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

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 1 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] 2 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. 3 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. 4 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

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