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)
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/1.73m(2)), 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.
--------------------------------------------------------------------
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)
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.
Do not administer Optimark to patients with:
chronic, severe kidney
disease (GFR<30 mL/min/1.73m(2)), 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 or diabetes), estimate the
glomerular filtration rate (GFR) through laboratory testing.
Do not exceed the recommended Optimark dose and allow a sufficient period
of time for elimination of the drug from the body prior to any re-
administration.
---
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/1.73m(2))
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.
View original content:http://www.prnewswire.com/news-releases/guerbet-statement-following-fda-medical-imaging-drugs-advisory-committee-september-8-2017-300516578.html
SOURCE Guerbet LLC USA
