Gadoteridol

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.

1 INDICATIONS AND USAGE Gadoteridol Injection is a gadolinium-based contrast agent indicated for magnetic resonance imaging (MRI) to visualize: lesions with disrupted blood brain barrier and/or abnormal vascularity in the brain (intracranial lesions), spine and associated tissues in adults and pediatric patients, including term neonates (1.1 ) lesions in the head and neck in adults ( 1.2 ) 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 DOSAGE AND ADMINISTRATION Recommended dose in adult and pediatric patients is 0.2 mL/kg (0.1 mmol/kg) body weight administered as rapid intravenous infusion or bolus ( 2.1 ) Follow injection with a saline flush of at least 5 mL normal saline ( 2.1 ) 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. Table 1: Recommended Volume of Gadoteridol Injection by Body Weight Body Weight (kg) Volume to be Administered (mL) 2.5 0.5 5 1 10 2 20 4 30 6 40 8 50 10 60 12 70 14 80 16 90 18 100 20 110 22 120 24 130 26 140 28 150 30 MRI of the CNS in Adults A supplementary dose of 0.4 mL/kg (0.2 mmol/kg) may be given up to 30 minutes after the first dose in adult patients with normal renal function suspected of having poorly visualized CNS lesions, in the presence of negative or equivocal scans The safety and efficacy of supplementary dosing have not been established in pediatric patients 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 Vials Draw Gadoteridol Injection into the syringe immediately before use. Do not pierce the rubber stopper more than once. Discard any unused vial contents.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information: Nephrogenic systemic fibrosis [see Boxed Warning and Warnings and Precautions ( 5.2 )] . Hypersensitivity reactions [see Contraindications ( 4 ) and Warnings and Precautions (5.3 )] . The most commonly reported adverse reactions are nausea and taste perversion with an incidence ≥ 0.9% ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 2: More frequent adverse reactions in clinical trials Reaction Rate (%) N=3174 Nausea 1.4% Dysgeusia 0.9% Headache 0.7% Dizziness 0.4% Urticaria 0.4% The following additional adverse events occurred in fewer than 0.4% of the subjects: General disorders and administration site conditions: Asthenia; chest discomfort, facial edema, feeling hot, injection site coldness, injection site erythema, injection site pain, injection site warmth, pain, pyrexia Cardiac: Angina pectoris, palpitations, atrio-ventricular block first degree Ear and labyrinth disorders: Ear discomfort, tinnitus Eye disorders: Eye pruritis, lacrimation increased Gastrointestinal disorders: Abdominal discomfort, abdominal pain, diarrhea, dry mouth, gingival pain, oral pruritis, swollen tongue, vomiting Infections and infestations: Gingivitis, rhinitis Investigations: Alanine aminotransferase increased, aspartate aminotransferase increased, blood chloride increased, blood pressure immeasurable, blood urea decreased, hemoglobin decreased, heart rate increased Metabolism and nutrition disorders: Decreased appetite, hypoglycemia Musculoskeletal and connective tissue disorders: Back pain, musculoskeletal stiffness Nervous system disorders: Formication, hypoesthesia, hypokinesia, lethargy, loss of consciousness, migraine, paresthesia, presyncope, seizure, syncope, taste disorder Psychiatric disorder: Anxiety, mental status changes Respiratory, thoracic and mediastinal disorders: Cough, dry throat, dyspnea, nasal discomfort, throat irritation Skin and subcutaneous tissue disorders: Hyperhidrosis, pruritis, rash, rash morbilliform Vascular disorders: Flushing, hypotension, peripheral coldness, vascular rupture, vasodilatation, vasospasm 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: General disorders and administration site conditions: Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions ( 5.4 )] . These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems. Cardiac disorders: Cardiac arrest, bradycardia, hypertension Gastrointestinal disorders: Acute pancreatitis with onset within 48 hours after GBCA administration Immune system disorders: Hypersensitivity/anaphylactoid reactions including cardiac arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, cough, sneezing, conjunctivitis, eyelid edema, hyperhidrosis, urticaria [see Warnings and Precautions ( 5.3 )] . Nervous system disorders: Coma, loss of consciousness, vasovagal reaction, tremor Respiratory, thoracic and mediastinal disorders: Respiratory arrest, acute respiratory distress syndrome, pulmonary edema Renal and urinary system disorders: Acute renal failure Cases of acute renal failure have been reported in patients with pre-existing severe renal impairment.