Drug Injury Watch

Gadolinium Toxicity Risks Higher For Children, Pregnant Women, And People Receiving Multiple Doses

Gadolinium Deposition Disease And Neurological Adverse Reactions Associated With The Use Of Gadolinium-Based Contrast Agents

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In May 2018 Health Canada announced the results of its second safety review of Magnevist, MultiHance, Omniscan, and Optimark, as well as other radiology contrast agents containing gadolinium.

From "Summary Safety Review - Gadolinium based contrast agents - Assessing the risk of gadolinium build-up in the brain and potential brain and nervous system (neurological) side effects" we get the following points, which are found in the Key Messages section:

• In 2016, Health Canada reviewed the risk of gadolinium build-up in the brain and the unknown potential neurological side effects because some published studies showed that gadolinium may stay in the brain when [gadolinium based contrast agents (GBCAs)] are given repeatedly. Health Canada’s review concluded that the risk of gadolinium build-up in the brain is higher with repeated doses of both types of GBCAs, and with the use of linear GBCAs compared to macrocyclic GBCAs....
• Health Canada carried out a second review in 2017 because new information was emerging, including: a review from the European Medicines Agency; reports from the manufacturers; and scientific publications. Health Canada’s second review concluded that children and pregnant women may be at greater risk of gadolinium build-up in the brain.

In more detail, as set forth in the Safety Review Findings part of that same May 2018 Health Canada document:

• This safety review looked at published and unpublished studies (57 in humans and 12 in animals) and 7 international case reports of gadolinium build-up in the brain linked to the use of GBCAs. The human studies and case reports found evidence of gadolinium build-up in the brain, in most cases this occurred many months after the use of GBCAs. Similar findings were seen in the animal studies.
• Evidence from these studies suggests that the risk of gadolinium build-up in the brain is higher with repeated use of GBCAs and with linear GBCAs. However, gadolinium build-ups were seen with both types of GBCAs.
• The review did not find any neurological side effects linked to gadolinium build-up in the brain based on the information available at the time. However, it is difficult to identify potential effects because they could take some time to appear and some patients may have similar symptoms because of their condition.
• Factors that may increase the risk of gadolinium build-up in the brain following the use of GBCAs are not yet completely understood. However, patients who may need repeated GBCA use and vulnerable populations (e.g. children, pregnant women) may be more at risk of gadolinium build-up in the brain.

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In conclusion, Health Canada -- similar to what the FDA has said here in the US -- stated that it will continue to monitor drug safely information involving GBCAs and, in particular, the link between repeated gadolinium contrast agents administration or injection and the risk of gadolinium build-up in the brain, i.e.,  Gadolinium Deposition Disease (GDD).

Our law firm is investigating possible products liability lawsuits against the pharmaceutical companies responsible for the linear gadolinium-based contrast agents, or contrast dyes, which are shown below:

Magnevist -- Bayer HealthCare Pharmaceuticals Inc.

Eovist -- Bayer HealthCare Pharmaceuticals Inc.

MultiHance -- Bracco Diagnostics Inc.

Omniscan -- GE Healthcare

OptiMARK -- Liebel-Flarsheim Company LLC

Ablavar -- Lantheus Medical Imaging, Inc.

If we can be of assistance to you or a loved one as regards a possible gadolinium contrast agents case, please do not hesitate to contact us.

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free. Confidential. No Obligation.  (Case review done by attorney Tom Lamb)

Gadolinium-Based Contrast Agents: Gadolinium Retention Higher For Linear Gadolinium Agents Than Macrocyclic Agents

Gadolinium Retention Can Cause Various Medical Problems With General Diagnosis Label Of Gadolinium Deposition Disease

 
(Posted by Tom Lamb at DrugInjuryWatch.com)

 

There are two types of gadolinium based contrast agents (GBCAs): linear and macrocyclic.  Generally, the macrocyclic GBCAs are regarded as “safer” than the linear GBCAs, as the structure of the macrocyclic gadolinium agents makes it more difficult for the gadolinium to break away from its bonding agent.   When this happens, there can be gadolinium retention and related harmful medical conditions -- or gadolinium contrast agent "side effects", one might say.

In more detail, this gadolinium retention situation can lead to various serious medical problems which have been given the general diagnosis label of Gadolinium Deposition Disease (GDD).  Essentially, this GDD diagnosis indicates there is some medical condition associated with gadolinium toxicity which is present in the patient.  Alternatively, this gadolinium retention situation is sometimes called Gadolinium Storage Condition.

In May 2018 the Radiology medical journal published an experimental study article which examined the difference between linear gadolinium contrast agents and macrocyclic agents with respect to gadolinium retention.  The study findings support the contention that following the injection of linear gadolinium based contrast agents there is more gadolinium retention.

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From the Abstract from this 2018 medical journal article, "One-year Retention of Gadolinium in the Brain: Comparison of Gadodiamide and Gadoterate Meglumine in a Rodent Model", we get an overview of the study and its findings:

Purpose:  To compare the long-term brain elimination kinetics and gadolinium species in healthy rats after repeated injections of the contrast agents [Omniscan (gadodiamide), which is a linear contrast agent,] or [Dotarem (gadoterate), which is a macrocyclic contrast agent].

Materials and Methods:  Nine-week-old rats received five doses of 2.4 mmol gadolinium per kilogram of body weight over 5 weeks and were followed for 12 months with T1-weighted MRI....

Results:  T1 hyperintensity of the deep cerebellar nuclei was observed only in [Omniscan (gadodiamide)]-treated rats and remained stable from the 1st month after the last injection.... Seventy-five percent of the total gadolinium detected after the last injection of [Omniscan (gadodiamide)]... was retained in the cerebellum at 1 year..., with binding of soluble gadolinium to macromolecules. No T1 hyperintensity was observed with [Dotarem (gadoterate)], consistent with a rapid, time-dependent washout of the intact gadolinium chelate down to background levels....

Conclusion:  After repeated administration of [Omniscan (gadodiamide)], a large portion of gadolinium was retained in the brain, with binding of soluble gadolinium to macromolecules. After repeated injection of [Dotarem (gadoterate)], only traces of the intact chelated gadolinium were observed with time-dependent clearance.

For some additional information about gadolinium based contrast agents (GBCAs) causing Gadolinium Deposition Disease (GDD) as a result of gadolinium retention, here is list of our articles written during the past ten months: 

• MRI Contrast Agents: Gadolinium Retention Warnings Added To Drug Label
• Gadolinium Deposition Disease Explained: How It Is Diagnosed, And More
• Gadolinium-Based Contrast Agents: Timeline of FDA Regulatory Actions
• Gadolinium Deposition Disease can Result from use of Contrast Agents During MRI & MRA Procedures
• FDA And MHRA Actions For Gadolinium-Containing Contrast Agents Differ
• MRI Drugs Magnevist, Omniscan, And OptiMARK Off The Market In Europe

If we can be of assistance to you or a loved one as regards a possible gadolinium contrast agents case, please do not hesitate to contact us.

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free. Confidential. No Obligation.  (Case review done by attorney Tom Lamb)

Gadolinium Retention Warnings Added To Drug Labels For Gadolinium Contrast Agents Used During MRI / MRA

Label Changes Announced By FDA In December 2017 Finally Approved For Magnevist, Omniscan, And Other GBCAs In April 2018

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

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

Over the past couple of years drug regulators around the world have started to pay attention to so-called "side effect" of certain GBCAs called Gadolinium Deposition Disease (GDD), which is a form of gadolinium toxicity and sometimes called, instead, Gadolinium Storage Condition.

However, as seen from the following excerpt from our December 2017 article "Gadolinium-Containing Contrast Agents Omniscan And Magnevist Being Recalled In The United Kingdom In February 2018", the actions taken by the FDA are different from what is being done by some other regulators:

In comparison, at the present time FDA is only requiring that there be certain changes made to the Prescribing Information, or drug label, of all gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) in the US. To be clear, none of these products will be recalled from the market here.

On December 19, 2017 this document was issued, "FDA Drug Safety Communication: FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings".

The gadolinium contrast agent label changes announced in December 2017, however, were not rolled-out until several months later. For example, the FDA waited until April 2018 to finally approved the new drug label for Omniscan.

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From the FULL PRESCRIBING INFORMATION Revised: 04/2018 document for Omniscan (accessed 5/16/18) we get the "class warnings" label change mandated by the FDA:

5.4 Gadolinium Retention

Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (e.g. 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. At equivalent doses, gadolinium retention varies among the linear agents with Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)].

It is important to understand that symptoms of gadolinium-related medical conditions can first appear anywhere from just a few hours until several weeks after the MRI or MRA procedure when a GBCA dye was administered by injection.

Some of the more common symptoms reported by patients are: 

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

Our law firm is investigating possible products liability lawsuits against the pharmaceutical companies responsible for the gadolinium-based contrast agents, or contrast dyes, which might cause any of these symptoms.

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free. Confidential. No Obligation.  (Case review done by attorney Tom Lamb)

Some MRI Contrast Agents Containing Gadolinium Can Cause Problems Ranging From "Brain Fog" To Permanent Disability

Gadolinium Deposition Disease Symptoms Typically Begin Couple Of Months After Use And Can Continue For Many Years Without Any Diagnosis

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

During MRI and MRA procedures patients often receive injections of gadolinium-based contrast agents (GBCAs).  Some of those contrast agents with gadolinium are classified as linear GBCAs -- as opposed to macrocyclic gadolinium contrast agents.

Some of the more popular linear contrast agents are Magnevist, Omniscan, and Multihance.  The Radiology Report medical record document for an MRI or MRA "with contrast" usually shows the brand name of the GBCA injected for the procedure.

A person who received an injection of Magnevist, for example, may develop some symptoms in the couple of months following their MRI or MRA procedure.  These various gadolinium-related symptoms include:

• Persistent headache;
• "Brain fog";
• Skin that appears spongy or rubbery, which is actually subcutaneous soft tissue thickening;
• Tendons and ligaments which are painful and have a thickened appearance;
• Bone and joint pain;
• Tightness in hands and feet; and, 
• Pain described as burning, cutting, or "pins and needles" in the arms or legs and the torso.

If a person starts experiencing one or more of these symptoms within two months after a linear gadolinium contrast agent was used, they may have developed gadolinium toxicity or poisoning due to the GBCA injection they received for their MRI.  This serious medical condition was rarely recognized in the medical community until the past couple of years, when it has begun to be diagnosed and labelled as "gadolinium deposition disease".

Where gadolinium toxicity is suspected by a patient or a doctor, testing for retained gadolinium is the next step in determining whether the symptoms are, in fact, due to the gadolinium contrast agent used for the MRI or MRA.  There are two types of tests which might be used:

1. 24-hour urine gadolinium test; and 
2. Heavy metal testing using blood, hair or nail samples, or urine.

If one or both of these tests are "positive" for gadolinium, the symptoms experienced by that person may be diagnosed by a doctor as related to the contrast agent injected before their MRI or MRA.

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For background we direct you to this medical journal article, "Gadolinium in Humans: A Family of Disorders", by Richard C. Semelka, MD, et al., published in the August 2016 edition of American Journal of Roentgenology.

In large part, as seen in the two excerpts set forth which follow, it is this 2016 medical article by Dr. Semelka that raised the profile of this relatively new set of side effects associated with gadolinium-based contrast agents (GBCAs).

We begin with a diagnostic label suggested by Dr. Semelka for the constellation of symptoms that are listed above:

“Gadolinium deposition disease” is the name we propose for a disease process observed in subjects with normal or near normal renal function who develop persistent symptoms that arise hours to 2 months after the administration of [gadolinium-based contrast agents (GBCAs)]. In these cases, no preexistent disease or subsequently developed disease of an alternate known process is present to account for the symptoms.

Then we take a closer look at those various symptoms:

In our experience, symptoms of gadolinium deposition disease are similar but not identical to those observed in [nephrogenic systemic fibrosis (NSF)]. Typical clinical features include persistent headache and bone and joint pain. Patients often complain of clouded mentation that many describe as a “brain fog.” More distinctive features are comparable with those observed in NSF but of lesser severity; patients often experience subcutaneous soft-tissue thickening that clinically appears somewhat spongy or rubbery without the hardness and redness observed in NSF. Tendons and ligaments in a comparable distribution may also be painful and have a thickened appearance. Patients may complain of tightness of the hands and feet that resembles the feeling of being fitted with extremely tight gloves or socks. Patients may experience excruciating pain, typically in a distal distribution, of the arms and legs but that may also be in the torso or generalized in location. This pain is often described as feeling like sharp pins and needles, cutting, or burning.

For more about this still-developing drug injury situation, you might want to visit our Gadolinium Based Contrast Agents Side Effects information page.  As indicated there, our law firm is investigating possible products liability lawsuits against the pharmaceutical companies responsible for the linear gadolinium-based contrast agents, or contrast dyes, which might cause any of the several symptoms that fall under the gadolinium deposition disease diagnosis label.

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free. Confidential. No Obligation.  (Case review done by attorney Tom Lamb)

New FDA Warning That Januvia, Onglyza, Tradjenta, And Nesina Are Associated With "joint pain that can be severe and disabling"

Label Changes About Side Effects For These Type 2 Diabetes Medicines In The Drug Class Called Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In August 2015 the FDA announced that it has found indications of a new side effect for a class of diabetes drugs -- dipeptidyl peptidase-4 (DPP-4) inhibitors -- that includes Januvia, Onglyza, Tradjenta, and Nesina.

The FDA found drug adverse event reports of arthralgia, or severe pain in one or more joints, associated with the use of DPP-4 inhibitor diabetes drugs, with Januvia being the one implicated most often, followed by Onglyza.

According to the FDA, patients started having symptoms of the new side effect from one day to years after they started taking Januvia, Onglyza, Tradjenta, Nesina or one of the "combination" DPP-4 inhibitors, e.g., Janumet (sitagliptin and metformin).

In more detail, the FDA reported that after the DPP-4 inhibitor medicine was discontinued, the patients' symptoms were usually relieved within less than a month of stopping the subject drug. Furthermore, some patients developed severe joint pain again when they restarted the same medicine or another DPP-4 inhibitor. 

This last fact provides some substantiation for linking this severe joint pain side effect with Januvia, Onglyza, Tradjenta, Nesina, and the other drugs in this DPP-4 inhibitors class.

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We get the following more detailed information from the "FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain" document that was issued on August 28, 2015:

In a search of the FDA Adverse Event Reporting System (FAERS) database, we identified 33 cases of severe arthralgia reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors from October 16, 2006, approval date of the first DPP-4 inhibitor, through December 31, 2013. Each case involved the use of one or more DPP-4 inhibitor. [Januvia (sitagliptin)] (n=28) was the most frequently reported, followed by [Onglyza (saxagliptin)] (n=5), [Tradjenta (linagliptin)] (n=2), [Nesina (alogliptin)] (n=1), and vildagliptin (n=2); vildagliptin is not marketed in the United States. In five cases, the patient experienced severe arthralgia with two different DPP-4 inhibitors. All 33 patients experienced arthralgia that resulted in a substantial reduction in their prior level of activity, including 10 patients who were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 month of initiation of treatment with a DPP-4 inhibitor. In 20 of the 33 cases, the DPP-4 inhibitor was suspected as a possible cause of arthralgia and was discontinued within a month following the onset of symptoms. However, 8 of the remaining 13 cases reported a period of 44 days to 1 year between the onset of symptoms and discontinuation of the DPP-4 inhibitor. In 23 of the 33 cases, symptoms resolved less than 1 month after discontinuation of the drug.

Reports of eight of the 33 cases documented a positive rechallenge. In these eight cases, individuals discontinued treatment, experienced a resolution of symptoms, restarted therapy with a DPP-4 inhibitor (a different member of the class in six of the eight cases), experienced the reappearance of the arthralgia, and subsequently, experienced resolution of the symptoms when DPP-4 inhibitor therapy was again discontinued. Twenty-one of the 33 patients were treated for arthritis with drug therapies that included corticosteroids, nonsteroidal anti-inflammatory drugs, methotrexate, and immune-modulating drugs....

We also searched the medical literature and identified seven case reports, two of which were also identified in the FAERS database....  [footnotes omitted]

Due to this drug safety development, the FDA has mandated that the respective drug companies add a new Warning and Precaution about this risk to the drug labels of all medicines in this dipeptidyl peptidase-4 (DPP-4) inhibitors class.

Here is a list of those drugs, which was included in this August 2015 FDA Drug Safety Communication:

Januvia -- sitagliptin
Janumet -- sitagliptin and metformin
Janumet XR -- sitagliptin and metformin extended release
Onglyza -- saxagliptin
Kombiglyze XR -- saxagliptin and metformin extended release
Tradjenta -- linagliptin
Glyxambi -- linagliptin and empagliflozin
Jentadueto -- linagliptin and metformin
Nesina -- alogliptin
Kazano -- alogliptin and metformin
Oseni -- alogliptin and pioglitazone

We will continue to monitor this emerging drug safety issue concerning reports of arthralgia, or severe pain in one or more joints, associated with the use of these newer diabetes drugs.

 

DrugInjuryLaw.com: Legal & Medical Information About Drug Side Effects  (All website content by attorney Tom Lamb)

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