Gadoterate Meglumine for Use with Magnetic Resonance Imaging

GBCAs have been associated with a risk for NSF [see WARNINGS AND PRECAUTIONS]. Confirmed diagnosis of NSF has not been reported in patients with a clear history of exposure to DOTAREM alone.

Hypersensitivity reactions and acute kidney injury are described in other sections of the labeling [see WARNINGS AND PRECAUTIONS].

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 2867 patients, representing 2682 adults and 185 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded, the ethnic distribution was 81% Caucasian, 11% Asian, 4% Black, and 4% others. The average age was 53 years (range from < 1 week to 97 years).

Overall, 4% of patients reported at least one adverse reaction, primarily occurring immediately or within 24 hours following DOTAREM administration. Most adverse reactions were mild or moderate in severity and transient in nature.

Table 2 lists adverse reactions that occurred in ≥ 0.2% patients who received DOTAREM.

Table 2: Adverse Reactions in Clinical Trials

Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, feeling hot, burning sensation, somnolence, pain, dizziness, dysgeusia, blood creatinine increased, hypotension, hypertension, asthenia, fatigue, injection site reactions (inflammation, extravasation, pruritus, swelling, warmth), paraesthesia, pruritus, laryngeal discomfort, pain in extremity, vomiting, anxiety and palpitations.

During clinical trials, 185 pediatric patients (52 aged < 24 months, 33 aged 2 - 5 years, 57 aged 6 - 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 7 pediatric patients (3.8%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.1%). Most adverse events were mild in intensity and transient in nature.

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.

Table 3: Adverse Reactions in the Postmarketing Experience

Included as part of the PRECAUTIONS section.

DOTAREM administered to healthy volunteers and to adult 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 can be removed from the body by hemodialysis [See CLINICAL PHARMACOLOGY].

Mechanism Of Action

Gadoterate is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues.

In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with:

1. differences in proton density
2. differences of the spin-lattice or longitudinal relaxation times (T1)
3. differences in the spin-spin or transverse relaxation time (T2)

When placed in a magnetic field, gadoterate shortens the T1 and T2 relaxation times in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.

Pharmacodynamics

Gadoterate affects proton relaxation times and consequently the MR signal, and the contrast obtained is characterized by the relaxivity of the gadoterate molecule. The relaxivity values for gadoterate are similar across the spectrum of magnetic field strengths used in clinical MRI (0.2-1.5 T).

Gadoterate does not cross the intact blood-brain barrier and, therefore, does not enhance normal brain or lesions that have a normal blood-brain barrier, e.g. cysts, mature post-operative scars. However, disruption of the blood-brain barrier or abnormal vascularity allows distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts.

Pharmacokinetics

The pharmacokinetics of total gadolinium assessed up to 48 hours following an intravenously administered 0.1 mmol/kg dose of DOTAREM in healthy adult subjects demonstrated a mean elimination half-life (reported as mean ± SD) of about 1.4 ± 0.2 hr and 2.0 ± 0.7 hr in female and male subjects, respectively. Similar pharmacokinetic profile and elimination half-life values were observed after intravenous injection of 0.1 mmol/kg of DOTAREM followed 20 minutes later by a second injection of 0.2 mmol/kg (1.7 ± 0.3 hr and 1.9 ± 0.2 hr in female and male subjects, respectively).

The volume of distribution at steady state of total gadolinium in healthy subjects is 179 ± 26 and 211 ± 35 mL/kg in female and male subjects respectively, roughly equivalent to that of extracellular water. Gadoterate does not undergo protein binding in vitro. The extent of blood cell partitioning of gadoterate is not known.

Gadoterate is not known to be metabolized.

Following a 0.1 mmol/kg dose of DOTAREM, total gadolinium is excreted primarily in the urine with 72.9 ± 17.0% and 85.4 ± 9.7% (mean ± SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values were achieved after a cumulative dose of 0.3 mmol/kg (0.1 ± 0.2 mmol/kg, 20 minutes later), with 85.5 ± 13.2% and 92.0 ± 12.0% recovered in urine within 48 hrs in female and male subjects respectively.

In healthy subjects, the renal and total clearance rates of total gadolinium are comparable (1.27 ± 0.32 and 1.74 ± 0.12 mL/min/kg in females; and 1.40 ± 0.31 and 1.64 ± 0.35 mL/min/kg in males, respectively) indicating that the drug is primarily cleared through the kidneys. Within the studied dose range (0.1 to 0.3 mmol/kg), the kinetics of total gadolinium appear to be linear.

Specific Populations

A single intravenous dose of 0.1 mmol/kg of DOTAREM was administered to 8 patients (5 men and 3 women) with impaired renal function (mean serum creatinine of 498 ± 98 μmol/L in the 10-30 mL/min creatinine clearance group and 192 ± 62 μmol/L in the 30-60 mL/min creatinine clearance group). Renal impairment delayed the elimination of total gadolinium. Total clearance decreased as a function of the degree of renal impairment. The distribution volume was unaffected by the severity of renal impairment (Table 5). No changes in renal function test parameters were observed after DOTAREM injection. The mean cumulative urinary excretion of total gadolinium was approximately 76.9 ± 4.5% in 48 hrs in patients with moderate renal impairment, 68.4 ± 3.5% in 72 hrs in patients with severe renal impairment and 93.3 ± 4.7% in 24 hrs for subjects with normal renal function.

Table 5: Pharmacokinetic Profile of Total Gadolinium in Normal and Renally Impaired Patients

Gadoterate was shown to be dialyzable after an IV injection of DOTAREM in 10 patients with end-stage renal failure who required hemodialysis treatment. Gd serum concentration decreased over time by 88%, 93% and 97% at 0.5 hr, 1.5 hr, and 4 hrs after start of dialysis, respectively. A second and third hemodialysis session further removed Gd. After the third dialysis, Gd serum concentration decreased by 99.7%.

The pharmacokinetics of gadoterate in pediatric patients receiving DOTAREM aged birth (term neonates) to 23 months, was investigated in an open label, multicenter study, using a population pharmacokinetics approach. A total of 45 subjects (22 males, 23 females) received a single intravenous dose of DOTAREM 0.1 mmol/kg (0.2 mL/kg). The age ranged from less than one week to 23.8 months (mean 9.9 months) and body weight ranged from 3 to 15 kg (mean 8.1 kg). Individual level of renal maturity in the study population, as expressed by eGFR ranged between 52 and 281 mL/min/1.73 m² and 11 patients had an eGFR below 100 mL/min/1.73 m² (range 52 to 95 mL/min/1.73 m²).

Gadoterate concentrations obtained up to 8 hours after DOTAREM administration were best fitted using a biphasic model with linear elimination from the intravascular space. The mean clearance adjusted to body weight was estimated at 0.16 ± 0.07 L/h/kg and increased with eGFR. The estimated mean elimination half-life was 1.47 ± 0.45 hr.

The body weight adjusted clearance of gadoterate after single intravenous injection of 0.1 mmol/kg of DOTAREM in pediatric subjects aged less than 2 years was similar to that observed in healthy adults.

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].

Toxicity of gadoterate meglumine was evaluated in neonatal and juvenile (pre- and post-weaning) rats following a single or repeated intravenous administration at doses 1, 2, and 4 times the MHD based on BSA. Gadoterate meglumine was well tolerated at all dose levels tested and had no effect on growth, pre-weaning development, behavior and sexual maturation.

Clinical Studies

Efficacy and safety of DOTAREM were evaluated in a multi-center clinical trial (Study A) that enrolled 364 adult and 38 pediatric patients (aged ≥ 2 years) with known or suspected CNS lesions. Adults were randomized 2 to 1 to receive either DOTAREM or gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. All pediatric patients received DOTAREM, also at a dose of 0.1 mmol/kg. In the trial, patients first underwent a baseline (pre-contrast) MRI examination followed by the assigned GBCA administration and a post-contrast MR examination. The images (pre-contrast, post-contrast and “paired pre- and post-contrast”) were interpreted by three independent off-site readers blinded to clinical information. The primary efficacy analysis compared three patient-level visualization scores (paired images) to baseline MRI (pre-contrast images) for adults who received DOTAREM. The three primary visualization components were: contrast enhancement, border delineation and internal morphology. For each of these components there was a pre-defined scoring scale. Lesion counting (up to five per patient) was also reflected within each component's patient-level visualization score.

Among the adult patients, 245 received DOTAREM and their data comprised the primary efficacy population. There were 114 (47%) men and 131 (53%) women with a mean age of 53 years (range 18 to 85 years), the racial and ethnic representations were 84% Caucasian, 11% Asian, 4% Black, and 1% other.

Table 6 displays a comparison of paired images (pre-and post-contrast) to pre-contrast images with respect to the proportion of patients who had paired image scores that were greater “better”, or same/worse “not better” than the pre-contrast scores and with respect to the difference in the mean patient level visualization score. Across the three readers 56% to 94% of patients had improved lesion visualization for paired images compared to pre-contrast images. DOTAREM provided a statistically significant improvement for all three primary visualization components. More lesions were seen on the paired images than the pre-contrast images.

Table 6: Study A. Improvement in Patient-level Lesion Visualization Scores, Paired versus Pre-contrast Imagesa

In secondary analyses, post-contrast images were improved in comparison to pre-contrast images. DOTAREM lesion visualization scores were similar to those for gadopentetate dimeglumine. DOTAREM imaging results in the pediatric patients were also similar to those seen in adults.

In a second clinical trial (Study B), MR images were reread from 150 adult patients with known CNS lesions who had participated in previously conducted clinical trial. DOTAREM administration and image interpretation was performed in the same manner as in Study A. Similar to Study A, this trial also demonstrated improved lesion visualization with DOTAREM.

A non-randomized study (Study C) with 28 pediatric patients under 2 years of age who were referred for contrast MRI of the CNS supported extrapolation of CNS efficacy findings from adults and older children. CNS lesions were identified in 16 of these 28 patients on paired pre- and post-contrast images compared to 15 patients on pre-contrast images alone. In the 16 patients who had identifiable lesions, the scores for the co-endpoints of lesion visualization were improved for at least one lesion on paired pre- and post-contrast images compared to pre-contrast images in 8 out of 16 (50%) patients for lesion border delineation, 8 out of 16 (50%) patients for lesion internal morphology, and 14 out of 16 (88%) patients for lesion contrast enhancement.

Nephrogenic Systemic Fibrosis

Instruct patients to inform their healthcare provider if they:

1. have a history of kidney disease, or
2. 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.

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.

General Precautions

• Pregnancy: Advise pregnant women of the potential risk of fetal exposure to gadoterate [see Use In Specific Populations]