1.1 MRI of the Central Nervous System (CNS)

Gadoteridol Injection is indicated for magnetic resonance imaging (MRI) in adults and pediatric patients including term neonates to visualize lesions with disrupted blood brain barrier and/or abnormal vascularity in the brain (intracranial lesions), spine and associated tissues.

1.2 MRI of Extracranial/Extraspinal Head and Neck

Gadoteridol Injection is indicated for MRI in adults to visualize lesions in the head and neck.

2.1 Recommended Dose

The recommended dose for adult and pediatric patients, including term neonates, is 0.2 mL/kg (0.1 mmol/kg) administered as a rapid intravenous infusion (10 mL/min to 60 mL/min) or bolus (greater than 60 mL/min). Table 1 provides weight-adjusted recommended dose volumes.

2.2 Administration

• Visually inspect Gadoteridol Injection for particulate matter and discoloration prior to use
• Do not administer the solution if it is discolored or particulate matter is present
• Concurrent medications or parenteral nutrition should not be physically mixed with contrast agents and should not be administered in the same intravenous line because of the potential for chemical incompatibility
• Inject at least a 5 mL normal saline flush immediately after Gadoteridol Injection to ensure complete administration
• Imaging procedures should be completed within 1 hour
• Gadoteridol Injection vials are intended only for single-dose administration. Administer immediately after opening and discard any unused product

2.3 Directions for Use

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 Gadoteridol injection have not been established with intrathecal use. Gadoteridol 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 Gadoteridol 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 less than 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 gadoteridol 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 (for example, age greater than 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 gadoteridol 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 Clinical Pharmacology ( 12)].

5.3 Hypersensitivity Reactions

Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of gadoteridol administration and resolved with prompt emergency treatment.

Prior to gadoteridol administration, ensure the availability of trained personnel and medications to treat hypersensitivity reactions. Consider the risk for hypersensitivity reactions, especially in patients with a history of hypersensitivity reactions or a history of asthma or other allergic disorders. If such a reaction occurs, stop gadoteridol and immediately begin appropriate therapy. Observe patients for signs and symptoms of a hypersensitivity reaction during and for up to 2 hours after gadoteridol administration.

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, 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), 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.

6.1 Clinical Trials 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 practice.

The adverse events described in this section were observed in clinical trials involving 3174 subjects (including 2896 adults and 278 pediatric subjects ages 0 to 17 years) exposed to Gadoteridol Injection. Approximately 48% of the subjects were men and ethnic distribution was 78% Caucasian, 6% Black, 3% Hispanic, 6% Asian, and 2% other. In 5% of the subjects, race was not reported. Average age was 47 years (range from 1 day to 91 years) and the exposure ranged from 0.03 to 0.3 mmol/kg.

Overall, approximately 5.8% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after Gadoteridol Injection administration.

Table 2 lists adverse reactions that occurred in ≥ 0.4% subjects who received Gadoteridol Injection.

The following additional adverse events occurred in fewer than 0.4% of the subjects:

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Gadoteridol Injection that were not observed in the clinical trials. 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.

The following adverse drug reactions have also been reported:

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Gadoteridol Injection have been established for use with MRI to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine, and associated tissues in pediatric patients from birth, including term neonates, to 17 years of age. Pediatric use is based on evidence of effectiveness in adults and in 103 pediatric patients 2 years of age and older, in addition to experience in 125 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)] .

The safety and efficacy of > 0.1 mmol/kg, and sequential and/or repeat procedures have not been studied in pediatric patients [see Indications and Usage ( 1) and Dosage and Administration ( 2)] .

No case of NSF associated with Gadoteridol Injection or any other GBCA has been identified in pediatric patients ages 6 years and younger. Pharmacokinetic studies suggest that weight normalized clearance of Gadoteridol Injection is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. Normal estimated GFR (eGFR) is around 30 mL/min/1.73 m 2at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. Clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum eGRF; 59.37 mL/min/1.73 m 2(age just after birth to < 30 days), 118.84 mL/min/1.73 m 2(age 30 days to < 6 months), 140.44 mL/min/1.73 m 2(age 6 to 12 months).

8.5 Geriatric Use

Of the total number of 2673 adult subjects in clinical studies of Gadoteridol Injection, 22% were 65 and over. No overall differences in safety were observed between these elderly subjects and the younger subjects.

Gadoteridol Injection is known to be substantially excreted by the kidneys, and the risk of toxic reactions from Gadoteridol Injection may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

8.6 Renal Impairment

No Gadoteridol Injection dosage adjustment is recommended for patients with renal impairment. Gadoteridol can be removed from the body by hemodialysis [see Warning and Precautions ( 5.2) and Clinical Pharmacology ( 12.3)] .

12.1 Mechanism of Action

Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent.

In MRI, visualization of normal and pathologic brain tissue depends, in part, on variations in the radiofrequency signal intensity that occur with: 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.

12.2 Pharmacodynamics

Gadoteridol affects proton relaxation times and consequently the MR signal. Signal intensity is affected by the dose and relaxivity of the gadoteridol molecule. Consistently, for all gadolinium based contrast agents, the relaxivity of gadoteridol decreases with the increase of the magnetic field strength used in clinical MRI (0.2-3.0T).

Disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of gadoteridol in various lesions is not known.

12.3 Pharmacokinetics

The pharmacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two-compartment open model.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been performed to evaluate the carcinogenic potential of gadoteridol.

No changes in reproductive performance and outcome of pregnancy were caused in rats and rabbits by daily intravenous administration of Gadoteridol Injection to parent animals before and during gestation up to 1.5 mmol/kg/day (15 times the recommended human dose).

Gadoteridol did not demonstrate genotoxic activity in: bacterial reverse mutation assays using Salmonella typhimuriumand Escherichia coli; a mouse lymphoma forward mutation assay; an in vitrocytogenetic assay measuring chromosomal aberration frequencies in Chinese hamster ovary cells; and an in vivomouse micronucleus assay at intravenous doses up to 5.0 mmol/kg.

14.1 MRI of the CNS

Gadoteridol was evaluated in two multicenter trials of 310 evaluable patients suspected of having neurological pathology. After the administration of gadoteridol 0.1 mmol/kg IV, the results were similar to those described below [see Clinical Studies ( 14.2)] .

In another multicenter study of 49 evaluable adult patients with known intracranial tumor with high suspicion of having cerebral metastases, two doses of gadoteridol were administered. First Gadoteridol Injection 0.1 mmol/kg was injected followed 30 minutes later with 0.2 mmol/kg. In comparison to the 0.1 mmol/kg dose alone, the addition of the 0.2 mmol/kg dose improved visualization in 67% and improved border definition in 56% of patients. In comparison to non-contrast MRI, the number of lesions after 0.1 mmol/kg increased in 34% of patients. After gadoteridol 0.2 mmol/kg, this increased to 44%.

Pediatric Patients

Gadoteridol was evaluated in a multicenter study of 103 patients undergoing brain or spine MRI. Among these patients, the age range was 2 to 20 years; 54 were between 2 and 12 years of age; 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2% other. Gadoteridol was given in one single 0.1 mmol/kg dose. Repeat dosing was not studied. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30 to 95% of the scans.

A prospectively planned study of 125 pediatric patients younger than 2 years of age retrospectively selected was performed. These patients (70 boys and 55 girls) had an age range of 1 day to 24 months old; 17 were less than 1 month of age, 40 were between 1 month and 6 months of age, 29 were between 6 months and 12 months of age, and 39 were between 12 months and 24 months of age; 56% were Caucasian, 25% Black, 5% Asian, and 14% other. Gadoteridol was given in one single 0.1 mmol/kg dose. Repeat dosing was not studied. Three independent, blinded readers evaluated pre-contrast MRI image sets and paired pre-plus-post-contrast MRI image sets using gadoteridol and rated the images according to three co-primary visualization endpoints: lesion border delineation, visualization of lesion internal morphology, and lesion contrast enhancement. All three blinded readers reported improvement in the paired image sets for each of the three co-primary endpoints.

14.2 MRI of the Head and Neck

Gadoteridol was evaluated in two blinded read studies in a total of 133 adults who had an indication for head and neck extracranial or extraspinal MRI. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and less than 1% other. The results of the non-contrast and contrast MRI scans were compared. Approximately 75-82% of the scans were enhanced, 45-48% of the scans provided additional diagnostic information, and 8-25% of the diagnoses were changed. The relevance of the findings to disease sensitivity and specificity has not been fully evaluated.