Guerbet Statement Following FDA Medical Imaging Drugs Advisory Committee September 8, 2017

PRINCETON, N.J., Sept. 8, 2017 /PRNewswire/ -- Magnetic resonance imaging (MRI) is a widely used diagnostic procedure which is critical to patient health. And vital to MRI are the contrast agents that give physicians a sharper, more accurate picture of tissue than they would otherwise be able to have.

There are two kinds of gadolinium based contrast agents (GBCAs), linear and macrocyclic. Although there are many similarities amongst these agents, they differ in their kinetic and thermodynamic stability. Linear GBCAs are generally less stable, and for this reason, more likely than macrocyclic agents to deposit gadolinium in tissue. Guerbet's GBCA, Dotarem^® (gadoterate meglumine) is a macrocyclic agent.

In light of the importance of contrast enhanced MRIs to patient health, Guerbet is strongly committed to ensuring that this critical diagnostic tool remains available as a safe and effective option for physicians. 

However, Guerbet notes that evidence supports precautionary measures primarily with respect to linear agents. As recent evidence has raised the possibility that repeated use of linear agents might lead to a much higher propensity for gadolinium deposits in tissues, the risk mitigation measure Guerbet proposed to the FDA is to comply with the National Institutes of Health (NIH) approach, and to use linear GBCAs only in cases where there is no alternative.

The clinical significance of gadolinium retention in the body and the brain is still unknown. Until evidence definitively dispels any lingering concerns about the safety of GBCAs as a whole, Guerbet supports taking precautions when using them in patients who will need multiple injections during their lifetime and in fragile populations (children and renal impaired patients). We also support using contrast agents at the lowest diagnostic dose.

Guerbet notes that, to date, there is no evidence of gadolinium accumulation in the brain or other tissues after repeated administration of its macrocyclic product, Dotarem^® (gadoterate meglumine). It is due to this that we have seen an increased demand for macrocyclics in the markets. Guerbet has previously announced it will globally phase out its linear agent, Optimark^® (gadoversetamide injection). Before this decision, Guerbet voluntarily proposed a label change in the US regarding linear agents' potential for gadolinium deposition. Guerbet was the only GBCA manufacturer to do so.

Guerbet appreciates the discussion of today's Medical Imaging Drugs Advisory Committee and will continue to work with the FDA to further understand the mechanisms and consequences of gadolinium deposition in tissue.

Important Safety Information for Dotarem® (gadoterate meglumine)

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

• 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.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch or call 1-800-FDA-1088.

Important Safety Information about Optimark® (gadoversetamide)

Indications and Usage
Optimark^® (gadoversetamide) injection is a prescription gadolinium-based paramagnetic contrast agent indicated for intravenous use with magnetic resonance imaging (MRI) in patients with abnormal blood-brain barrier or abnormal vascularity of the brain, spine, and associated tissues. It is also indicated for use with MRI to provide contrast enhancement and facilitate visualization of lesions with abnormal vascularity in the liver in patients who are highly suspect for liver structural abnormalities on computed tomography.

Contraindications
Optimark is also contraindicated in patients with:

• Known hypersensitivity reactions to gadolinium, versetamide or any of the inert ingredients.

Warnings and Precautions

• Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs (<30 mL/ min/1.73m²) and patients with acute kidney injury. Do not administer Optimark to these patients.
• Screen patients for acute kidney injury and other conditions that may reduce renal function. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronic kidney disease (e.g., age >60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.
• When administering Optimark, do not exceed the recommended dose and allow a sufficient period of time for elimination of the drug prior to any re-administration. Record the specific GBCA and the dose administered to a patient.
• 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.
• Severe hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products including Optimark. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders may be at greater risk and should be closely observed during the procedure and for several hours after drug administration.
• Interference by Optimark in the measurements of serum iron, copper and zinc has been observed.
• In the presence of Optimark, the Ortho-cresophthalin complexone (OCP) produces an erroneous, low value for serum calcium. The magnitude of this artifact is proportional to the concentration of Optimark in the blood, and accurate values can be obtained approximately 90 minutes following injection. In patients with renal insufficiency, clearance of Optimark is slowed and the interference with calcium determination by OCP is prolonged.

Adverse Reactions

• The following adverse reactions have been identified during post-approval use of Optimark. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Optimark.
• Nephrogenic Systemic Fibrosis
• Hypersensitivity reactions including bronchospasm and laryngeal/pharyngeal edema
• Seizures
• Common adverse reactions were injection associated discomfort, headache, vasodilatation, taste perversion, dizziness, nausea, and paresthesia.

Use in Specific Populations

• Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Optimark should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Nursing Mothers: Women should discontinue nursing and discard breast milk up to 72 hours after Optimark injection.
• Pediatric Use: The safety and effectiveness of Optimark injection in pediatric patients have not been established. Pediatric patients may be particularly vulnerable to adverse GBCA reactions due to renal immaturity and/or unrecognized renal insufficiency.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch or call 1-800-FDA-1088.

SOURCE Guerbet LLC USA