gadoterate meglumine

1 INDICATIONS AND USAGE Gadoterate Meglumine Injection 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 (including term neonates) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. Gadoterate Meglumine Injection 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 (including term neonates) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. ( 1 )

2 DOSAGE AND ADMINISTRATION Adult and pediatric patients: The recommended dose of Gadoterate Meglumine Injection is 0.2 mL/kg (0.1 mmol/kg) body weight administered as an intravenous bolus injection at a flow rate of approximately 2 mL/second for adults and 1 to 2 mL/second for pediatric patients (including term neonates). The dose is delivered by manual or power injection. 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 to 2 mL/second for pediatric patients. Table 1 provides weight-adjusted dose volumes. Table 1: Volumes of Gadoterate Meglumine Injection by Body Weight Body Weight Volume Pounds (lb) Kilograms (kg) Milliliters (mL) 5.5 2.5 0.5 11 5 1 22 10 2 44 20 4 66 30 6 88 40 8 110 50 10 132 60 12 154 70 14 176 80 16 198 90 18 220 100 20 242 110 22 264 120 24 286 130 26 308 140 28 330 150 30 To ensure complete injection of Gadoterate Meglumine Injection the injection may be followed by normal saline flush. Contrast MRI can begin immediately following injection of 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. • When Gadoterate Meglumine Injection is to be injected using plastic disposable syringes, the contrast medium should be drawn into the syringe and used immediately. Pharmacy Bulk Package Preparation: • Do not use the Pharmacy Bulk Package for direct intravenous infusion. • Perform the transfer of Gadoterate Meglumine Injection from the Pharmacy Bulk Package in an aseptic work area, such as laminar flow hood and using aseptic technique and suitable transfer device. Penetrate the closure only one time. • Once the container closure is punctured, do not remove the Pharmacy Bulk Package from the aseptic work area. • The Pharmacy Bulk Package is used as a multiple dose container with an appropriate transfer device for filling empty sterile syringes. • Use each individual dose of Gadoterate Meglumine Injection promptly following withdrawal from the Pharmacy Bulk Package. • Use the contents of the Pharmacy Bulk Package within 24 hours after initial puncture.

3 DOSAGE FORMS AND STRENGTHS Gadoterate Meglumine Injection, USP 0.5 mmol per mL is a sterile, clear, colorless to yellow, aqueous solution for intravenous injection containing 376.9 mg per mL gadoterate meglumine. Gadoterate Meglumine Injection, USP Pharmacy Bulk Package is available in vials. Gadoterate Meglumine Injection 0.5 mmol per mL contains 376.9 mg per mL of gadoterate meglumine. Gadoterate Meglumine Injection Pharmacy Bulk Package is available in vials.

4 CONTRAINDICATIONS History of clinically important hypersensitivity reactions to Gadoterate Meglumine Injection [see Warnings and Precautions ( 5.3 )] . Clinically important hypersensitivity reactions to Gadoterate Meglumine Injection. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Nephrogenic systemic fibrosis [see Warnings and Precautions ( 5.2 )] . Hypersensitivity reactions [see Warnings and Precautions ( 5.3 )]. Gadolinium Retention [see Warnings and Precautions ( 5.4 )] . The most frequent (≥ 0.2%) adverse reactions in clinical studies were nausea, headache, injection site pain, injection site coldness, and rash. ( 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 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. Table 2: Adverse Reactions in Clinical Trials Reaction Rate (%) n=2867 Nausea 0.6% Headache 0.4% Injection Site Pain 0.4% Injection Site Coldness 0.2% Rash 0.2% 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. Adverse Reactions in Pediatric Patients 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 years) received Gadoterate Meglumine Injection. Overall, 7 pediatric patients (3.8%) reported at least one adverse reaction following Gadoterate Meglumine Injection administration. The most frequently reported adverse reaction was headache (1.1%). Most adverse events were mild in intensity and transient in nature. 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. Table 3: Adverse Reactions in the Postmarketing Experience System Organ Class Adverse Reaction Cardiac Disorders bradycardia, tachycardia, arrhythmia Immune System Disorders hypersensitivity/anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria Nervous System Disorders coma, convulsion, syncope, presyncope, parosmia, tremor Musculoskeletal and Connective Tissue Disorders muscle contracture, muscle weakness Gastrointestinal Disorders diarrhea, salivary hypersecretion, acute pancreatitis with onset within 48 hours after GBCA administration General Disorders and Administration Site Conditions malaise, fever Adverse events with variable onset and duration have been reported after GBCA adm …

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

8 USE IN SPECIFIC POPULATIONS Pregnancy: Use only if imaging is essential during pregnancy and cannot be delayed. ( 8.1 ) 8.1 Pregnancy Risk Summary GBCAs cross the human placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive (see Data ) . In animal reproduction studies, there were no adverse developmental effects observed in rats or rabbits with intravenous administration of gadoterate meglumine during organogenesis at doses up to 16 and 10 times, respectively, the recommended human dose (see Data ) . Because of the potential risks of gadolinium to the fetus, use Gadoterate Meglumine Injection only if imaging is essential during pregnancy and cannot be delayed. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20% respectively. Data Risk Summary GBCAs cross the human placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive (see Data ) . In animal reproduction studies, there were no adverse developmental effects observed in rats or rabbits with intravenous administration of gadoterate meglumine during organogenesis at doses up to 16 and 10 times, respectively, the recommended human dose (see Data) . Because of the potential risks of gadolinium to the fetus, use Gadoterate Meglumine Injection only if imaging is essential during pregnancy and cannot be delayed. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20% respectively. Human Data Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA administration. Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with non-contrast MRI and lack of information about the material indication for MRI. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy. Animal Data Gadolinium Retention GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age. Reproductive Toxicology Gadoterate meglumine was administered in intravenous doses of 0, 2, 4 and 10 mmol/kg/day [3, 7 and 16 times the recommended human dose (RHD) based on body surface area (BSA)] to female rats for 14 days before mating, throughout the mating period and until gestation day (GD) 17. Pregnant rabbits were administered gadoterate meglumine in intravenous doses of 0, 1, 3 and 7 mmol/kg/day ( 3, 10 and 23 times the RHD based on BSA) from GD6 to GD19. No effects on embryo-fetal development were observed at …

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.

11 DESCRIPTION Gadoterate Meglumine Injection, USP is a paramagnetic macrocyclic ionic contrast agent administered for magnetic resonance imaging. The chemical name for gadoterate meglumine is D-glucitol, 1-deoxy-1-(methylamino)-,[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceto(4-)-.kappa.N1, .kappa.N4, .kappa.N7, .kappa.N10, .kappa.O1, .kappa.O4, .kappa.O7, .kappa.O10]gadolinate(1-)(1:1); it has a formula weight of 753.9 g/mol and empirical formula of C 23 H 42 O 13 N 5 Gd (anhydrous basis). The structural formula of gadoterate meglumine in solution is as follows: CAS Registry No. 92943-93-6 Gadoterate Meglumine Injection, USP is a sterile, nonpyrogenic, clear, colorless to yellow, aqueous solution of 0.5 mmol/mL of gadoterate meglumine, for intravenous use. No preservative is added. Each mL of Gadoterate Meglumine Injection, USP contains 376.9 mg of gadoterate meglumine, 0.25 mg of DOTA and water for injection. Gadoterate Meglumine Injection, USP has a pH of 6.5 to 8.0. The main physiochemical properties of Gadoterate Meglumine Injection, USP are provided below: Table 4: Physicochemical Properties Parameter Value Density @ 20°C 1.1753 g/cm 3 Viscosity @ 20°C 3.4 mPa·s Viscosity @ 37°C 2.4 mPa·s Osmolality 1350 mOsm/kg water The thermodynamic stability constants for gadoterate (log K therm and log K cond at pH 7.4) are 25.6 and 19.3, respectively. structural formula

10 OVERDOSAGE Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection have not been reported. Gadoterate meglumine can be removed from the body by hemodialysis [see Clinical Pharmacology (12.3)] .

16 HOW SUPPLIED/STORAGE AND HANDLING Gadoterate Meglumine Injection, USP is a clear, colorless to yellow solution containing 0.5 mmol per mL of gadoterate meglumine. It is supplied in single dose vials. • Gadoterate Meglumine Injection, USP is supplied in 10 mL vials containing 5 mL or 10 mL of solution, in 20 mL vials containing 15 mL or 20 mL of solution. Each single dose vial is closed with a rubber stopper and sealed with an aluminum cap and the contents are sterile. Gadoterate Meglumine Injection, USP single-dose vials are individually packaged in a box of 10, in the following configurations: Product Code Unit of Sale Each 800105 NDC 65219-080-05 Unit of 10 NDC 65219-080-01 5 mL in glass vial 800110 NDC 65219-082-10 Unit of 10 NDC 65219-082-01 10 mL in glass vial 800115 NDC 65219-084-15 Unit of 10 NDC 65219-084-01 15 mL in glass vial 800120 NDC 65219-086-20 Unit of 10 NDC 65219-086-01 20 mL in glass vial Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Should solidification occur in the vial because of exposure to the cold, bring Gadoterate Meglumine Injection, USP to room temperature before use. If allowed to stand at room temperature for a minimum of 90 minutes, Gadoterate Meglumine Injection, USP should return to a clear, colorless to yellow solution. Before use, examine the product to assure that all solids are dissolved and that the container and closure have not been damaged. Discard the vial if solids persist.