reimer P, Webb J a W, Thomsen HS, Morcos SK, et al. Contrast induced nephropathy: updated ESUR Contrast Media Safety Committee guidelines. Eur Radiol [Internet]. 2011 Dec [cited 2014 Dec 2];21(12):2527–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21866433

14. Grobner T. Gadolinium‐‐a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? . Nephrol Dial Transpl. 2006;21:1104–8.

15. Marckmann P, Skov L, Rossen K. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast‐enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17:2359–62.

16. Agarwal R, Brunelli SM, Williams K, Mitchell MD, Feldman HI, Umscheid CA. Gadolinium‐based contrast agents and nephrogenic systemic fibrosis: a systematic review and meta‐analysis. Nephrol Dial Transplant [Internet]. 2009 [cited 2014 Dec 11];24:856–63. Available from: http://ndt.oxfordjournals.org/content/24/3/856.short

17. Heverhagen J, Krombach GA, Gizewski E. Application of Extracellular Gadolinium‐ based MRI Contrast Agents and the Risk of Nephrogenic Systemic Fibrosis. RöFo‐ Fortschritte auf … [Internet]. 2014 [cited 2014 Dec 11];186:661–9. Available from: https://www.thieme‐connect.com/products/ejournals/abstract/10.1055/s‐0033‐ 1356403

18. Food and drug administration. FDA Drug Safety Communication: New warnings for using gadolinium‐based contrast agents in patients with kidney dysfunction. 2010.

19. European Society of Urogenital Radilogy. NSF. 2012; Available from: http://www.esur.org/esur‐guidelines/nsf/

20. The Royal College of Radiologists. Standards for intravascular contrast agent administration to adult patients Second edition. 2010.

21. Zech CJ, Grazioli L, Jonas E, Ekman M, Niebecker R, Gschwend S, et al. Health‐ economic evaluation of three imaging strategies in patients with suspected colorectal liver metastases: Gd‐EOB‐DTPA‐enhanced MRI vs. extracellular contrast media‐ enhanced MRI and 3‐phase MDCT in Germany, Italy and Sweden. Eur Radiol [Internet]. 2009 Jun [cited 2014 Dec 12];19 Suppl 3:S753–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19484243

22. Meng Y, Ward S, Cooper K, Harnan S, Wyld L. Cost‐effectiveness of MRI and PET imaging for the evaluation of axillary lymph node metastases in early stage breast cancer. Eur J Surg Oncol [Internet]. Elsevier Ltd; 2011 Jan [cited 2014 Dec 10];37(1):40–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21115232

23. Department of health. NHS Reference Costs 2008. London; 2009.

24. European Medicines Agency. Questions and answers on the review of gadolinium‐ containing contrast agents [Internet]. 2010. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/gad olinium_31/WC500015635.pdf

25. Food and drug administration. FDA approves Dotarem, a new magnetic resonance imaging agent [Internet]. FDA NEWS RELEASE. 2013 [cited 2014 Dec 12]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm344758.htm

Appendix: Search strategies and results about the harms of gadolinium‐enhanced MRI used in the review by Bruening et.al., 2014 (11).

Search strategies

Search results