First Injection of Dotarem® (gadoterate meglumine) in US Performed at Cincinnati Children's Hospital Medical Center

PRINCETON, N.J., July 25, 2013 /PRNewswire/ -- Guerbet announced today that Cincinnati Children's Hospital Medical Center (Cincinnati Children's) last week performed the first US injection of Dotarem^® (gadoterate meglumine), the only macrocyclic and ionic gadolinium-based contrast agent (GBCA) approved by the US Food and Drug Administration. The procedure was performed in a school age child.

Dotarem^® is 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.

"The availability of a macrocyclic and ionic gadolinium-based contrast agent that is FDA-approved for use in children ages 2-18 is very desirable," said Dr. Daniel Podberesky, chief of thoracoabdominal imaging in the Department of Radiology, Cincinnati Children's.

Dotarem^® was approved by the FDA in March 2013 and was released for the US market in early July. Cincinnati Children's was the first hospital to order the product in the US. In the past year, Cincinnati Children's performed 18,000 total MRIs, with more than 6,600 performed as contrast-enhanced MRIs.

"We are extremely pleased that Cincinnati Children's Hospital Medical Center is the first hospital to use Dotarem^® to enhance an MRI procedure," said Massimo Carrara, general manager, Guerbet US. "This reinforces the need for this product."

Cincinnati Children's Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in US News and World Report's 2013 Best Children's Hospitals ranking. It is ranked No. 1 for oncology and in the top 10 for all pediatric specialties—a distinction shared by only two other pediatric hospitals in the US. Cincinnati Children's is one of the top two recipients of pediatric research grants from the National Institutes of Health.

Important Safety Information, including Boxed WARNING, contained on the second page.

Dotarem^®—which has been commercialized widely outside the US since 1989 and more than 37 million doses administered^[1]—is the only macrocyclic and ionic GBCA. The recommended dose is 0.2 mL/kg (0.1 mmol/kg) body weight (BW). Dotarem^® Injection 0.5 mmol/mL contains 376.9 mg/mL of gadoterate meglumine, and is available in vials and pre‑filled syringes.

MRI has become the mainstay of central nervous system imaging since its introduction over 20 years ago. It is estimated that there were more than 10 million contrast-enhanced MRI examinations performed in the US in 2011, with approximately 60% of these examinations performed to image the CNS.

Important Safety Information

The possibility of serious or life-threatening anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, should be considered.

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.

The most common adverse reactions associated with Dotarem^® in clinical studies were nausea, headache, injection site pain, injection site coldness, and burning sensation.

For more information about Dotarem^®, including full Boxed WARNING, please see the Full Prescribing Information.

Clinical Studies

The Dotarem^® New Drug Application included two Phase III clinical studies. These studies evaluated the diagnostic efficacy and safety of Dotarem^® 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. Both phase III studies evaluated the superiority of the enhanced images over the unenhanced images for central nervous system (CNS) lesion visualization in all three co-primary endpoints. All defined primary and key secondary efficacy analyses were met and support the efficacy of Dotarem® at a standard dose of 0.1 mmol/kg BW. In addition to these two studies, 21 supportive clinical studies evaluated the efficacy and safety of Dotarem^®-enhanced MRI.

About Dotarem^®

Commercialized widely in over 70 countries in Europe, Asia, Africa, Middle East and South America, more than 37 million doses of Dotarem^® have been administered. The approved indications for Dotarem® may vary between countries. Dotarem® is the leading contrast agent in Europe with 47% market share in 2012^[2].

About Guerbet

A pioneer in the field of contrast agents with more than 80 years of experience, Guerbet is the only pharmaceutical group fully dedicated to medical imaging worldwide. As such it has a complete offering of contrast products for Xray and MRI and for interventional radiology, along with a range of injectors and related medical equipment to provide improved diagnosis and treatment of patients.

To promote the discovery of new products and assure future growth, Guerbet devotes significant resources to research and development every year (approximately 10% of sales). Guerbet (GBT) is listed on NYSE Euronext Paris (Eurolist Segment B – Mid Caps) and had sales of €403 million in 2012 with a total workforce of 1,400 employees. Guerbet also markets other contrast agents in the US.

This press release may contain forward-looking statements based on current assumptions and forecasts made by Guerbet Group management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performances of the company and the estimates given here. These factors include those discussed in Guerbet's public reports which are available on the Guerbet website at www.guerbet.com. The company assumes no liability whatsoever to update these forward-looking-statements or to conform them to future events or developments.

Dotarem® is registered in U.S. Patent and Trademark Office by Guerbet.

^[1] Data of file as of January 1, 2013.
^[2] In MRI, in volume. ECMIG 2011.

DOTAREM^® (gadoterate meglumine) injection, for intravenous use

Initial U.S. Approval: 2013

BRIEF SUMMARY OF PRESCRIBING INFORMATION
CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

1       INDICATIONS 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. (1)

4       CONTRAINDICATIONS
History of clinically important hypersensitivity reactions to DOTAREM. (4)

5       WARNINGS AND PRECAUTIONS

5.1    Nephrogenic Systemic Fibrosis
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 [see Dosage and Administration (2) and Clinical Pharmacology (12)].

5.2    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 [see Adverse Reactions (6)].

• 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.

5.3    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.

5.4    Extravasation and Injection Site Reactions
Ensure catheter and venous patency before the injection of DOTAREM. Extravasation into tissues during DOTAREM administration may result in tissue irritation [see Nonclinical Toxicology (13.2)].

6      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. For hypersensitivity reactions and acute kidney injury see Warnings and Precautions (5.2) and (5.3).

6.1    Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described below reflect DOTAREM exposure in 2813 patients, representing 2672 adults and 141 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded the ethnic distribution was 74% Caucasian, 12% Asian, 4% Black, and 10% others. The average age was 53 years (range from 0.1 to 97 years).

Overall, 3.9% of patients reported at least one adverse reaction, primarily occurring immediately or several days following DOTAREM administration. Most adverse reactions were mild or moderate in severity and transient in nature.

Table 1 lists adverse reactions that occurred in ≥ 0.2% patients who received DOTAREM.

Table 1: Adverse Reactions in Clinical Trials

Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth.

Adverse Reactions in Pediatric Patients 
During clinical trials, 141 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 58 aged 6 - 11 years and 43 aged 12 ‑17) received DOTAREM. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.5%). Most adverse events were mild in severity and transient in nature, and all patients recovered without treatment.

6.2    Postmarketing Experience
The following additional adverse reactions have been identified during postmarketing use of DOTAREM. 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 drug exposure.

• bradycardia, tachycardia, arrhythmia
• hypersensitivity / anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria
• coma, convulsion, syncope, presyncope, parosmia, tremor
• muscle contracture, muscle weakness
• diarrhea, salivary hypersecretion
• malaise, fever
• NSF, in patients whose reports were confounded by the receipt of other GBCAs or in situations where receipt of other GBCAs could not be ruled out. No unconfounded cases of NSF have been reported with DOTAREM.
• superficial phlebitis

7        DRUG INTERACTIONS
DOTAREM does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Specific drug interaction studies with DOTAREM have not been conducted.

8        USE IN SPECIFIC POPULATIONS

8.1     Pregnancy 
Pregnancy Category C
There are no adequate and well-controlled studies with DOTAREM conducted in pregnant women. Limited published human data on exposure to other GBCAs during pregnancy did not show adverse effects in exposed neonates. No effects on embryo fetal development were observed in rats or rabbits at doses up to 10 mmol/kg/day in rats or 3 mmol/kg/day in rabbits. The doses in rats and rabbits were respectively 16 and 10 times the recommended human dose based on body surface area. DOTAREM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

While it is unknown if DOTAREM crosses the human placenta, other GBCAs do cross the placenta in humans and result in fetal exposure.

Reproductive and developmental toxicity studies were conducted with gadoterate meglumine in rats and rabbits. Gadoterate meglumine was administered intravenously in doses of 0, 2, 4 and 10 mmol/kg/day (or 3.2, 6.5 and 16.2 times the recommended human dose based on body surface area) to female rats for 14 days before mating throughout the mating period and until gestation day (GD) 17. Pregnant rabbits were intravenously administered gadoterate meglumine at the dose levels of 0, 1, 3 and 7 mmol/kg/day (or 3.3, 10 and 23 times the human doses based on body surface area) from GD6 to GD19. No effects on embryo fetal development were observed in rats or rabbits at doses up to 10 mmol/kg/day in rats or 3 mmol/kg/day in rabbits. Maternal toxicity was observed in rats at 10 mmol/kg/day (or 16 times the human dose based on body surface area) and in rabbits at 7 mmol/kg/day (23 times the human dose based on body surface area).

8.3     Nursing Mothers
It is not known whether DOTAREM is excreted in human milk. Limited case reports on use of GBCAs in nursing mothers indicate that 0.01 to 0.04% of the maternal gadolinium dose is excreted in human breast milk. Because many drugs are excreted in human milk, exercise caution when DOTAREM is administered to a nursing woman. Nonclinical data show that gadoterate meglumine is excreted into breast milk in very small amounts (< 0.1% of the dose intravenously administered) and absorption via the gastrointestinal tract is poor.

8.4     Pediatric Use
The safety and efficacy of DOTAREM at a single dose of 0.1 mmol/kg have been established in pediatric patients from 2 to 17 years of age. No dosage adjustment according to age is necessary in this population [See Dosage and Administration (2.1) and Clinical Studies (14)]. The safety and efficacy of DOTAREM have not been established in pediatric patients below 2 years of age. GFR does not reach adult levels until 1 year of age [see Warnings and Precautions (5.1)].

8.5     Geriatric Use
In clinical studies of DOTAREM, 900 patients were 65 years of age and over, and 312 patients were 75 years of age and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects. In general, use of DOTAREM in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No age-related dosage adjustment is necessary.

8.6     Renal Impairment 
No DOTAREM dosage adjustment is recommended for patients with renal impairment. Gadoterate meglumine can be removed from the body by hemodialysis [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

10      OVERDOSAGE
DOTAREM administered to healthy volunteers and to patients at cumulative doses up to 0.3 mmol/kg was tolerated in a manner similar to lower doses. Adverse reactions to overdosage with DOTAREM have not been reported. Gadoterate meglumine can be removed from the body by hemodialysis [See Clinical Pharmacology (12.3)].

13      NONCLINICAL TOXICOLOGY

13.1   Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadoterate meglumine.

Gadoterate meglumine did not demonstrate mutagenic potential in in vitro bacterial reverse mutation assays (Ames test) using Salmonella typhimurium, in an in vitro chromosome aberration assay in Chinese hamster ovary cells, in an in vitro gene mutation assay in Chinese hamster lung cells, nor in an in vivo mouse micronucleus assay.

No impairment of male or female fertility and reproductive performance was observed in rats after intravenous administration of gadoterate meglumine at the maximum tested dose of 10 mmol/kg/day (16 times the maximum human dose based on surface area), given during more than 9 weeks in males and more than 4 weeks in females. Sperm counts and sperm motility were not adversely affected by treatment with the drug.

13.2   Animal Toxicology and/or Pharmacology
Local intolerance reactions, including moderate irritation associated
with infiltration of inflammatory cells were observed after perivenous injection in rabbits suggesting the possibility of local irritation if the contrast medium leaks around the veins in a clinical setting [see Warnings and Precautions (5.4)].

17      PATIENT COUNSELING INFORMATION

17.1   Nephrogenic Systemic Fibrosis
Instruct patients to inform their healthcare provider if they:

• have a history of kidney disease, or
• have recently received a GBCA.

GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF:

• Describe the clinical manifestations of NSF.
• Describe procedures to screen for the detection of renal impairment.

Instruct the patients to contact their physician if they develop signs or symptoms of NSF following DOTAREM administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness.

17.2   Common Adverse Reactions
Inform patients that they may experience:

• Reactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site.
• Side effects of headache, nausea, abnormal taste and feeling hot.

17.3   General Precautions
Instruct patients receiving DOTAREM to inform their physician if they:

• Are pregnant or breastfeeding.
• Have a history of allergic reaction to contrast media, bronchial asthma or allergy.
• Are taking any medications.

Rx Only

Guerbet LLC
120 W 7^th Street. Suite 108
Bloomington, IN 47404

Pre-filled syringes manufactured by Catalent, Belgium for Guerbet
Vials manufactured by Recipharm, France for Guerbet

GU06131043
Revised 06/2013

SOURCE Guerbet

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