2.1 Dosing Guidelines

For adult and pediatric patients (including term neonates), the recommended dose of Gadoterate Meglumine Injection is 0.2 mL/kg (0.1 mmol/kg) body weight administered as an intravenous bolus injection, manually or by power injector, at a flow rate of approximately 2 mL/second for adults and 1-2 mL/second for pediatric patients. Table 1 provides weight-adjusted dose volumes.

To ensure complete injection of Gadoterate Meglumine the injection may be followed by normal saline flush. Contrast MRI can begin immediately following Gadoterate Meglumine Injection.

2.2 Drug Handling

• Visually inspect Gadoterate Meglumine Injection for particulate matter prior to administration. Do not use the solution if particulate matter is present or if the container appears damaged. Gadoterate Meglumine Injection should be a clear, colorless to yellow solution.
• Do not mix with other drugs or parenteral nutrition.
• Discard any unused portions of the drug.

Directions for Use of the Gadoterate Meglumine Injection

Glass vial:

Aseptically draw up the contrast medium into a disposable syringe and use immediately.

5.1 Risk Associated with Intrathecal Use

Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of Gadoterate Meglumine Injection have not been established with intrathecal use. Gadoterate Meglumine Injection is not approved for intrathecal use [see Dosage and Administration ( 2.1)] .

5.2 Nephrogenic Systemic Fibrosis

GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of gadoterate meglumine injection 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/1.73 m 2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73 m 2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m 2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following Gadoterate Meglumine Injection administration to Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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.

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 Gadoterate Meglumine Injection 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)] .

5.3 Hypersensitivity Reactions

Anaphylactic and anaphylactoid reactions have been reported with Gadoterate Meglumine Injection, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of Gadoterate Meglumine Injection administration and resolved with prompt emergency treatment [see Adverse Reactions ( 6)] .

• Before Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection.
• Administer Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection administration, observe patients for signs and symptoms of hypersensitivity reactions.

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)].

Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function [see Warnings and Precautions ( 5.2)] . There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention [see Adverse Reactions ( 6.2)] .

While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA imaging studies, particularly closely spaced studies when possible.

5.5 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.

5.6 Extravasation and Injection Site Reactions

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

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 Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection.

Adverse reactions that occurred with a frequency < 0.2% in patients who received Gadoterate Meglumine Injection 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), paresthesia, pruritus, laryngeal discomfort, pain in extremity, vomiting, anxiety and palpitations.

6.2 Post-Marketing Experience

The following additional adverse reactions have been identified during postmarketing use of Gadoterate Meglumine Injection. 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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and efficacy of Gadoterate Meglumine Injection at a single dose of 0.1 mmol/kg have been established in pediatric patients from birth (term neonates ≥ 37 weeks gestational age) to 17 years of age based on clinical data in 133 pediatric patients 2 years of age and older, and clinical data in 52 pediatric patients birth to less than 2 years of age that supported extrapolation from adult data [see Clinical Studies ( 14)] . Adverse reactions in pediatric patients were similar to those reported in adults [see Adverse Reactions ( 6.1)] . No dosage adjustment according to age is necessary in pediatric patients [see Dosage and Administration ( 2.1), Pharmacokinetics ( 12.3)] . The safety of Gadoterate Meglumine Injection has not been established in preterm neonates.

No cases of NSF associated with Gadoterate Meglumine Injection or any other GBCA have been identified in pediatric patients age 6 years and younger [see Warnings and Precautions ( 5.2)] . Normal estimated GFR (eGFR) is approximately 30 mL/minute/1.73 m 2at birth and increases to adult values by 2 years of age.

8.5 Geriatric Use

In clinical studies of Gadoterate Meglumine Injection, 900 patients were 65 years of age and over, and 304 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 Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection dosage adjustment is recommended for patients with renal impairment. Gadoterate can be removed from the body by hemodialysis [see Warnings and Precautions (5.2) and Clinical Pharmacology ( 12.3)] .

12.1 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.

12.2 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).

Disruption of the blood-brain barrier or abnormal vascularity allows distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts.

12.3 Pharmacokinetics

The pharmacokinetics of total gadolinium assessed up to 48 hours following an intravenously administered 0.1 mmol/kg dose of Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection 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).

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 vitrobacterial reverse mutation assays (Ames test) using Salmonella typhimurium, in an in vitrochromosome aberration assay in Chinese hamster ovary cells, in an in vitrogene mutation assay in Chinese hamster lung cells, nor in an in vivomouse 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 ( 5.5)] .

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.

CNS Imaging

Efficacy and safety of Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection or gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. All pediatric patients received Gadoterate Meglumine Injection, 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 Gadoterate Meglumine Injection. 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 Gadoterate Meglumine Injection 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. Gadoterate Meglumine Injection provided a statistically significant improvement for all three primary visualization components. More lesions were seen on the paired images than the pre-contrast images.

(a) Better: number of patients with paired (pre-and post-contrast) score greater than the pre-contrast score, Not better: number of patients with paired score same as or worse than the pre-contrast score, Missing: number of patients with missing score

(b) Difference = paired mean score minus pre-contrast mean score

*Statistically significant improvement by paired t-test

In secondary analyses, post-contrast images were improved in comparison to pre-contrast images. Gadoterate Meglumine Injection lesion visualization scores were similar to those for gadopentetate dimeglumine. Gadoterate Meglumine Injection 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. Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection.

CNS Imaging in the Sub-Population of Pediatric Patients < 2 Years Old

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.

17.1 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 Gadoterate Meglumine Injection 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

• Pregnancy: Advise pregnant women of the potential risk of fetal exposure to gadoterate [see Use in Specific Populations ( 8.1)]
• Gadolinium Retention: Advise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions ( 5.4)] .

Manufactured by: Hainan Poly Pharm. Co., Ltd., Guilinyang Economic Development Zone, Haikou, Hainan, China 571127

Distributed by: Slate Run Pharmaceuticals, LLC, Columbus, Ohio 43215

10000414/05

Revised: 04/2025