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We would like to share with you an update on an important area that supports DOTAREM® (gadoterate meglumine) injection.

Results from several recently published studies performed on animal models aimed at elucidating the retention of Gd in various tissues.

While experts may agree that levels of Gd retention can vary among macrocyclic agents, recent peer reviewed animal studies demonstrate the complexities of the topic and that a myriad of uncertainties remain. Also, notably, the clinical significance, if any, of Gd retention in patients with normal renal function has not been demonstrated.2-7

Bussi et al. compared Gd levels in blood, cerebrum, cerebellum, liver, femur, kidneys, and skin after multiple exposures of rats to DOTAREM, Gadavist®, and ProHance®, and found that at 28 days (4 weeks), there was less Gd retention with ProHance than with DOTAREM or Gadavist in most tissues. However, DOTAREM had significantly less Gd presence in the femur, where higher levels of Gd deposition were noted for all the GBCAs.2

Jost et al. examined rats that received multiple administrations of one of the three macrocyclic agents on the market (ProHance, Dotarem and Gadavist) at 5, 26 and 52 weeks following administration. This study confirmed that after 5 weeks, gadolinium concentrations in the cerebrum, cerebellum and brainstem were higher with Dotarem when compared to ProHance, similar to the study by Bussi et al. However, while the washout of all the macrocyclic agents were similar, after 26 and 52 weeks, Dotarem measured the lowest total concentration of retained gadolinium across brain regions studied, illustrating a continuous and long-term elimination.3

The Conclusion
Tissue retention of Gd in animal models likely depends on the timeframe investigated, with washout of macrocyclic GBCAs continuing up to 1 year.3

For more information regarding Dotarem’s
molecular structure and gadolinium release,
please visit www.dotarem-us.com/safety-profile.

DOTAREM® IMPORTANT SAFETY INFORMATION1

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.

  • The risk for NSF appears highest among patients with:

    • Chronic, severe kidney disease (GFR < 30 mL/min/1.73m2),

    • Acute kidney injury.

  • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.

  • For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration.

Indications and Usage

DOTAREM® (gadoterate meglumine) injection is a prescription gadolinium-based contrast agent indicated for intravenous use with magnetic resonance imaging (MRI) in brain (intracranial), spine and associated tissues in adult and pediatric patients (including term neonates) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity.

Contraindications

History of clinically important hypersensitivity reactions to DOTAREM.

Warnings and Precautions

  • Hypersensitivity Reactions: Anaphylactic and anaphylactoid reactions have been reported with DOTAREM, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of DOTAREM administration and resolved with prompt emergency treatment.

  • Before DOTAREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to DOTAREM.

  • Administer DOTAREM only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation.

  • Gadolinium Retention: Gadolinium is retained for months or years in several organs. The highest concentrations have been identified in the bone, followed by brain, skin, kidney, liver and spleen. The duration of retention also varies by tissue, and is longest in bone. Linear GBCAs cause more retention than macrocyclic GBCAs.

  • Consequences of gadolinium retention in the brain have not been established. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention.

  • Acute Kidney Injury: In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging.

  • Extravasation and Injection Site Reactions: Ensure catheter and venous patency before the injection of DOTAREM. Extravasation into tissues during DOTAREM administration may result in tissue irritation.

Adverse Reactions

  • The most common adverse reactions associated with DOTAREM in clinical trials were nausea, headache, injection site pain, injection site coldness and rash.

  • Serious adverse reactions in the Postmarketing experience have been reported with DOTAREM. These serious adverse reactions include but are not limited to: arrhythmia, cardiac arrest, respiratory arrest, pharyngeal edema, laryngospasm, bronchospasm, coma and convulsion.

Use in Specific Populations

  • Pregnancy: GBCAs cross the human placenta and result in fetal exposure and gadolinium retention. Use only if imaging is essential during pregnancy and cannot be delayed.

  • Lactation: There are no data on the presence of gadoterate in human milk, the effects on the breastfed infant, or the effects on milk production. However, published lactation data on other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk.

  • Pediatric Use: The safety and efficacy of DOTAREM at a single dose of 0.1 mmol/kg has been established in pediatric patients from birth (term neonates ≥ 37 weeks gestational age) to 17 years of age based on clinical data. The safety of DOTAREM has not been established in preterm neonates. No cases of NSF associated with DOTAREM or any other GBCA have been identified in pediatric patients age 6 years and younger.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.Please see the full Prescribing Information, including the patient Medication Guide, for additional important safety information.

DOTAREM® is a registered trademark of Guerbet LLC, and is available by prescription only.

Gadavist® is a registered trademark of the Bayer group of companies, and is available by prescription only.

ProHance® is a registered trademark of the Bracco Diagnostics, Incorporated and is available by prescription only.

*Dotarem was launched globally in 1989 and approved by the FDA for use in the US in 2013.

References 1. Dotarem Package Insert;July 2019 2. Bussi S et al. Differences in Gadolinium Retention After Repeated Injections of Macrocyclic MR Contrast Agents to Rats J Magn Reson Imaging. 2018;47:746-752. 3. Jost G et al. Long-term Excretion of Gadolinium-based Contrast Agents: Linear versus Macrocyclic Agents in an Experimental Rat Model: Radiology. 2019;290:340-348. 4. Behzadi AH et al. Radiology. 2018;286:471-482. 5. McDonald RJ et al. Comparison of Gadolinium Concentrations within Multiple Rat Organs after Intravenous Administration of Linear versus Macrocyclic Gadolinium Chelates. Radiology. 2017;285:536-545 6. McDonald JS et al. Radiology. Acute Adverse Events Following Gadolinium-Based Contrast Agent Adminstration: A Single-Center Retrospective Study of 281,945 Injections. 2019; Jul 2;182834. 7. de Kerviler E et al. Adverse Reactions to Gadoterate Meglumine: Review of Over 25 Years of CLinical Use and More Than 50 Million Doses. Invest Radiol. 2016;51:544-551.

GU09191204

 
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