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FDA Approves Guerbet’s Dotarem® (gadoterate meglumine) for Pediatric Patients Younger than Two Years

05.09.2017 19:00

Princeton (NJ, USA), September 5, 2017 – Guerbet LLC USA, the US affiliate of the global specialist in contrast products and solutions for medical imaging, announced today that the US Food and Drug Administration (FDA) has approved Dotarem® (gadoterate meglumine) for intravenous use with magnetic resonance imaging (MRI) in pediatric patients under two years old, including term neonates, to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system (CNS).

Dotarem was previously approved for this use in patient populations over the age of two. 

 

This supplemental indication fulfills a post marketing requirement, acknowledged when Dotarem was first registered in March 2013, to strictly comply with the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c).

The FDA’s review was based on a study showing that at the standard dose (0.1 mmol/kg),1 the pharmacokinetic (PK) and safety profiles in pediatric patients under two were similar to those of older children and adults.

The study enrolled 51 pediatric patients in nine centers, with ages spanning from term neonates to 23 months and with normal renal function. It evaluated forty-five pediatric patients for PK profile and safety, including five subjects aged less than one month and nine subjects aged one to three months. It assessed efficacy in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues.

In this pediatric population the observed safety profile of Dotarem was consistent with what has been reported in older populations. In one patient, rash was reported as a moderate adverse event. Serious AEs unrelated to Dotarem were reported in one out of 45 patients. Evaluation of images from contrast-enhanced MRI of the CNS supported extrapolation of CNS efficacy findings reported in adults and older children.

“It is critical for Guerbet to help patients and their healthcare providers meet this medical need. We are committed to providing safe and effective contrast media to improve diagnosis of all populations including those who need special care, like young children. In fact, a study published earlier this year in Pediatric Radiology found that 80% of children’s hospitals surveyed now use macrocyclic contrast agents2,” said Massimo Carrara, VP North America.

Dotarem is the only macrocyclic and ionic gadolinium-based contrast medium (a kind that provides high molecular stability) available in the US.

To date, Dotarem is approved in 79 countries worldwide. More than 65 million doses of Dotarem have been administered since first launch. No unconfounded cases of NSF have been reported for Dotarem.

Read the press release

Ref 1:  Dotarem®(gadoterate meglumine) US Prescribing Information 
Ref 2: Use of gadolinium-based magnetic resonance imaging contrast agents and awareness of brain gadolinium deposition among pediatric providers in North America.Pediatr Radiol. 2017 May;47(6):657-664.

 

About DOTAREM® (gadoterate meglumine) Injection 

For more information about DOTAREM, including complete Boxed Warning, please see the Full Prescribing Information.

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), or
    • 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. 

Indication 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

Warnings and Precautions

  • 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.
  • 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.
  • 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: There are no available data with DOTAREM use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. While it is unknown if gadoterate crosses the placenta, other GBCAs have been shown to cross the human placenta and result in fetal exposure.  Advise pregnant women of the potential risk of fetal exposure to GBCAs.
  • 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.

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