Guerbet concurs with the PRAC Recommendations on Gadolinium-based Contrast Agents and announces changes to the US labeling for its linear agent Optimark® (gadoversetamide injection)

PRINCETON, N.J., March 31, 2017 /PRNewswire/ -- Guerbet LLC., subsidiary of Guerbet Group (FR0000032526 GBT), the global specialist in contrast products and solutions for medical imaging, takes note of the recent recommendations issued March 10, 2017 by the European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC), on Gadolinium-based Contrast Agents - procedure under Article 31 of Directive 2001/83/EC.

In March 2016, the EMA initiated a review of the risk of gadolinium deposition in brain tissue following the repeated use of gadolinium contrast agents in patients undergoing magnetic resonance imaging (MRI) scans.¹ After a nearly yearlong in depth review, the PRAC has identified linear agents as more likely to release gadolinium and has recommended the suspension of four linear agents from the market:

• MultiHance® (gadobenic acid) 
• Optimark® (gadoversetamide) 
• Magnevist® (gadopentetic acid)
• Omniscan™ (gadodiamide)

The PRAC recommendations¹ were announced on March 10, 2017 as follows:

"EMA's Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended the suspension of the marketing authorisations for four linear gadolinium contrast agents because of evidence that small amounts of the gadolinium they contain are deposited in the brain.

The agents concerned are intravenous injections of gadobenic acid, gadodiamide, gadopentetic acid and gadoversetamide, which are given to patients to enhance images from magnetic resonance imaging (MRI) body scans. (…)

The four agents recommended for suspension are referred to as linear agents. Linear agents have a structure more likely to release gadolinium, which can build up in body tissues.

Other agents, known as macrocyclic agents, are more stable and have a much lower propensity to release gadolinium. The PRAC recommends that macrocyclic agents² be used at the lowest dose that enhances images sufficiently to make diagnoses and only when unenhanced body scans are not suitable.

Some linear agents will remain available: gadoxetic acid, a linear agent used at a low dose for liver scans, can remain on the market as it meets an important diagnostic need in patients with few alternatives. In addition, a formulation of gadopentetic acid injected directly into joints is to remain available because its gadolinium concentration is very low – around 200 times lower than those of intravenous products. Both agents should be used at the lowest dose that enhances images sufficiently to make diagnoses and only if unenhanced scans are not suitable. (…)"

"The companies concerned by this review have the right to request the PRAC to re-examine its recommendations.

The PRAC's final recommendations will be sent to the [EMA's] Committee for Medicinal Products for Human Use (CHMP) for its opinion. Further details will be published at the time of the CHMP opinion."

Guerbet concurs with the PRAC recommendations and does not intend to request a re-examination of the recommendations.

In the U.S., Guerbet markets Optimark® (gadoversetamide) injection and Dotarem® (gadoterate meglumine) injection. Optimark is a product belonging to the class of linear gadolinium-based contrast agents, a class of agents the PRAC has identified as having "a structure more likely to release gadolinium." Dotarem is a product belonging to the class of macrocyclic gadolinium-based contrast agents (GBCAs) for which PRAC specifies has a "much lower propensity to release gadolinium."²

Although the PRAC recommendations do not apply to the U.S. market, the company had proactively requested a labeling change in the U.S. to Optimark (gadoversetamide) injection.  The FDA approved Guerbet's request at the end of August 2016 and is currently reflected in the Optimark® Prescribing Information. This change is included in the Pharmacokinetics section (12.3) of the Prescribing Information and notes: Increased signal intensity on non-contrast T1-weighted images within the brain, mainly the globus pallidus and the dentate nucleus, has been observed after multiple administrations of linear (ionic and nonionic) gadolinium-based contrast agents due to gadolinium deposition.

"Guerbet proactively sought this labeling change to ensure that prescribers and patients have all the relevant information clearly available regarding linear GBCAs," said Massimo Carrara, General Manager, Guerbet US. "Providing accurate and up-to-date scientific information to healthcare providers is our highest priority."

The Prescribing Information further notes that following repeated GBCA administration gadolinium deposits may be present for months or years in bone, liver, skin, brain, and other organs. Deposition depends on multiple factors, and may be greater following administration of linear GBCAs than following administration of macrocyclic GBCAs. The clinical significance of gadolinium retention in the body and brain is otherwise unknown.

Optimark (gadoversetamide) injection will continue to be available for clinical use in the approved indications. This position will be reconsidered once Regulatory Authorities provide the final decision.

In the meantime, Guerbet will closely collaborate with Authorities and Pharmacovigilance Committees to assess the benefit-risk balance of its contrast agents.

Guerbet is committed to providing healthcare professionals with a comprehensive range of effective and safe contrast media in order to improve diagnosis, prognosis and quality of life for patients.

About Optimark (Gadoversetamide) Injection

Indication and Usage

Optimark^® (gadoversetamide) injection is a 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.

Important Risk Information

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.

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

About DOTAREM^® (gadoterate meglumine) Injection

Indication and Usage

DOTAREM is a 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 (2 years of age and older) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity.

Important Safety Information

Contraindications

DOTAREM is contraindicated in patients with:

• History of clinically important hypersensitivity reactions to DOTAREM 

Warnings and Precautions

• Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m²) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73m²) and little, if any, for patients with chronic, mild kidney disease (GFR 60 -89 mL/min/1.73m²). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.
• Report any diagnosis of NSF following DOTAREM administration to Guerbet LLC (1-877-729-6679) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).
• Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. 
• Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. 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 prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown.

Hypersensitivity Reactions

• 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. 
• During and following DOTAREM administration, observe patients for signs and symptoms of hypersensitivity reactions.

Acute Kidney Injury

• 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. Screen all patients for renal impairment by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction.

Adverse Reactions

• GBCAs have been associated with a risk for NSF [see Warnings and Precautions (5.1)]. NSF has not been reported in patients with a clear history of exposure to DOTAREM alone.
• The most frequent (≥ 0.2%) adverse reactions in clinical studies were nausea, headache, injection site pain, injection site coldness, and burning sensation.

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

About Guerbet

Guerbet is a pioneer in the contrast agent field, with 90 years' experience, and is the only pharmaceutical group dedicated to medical imaging worldwide. It offers a comprehensive range of X-Ray, Magnetic Resonance Imaging (MRI) and Interventional Radiology and Theranostics (IRT) products, along with a range of injectors and related medical devices to improve the diagnosis and treatment of patients. To discover new products and ensure future growth, Guerbet invests heavily in R&D on which it spends around 9% of its sales each year. Guerbet (GBT) is listed on Euronext Paris (Segment B – Mid Caps) and generated €776 million in revenue in 2016.

GU03171036

¹ http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Gadolinium-containing_contrast_agents/human_referral_prac_000056.jsp&mid=WC0b01ac05805c516f 
² Gadobutrol, gadoteric acid and gadoteridol

SOURCE Guerbet LLC