Drug Safety Developments

Gadolinium-Based Contrast Agents: Timeline of FDA Regulatory Actions

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P.A.

 

In my last article on Gadolinium based contrast agents (GBCAs), I discussed some of the side effects of these injections, which are administered to patients during a Magnetic Resonance Imaging (MRI) or Magnetic Resonance Angiography (MRA).

While GBCAs have started to draw attention in the pharmaceutical products liability legal realm, they have been the subject of several drug safety regulatory actions here and abroad over the past 12 years.

The timeline below provides dates and descriptions of the regulatory actions pertaining to GBCAs, based on information from the US Food and Drug Administration (FDA).

 

Timeline of Regulatory Action for GBCAs

2006	The FDA released a Public Health Advisory announcing their investigation of nephrogenic systemic fibrosis (NSF) as a result of GBCA exposure in patients with some degree of kidney failure.  A report of 25 cases of NSF served as a catalyst for the FDA's investigation.
2007	The FDA added a “black box warning” to the drug labels of GBCAs, advising those with renal insufficiency to avoid GBCAs given the increased risk for NSF.
2010	The FDA made a Safety Announcement that they were "requiring changes in the drug label for gadolinium-based contrast agents (GBCAs) to minimize the risk of nephrogenic systemic fibrosis (NSF), a rare, but serious, condition associated with the use of GBCAs in certain patients with kidney dysfunction."
2015	The FDA issued a Drug Safety Communication stating that "Recent publications in the medical literature have reported that deposits of GBCAs remain in the brains of some patients who undergo four or more contrast MRI scans, long after the last administration."
May 2017	The FDA issued a Drug Safety Communication announcing that they have "not identified adverse health effects from gadolinium retained in the brain after the use of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI)." They also reported that various scientific "publications and [adverse event] reports show that gadolinium is retained in organs such as the brain, bones, and skin. The publications show that linear GBCAs retain more gadolinium in the brain than macrocyclic GBCAs. However, the review did not identify adverse health effects related to this brain retention." The European Medicines Agency (EMA), however, recommended a ban on the use of Linear GBCAs based on the results of their Pharmacovigilance and Risk Assessment Committee's (PRAC) assessment.  They also state that "Although no symptoms or diseases linked to gadolinium in the brain have been reported, the PRAC took a precautionary approach, noting that data on the long-term effects in the brain are limited."
Dec. 2017	The FDA issued a Drug Safety Communication announcing that they are "requiring a new class warning and other safety measures for all gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) concerning gadolinium remaining in patients’ bodies, including the brain, for months to years after receiving these drugs."
2018	The FDA released new drug labels for GBCAs, which include more information on gadolinium retention.

 

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Looking Ahead

Lawsuits are already emerging for conditions such as Gadolinium Deposition Disease (GDD), which are caused by retention of gadolinium in the brain, bones, and other organs.

While the FDA has warned that gadolinium retention is possible after receiving GBCAs, they claim that they have yet to find any evidence that such retention causes serious adverse events in patients with normal / adequate renal function.

It will be interesting to see if further research and publications in the medical literature will cause the FDA to change their position on this issue.

We will continue to monitor the medical and regulatory literature concerning the risk of GDD as a result of GBCA use during MRI and MRA procedures, and report on any significant developments.

 

 

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Gadolinium Deposition Disease can Result from use of Contrast Agents During MRI & MRA Procedures

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P.A.

 

What are Gadolinium-Based Contrast Agents (GBCAs)?

GBCAs are substances that are injected into patients during Magnetic Resonance Imaging (MRI) or Magnetic Resonance Angiography (MRA) in order to produce clearer radiology images.

Here is a list of GBCAs that are currently approved by the FDA:

• Ablavar
• Dotarem
• Eovist
• Gadavist
• Magnevist
• MultiHance
• Omniscan
• OptiMARK
• ProHance

These substances contain gadolinium, a toxic synthetic heavy metal, which is bonded to a linear or macrocyclic compound in order to reduce toxicity. 

While the bonding compounds are designed to help usher gadolinium out of the body, sometimes the bonds break and gadolinium is left behind in the bones, brain, and various tissues within the body.

 

What can happen when Gadolinium remains in the body?

Several conditions can occur as a result of gadolinium retention:

• Nephrogenic systemic fibrosis (NSF)
• Gadolinium storage condition
• Gadolinium deposition disease

NSF occurs in patients with renal insufficiency.  In these patients, gadolinium cannot be removed from the body adequately as a result of decreased kidney function.  As a result, thickening and darkening of the skin, shortening of the muscles and tendons, and other symptoms can occur.  This condition can potentially be fatal.

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Gadolinium storage condition is the excess of gadolinium in patients with normal renal function. 

Gadolinium deposition disease occurs when a patient has an excess of gadolinium in their system, but they have normal or adequate renal function. Symptoms of this condition can manifest anywhere from a few hours to several weeks after the GBCA injection was administered, and are as follows:

• Persistent headache
• Severe pain in the bones, joints, arms, and legs
• Sensation of sharp pins and needles, cutting, or burning
• Cognitive impairment
• Clouded mentation (“brain fog”)
• Nausea / vomiting
• Thickening of soft-tissue, tendons, and ligaments
• Tightness in the hands and feet

 

What actions are being taken?

Regulatory agencies here and abroad have taken steps to warn patients about the potential for gadolinium retention as a result of GBCA use.

In my next article, I will further discuss the specific regulatory actions that have occurred over the years.  I will also discuss the current status of this situation in the U.S. as well as in Europe.

Rest assured that we will continue to monitor the medical literature concerning the risk of NSF and gadolinium deposition disease as a result of GBCA use during MRI and MRA procedures, and report on any significant developments.

 

 

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Uterine Fibroid Drug Esmya Investigated Due to Severe Liver Injuries

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P.A.

 

About Esmya

Esmya (ulipristal acetate) is indicated for the treatment of severe symptoms caused by uterine fibroids -- or noncancerous growths in the uterus -- in women of reproductive age.

While Esmya is currently available in Europe, it is still pending FDA approval in the U.S. 

The active ingredient, ulipristal acetate is the same as that of Ella, an emergency birth control medication that is approved in the U.S.  However, a key difference between the two medications is the dose amount and frequency.  While Ella is a 30mg tablet meant to be used once, Esmya is a 5mg tablet to be used once daily for treatment courses of up to 3 months each.

 

Reports of Severe Liver Injury

The European Drug Label for Esmya lists "Hepatic impairment" in the "Special warnings and precautions for use" section. 

Here is an alarming excerpt from this section:

During the post-marketing experience, cases of liver injury and hepatic failure were reported.  During treatment, liver function tests should be performed at least monthly. In addition liver testing 2- 4 weeks after treatment has stopped is recommended. If a patient shows signs or symptoms compatible with liver injury (nausea, vomiting, right hypochondrial pain, anorexia, asthenia, jaundice, etc.), the patient should be investigated immediately, and liver function tests performed.

Four cases of severe liver injuries in patients using the drug have already been reported to the European Medicines Agency (EMA), three of which resulted in liver transplants.

 

Ongoing Investigation

In December 2017, the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) began their investigation of the association between Esmya and liver failure.  

They provide the following information in their investigation announcement letter:

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has made an initial assessment of the cases of liver injury and considered that Esmya could be the cause.

Given the seriousness of the observed liver injury and its possible link to the medicine, a more in depth review is warranted.

While the investigation is still underway, the EMA has advised healthcare providers to refrain from initiating treatment with Esmya.  They also encouraged doctors to closely monitor the liver function of patients already taking the drug to see if stopping treatment is necessary.

We will continue to monitor the medical literature here and abroad for developments in the PRAC's investigation of Esmya, and report accordingly.

 

 

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