Ambelvist

1 INDICATIONS AND USAGE AMBELVIST is indicated in adult and pediatric patients, including term neonates, for use with magnetic resonance imaging (MRI) to detect and visualize lesions with abnormal vascularity in: the central nervous system (brain, spine, and associated tissues) the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system) AMBELVIST is a gadolinium-based contrast agent indicated in adult and pediatric patients, including term neonates, for use with magnetic resonance imaging (MRI) to detect and visualize lesions with abnormal vascularity in: the central nervous system (brain, spine, and associated tissues) the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system) ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dose for adult and pediatric patients, including term neonates, is 0.01 mmol/kg actual body weight (equivalent to an injection volume of 0.1 mL/kg). ( 2.1 ) Administer the dose by intravenous injection, manually or by compatible power injector, at 1 mL/sec to 4 mL/sec followed by a flush of 0.9% sodium chloride injection; for pediatric patients, adjust the flow rate and flush volume based on age. ( 2.2 ) 2.1 Recommended Dose The recommended dose of AMBELVIST for adult and pediatric patients, including term neonates, is 0.01 mmol/kg actual body weight (equivalent to an injection volume of 0.1 mL/kg) administered intravenously. Clarification on Gadolinium Content Each molecule of gadoquatrane contains four gadolinium (Gd) ions [see Description (11) ] . Therefore, the recommended dose of 0.01 mmol/kg of gadoquatrane (administered as AMBELVIST) delivers 0.04 mmol Gd/kg. 2.2 Administration and Imaging Instructions Administer AMBELVIST as an intravenous injection, manually or by compatible power injector, at a flow rate of approximately 1 mL/second to 4 mL/second, followed by a flush of 0.9% sodium chloride injection. For pediatric patients, adjust the flow rate and flush volume based on age. AMBELVIST is for intravenous use only and must not be administered intrathecally [see Warnings and Precautions (5.1) ]. Use aseptic technique when preparing and administering AMBELVIST. Visually inspect AMBELVIST for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored, particulate matter is present, or the container appears damaged. If solidification occurs due to cold exposure, bring AMBELVIST to room temperature before use and inspect to ensure that the solution is clear and colorless to pale yellow. Do not mix AMBELVIST with other medications, and do not administer AMBELVIST in the same intravenous line simultaneously with other medications because of the potential for chemical incompatibility. Contrast MRI can begin immediately following the injection of AMBELVIST. 2.3 Directions for Use of Single-Dose Containers Single-Dose Vials Pierce the rubber stopper only once. Aseptically draw AMBELVIST into the syringe immediately before use. Each vial of AMBELVIST is intended for one single dose. Discard any unused vial contents. Single-Dose Pre-Filled Syringes Remove the tip cap from the pre-filled syringe immediately before use. Each pre-filled AMBELVIST syringe is for one single dose. Discard any unused syringe contents. 2.4 Directions for Use of Imaging Bulk Package AMBELVIST Imaging Bulk Package (IBP) is not for direct infusion. The IBP is for use only with an automated contrast injection system, contrast management system, or contrast media transfer set approved or cleared for use with this contrast agent in this IBP. See drug and device labeling for information on devices indicated for use with this IBP and techniques to help assure safe use. The AMBELVIST IBP is to be used only in a room designated for radiological procedures that involve intravascular administration of a contrast agent. Utilize aseptic technique for penetrating the container closure of the AMBELVIST IBP and transferring AMBELVIST. Penetrate the container closure only one time with a suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) approved or cleared for use with this contrast agent in this IBP. Once the AMBELVIST IBP is punctured, do not remove it from the work area during the entire period of use. Storage temperature of AMBELVIST IBP after the closure has been entered is 20°C to 25°C (68°F to 77°F). Maximum use time is 6 hours from puncture. Discard any unused portion 6 hours after puncture of the IBP. After the container closure is punctured, if the integrity of the IBP and the delivery system cannot be assured through direct continuous supervision, the IBP and all associated …

3 DOSAGE FORMS AND STRENGTHS Injection: 0.1 mmol/mL of gadoquatrane as a clear and colorless to pale yellow solution available as: Strength Package Type 0.2 mmol/2 mL (0.1 mmol/mL) 0.75 mmol/7.5 mL (0.1 mmol/mL) 1 mmol/10 mL (0.1 mmol/mL) 1.5 mmol/15 mL (0.1 mmol/mL) Single-Dose Vials 0.75 mmol/7.5 mL (0.1 mmol/mL) 1 mmol/10 mL (0.1 mmol/mL) 1.5 mmol/15 mL (0.1 mmol/mL) Single-Dose Pre-Filled Syringes 3 mmol/30 mL (0.1 mmol/mL) 6.5 mmol/65 mL (0.1 mmol/mL) Imaging Bulk Packages 3 mmol/30 mL (0.1 mmol/mL) 6.5 mmol/65 mL (0.1 mmol/mL) Pharmacy Bulk Packages Injection: 0.1 mmol/mL of gadoquatrane in single-dose vials, single-dose pre-filled syringes, imaging bulk packages, and pharmacy bulk packages. ( 3 )

4 CONTRAINDICATIONS AMBELVIST is contraindicated in patients with a history of severe hypersensitivity reactions to AMBELVIST. History of severe hypersensitivity to AMBELVIST. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Nephrogenic Systemic Fibrosis [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.3) ] Most frequently observed adverse reactions (incidence ≥ 0.2%) were dizziness, headache, injection site reactions, nausea, vomiting, feeling hot, paresthesia, and pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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 clinical practice. The safety of AMBELVIST was evaluated in four clinical studies in a total of 842 patients who received a single 0.01 mmol/kg dose. This safety population included 697 adult patients from two active comparator, cross-over studies [see Clinical Studies (14.1) ], 52 adult patients from a dose-finding study, and 93 pediatric patients [see Use in Specific Populations (8.4) ] . Adult Patients Among the 749 adult patients (who were exposed to gadoquatrane), the mean age was 56 years (range: 18 years to 89 years). Of these patients, 67% were White, 29% Asian, 1% Black or African American, and 3% of other or unspecified race, and 10% were Hispanic or Latino, 76% not Hispanic or Latino, and 14% of unspecified ethnicity. Table 1 lists adverse reactions that occurred in ≥ 0.2% of adult patients who received 0.01 mmol/kg AMBELVIST. Table 1: Adverse Reactions Reported in ≥ 0.2% of Adult Patients Who Received AMBELVIST Adverse Reaction AMBELVIST 0.01 mmol/kg N=749 (%) Dizziness 0.9 Headache 0.9 Injection site reactions Injection site reactions include injection site pain, catheter site pain, injection site coldness, and injection site erythema. 0.7 Nausea 0.5 Vomiting 0.4 Feeling hot 0.4 Paresthesia 0.3 Pruritus 0.3 Adverse reactions that occurred in < 0.2% of adult patients who received 0.01 mmol/kg AMBELVIST included erythema, abdominal discomfort, toothache, feeling cold, decreased glomerular filtration rate, urinary sediment, urinary white blood cells, urticaria, dyspnea, rhinalgia, arthralgia, limb discomfort, hematuria, vertigo, and hyperbilirubinemia. Pediatric Patients Among the 93 pediatric patients, the mean age was 7 years (range: 28 days to less than 18 years). Of these patients, 57% were White, 38% Asian, 1% Black or African American, and 4% of unspecified race, and 14% were Hispanic or Latino, 80% not Hispanic or Latino, and 6% of unspecified ethnicity. Adverse reactions in pediatric patients who received 0.01 mmol/kg AMBELVIST included (each occurring in 1% of patients): apnea, pyrexia, decreased platelet count, erythema, and rash [see Use in Specific Populations (8.4) ] . 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of GBCAs. 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. Gastrointestinal Disorders : Acute pancreatitis with onset within 48 hours after GBCA administration. General Disorders and Administration Site Conditions : Fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems with variable onset and duration after GBCA administration [see Warnings and Precautions (5.4) ] Respiratory, Thoracic, and Mediastinal Disorders : Acute respiratory distress syndrome, pulmonary edema. Skin Disorders : Gadolinium-associated plaques

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 There are no available data on AMBELVIST use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. GBCAs cross the placenta and result in fetal exposure. In human placental imaging studies, contrast was visualized in the placenta and fetal tissues after maternal GBCA administration. Based on animal studies, use of GBCAs during pregnancy may result in fetal gadolinium retention. Published epidemiological studies on the association between GBCAs and adverse fetal outcomes have reported inconsistent findings and have important methodological limitations (see Data ) . In animal reproduction studies, there were no adverse developmental effects observed in rats or rabbits with intravenous administration of gadoquatrane during organogenesis (see Data ) . Because of the potential risks of gadolinium to the fetus, use AMBELVIST only if imaging is essential during pregnancy and cannot be delayed. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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 Human Data Available data regarding exposure to GBCAs during pregnancy from published epidemiological studies are not sufficient to assess the risk of adverse fetal and neonatal effects that may be associated with GBCAs. A retrospective cohort study of over 1.4 million pregnancies in Ontario, Canada, 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 maternal indication for MRI. Another retrospective cohort study of over 11 million pregnancies in the Medicaid database found no increased risk of fetal or neonatal death or Neonatal Intensive Care Unit admission when comparing pregnancies exposed to GBCA MRI versus non-contrast MRI. These two retrospective observational studies assessed a limited number of potential pregnancy outcomes and did not evaluate the full spectrum of potential fetal risk. Animal Data Gadolinium Retention GBCAs administered to pregnant non-human primates (0.1 mmol Gd/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 Gd/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 Gadoquatrane had no effect on embryo-fetal development in rats and rabbits at dose levels of up to 1.55 mmol Gd/kg/day (corresponding to 18 and 23 times the human exposure in rats and rabbits, respectively). When rats were treated through pregnancy and lactation at dose levels of up to 1.56 mmol Gd/kg/day (39 times the recommended human dose), there were no adverse effects observed on survival, growth, sexual maturation, or neurobehavioral and reproductive function in the offspring. The exposure at the highest dose corresponded to 38 times (Lactation Day 4) and 12 times (Lactation Day 20) the exposure in terms of AUC in humans. 8.2 Lactation Risk Summary There are no data on the presence of gadoquatrane in human milk, the effects on the breastfed infant, or the effects on milk production. However, published lactation data on other GBCAs indicate that 0.01% to 0.04% of the maternal gadolinium dose is pres …

12.1 Mechanism of Action Gadoquatrane is a paramagnetic tetrameric macrocyclic non-ionic complex of gadolinium that develops a magnetic moment when placed in a magnetic field. The magnetic moment alters the relaxation rates of water protons in its vicinity in the body, leading to an increase in the signal intensity (brightness) of tissues.

11 DESCRIPTION AMBELVIST (gadoquatrane) injection is a paramagnetic tetrameric macrocyclic gadolinium-based contrast agent for intravenous use. The chemical name for gadoquatrane is tetragadolinium [4,10-bis(carboxylatomethyl)-7-{3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]-amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate, with a molecular formula of C 81 H 128 Gd 4 N 24 O 32 and a molecular weight of 2,579.1 g/mol. The structural formula of gadoquatrane is: AMBELVIST is a sterile, clear, colorless to pale yellow solution. Each mL contains 257.9 mg (0.1 mmol) of gadoquatrane (containing 0.4 mmol of gadolinium) and the following inactive ingredients: 0.196 mg of calcobutrol, 3.14 mg of sodium chloride,1.21 mg of trometamol, hydrochloric acid (for pH adjustment), and water for injection. The main physicochemical properties of AMBELVIST are listed in Table 2: Table 2: Physicochemical Properties of AMBELVIST Parameter Value Osmolality at 37°C (mOsm/kg H 2 O) 270 to 370 Viscosity at 20°C (mPa∙s) 2.55 Viscosity at 37°C (mPa∙s) 1.76 pH 6.9 to 7.9 Chemical Structure

10 OVERDOSAGE AMBELVIST can be removed by hemodialysis in the event of an overdose [see Clinical Pharmacology (12.3) ] . For additional management recommendations, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied AMBELVIST (gadoquatrane) injection is a clear and colorless to pale yellow solution available in the following presentations: Strength Package Type Sale Unit NDC 0.2 mmol/2 mL (0.1 mmol/mL) Single-Dose Vial Cartons of 3 vials 50419-321-11 0.75 mmol/7.5 mL (0.1 mmol/mL) Single-Dose Vial Cartons of 10 vials 50419-322-11 1 mmol/10 mL (0.1 mmol/mL) Single-Dose Vial Cartons of 10 vials 50419-323-11 1.5 mmol/15 mL (0.1 mmol/mL) Single-Dose Vial Cartons of 10 vials 50419-324-11 0.75 mmol/7.5 mL (0.1 mmol/mL) Single-Dose Pre-Filled Syringe Cartons of 5 syringes 50419-330-11 1 mmol/10 mL (0.1 mmol/mL) Single-Dose Pre-Filled Syringe Cartons of 5 syringes 50419-331-11 1.5 mmol/15 mL (0.1 mmol/mL) Single-Dose Pre-Filled Syringe Cartons of 5 syringes 50419-332-11 3 mmol/30 mL (0.1 mmol/mL) Imaging Bulk Package Cartons of 10 bottles 50419-326-11 6.5 mmol/65 mL (0.1 mmol/mL) Imaging Bulk Package Cartons of 10 bottles 50419-327-11 3 mmol/30 mL (0.1 mmol/mL) Pharmacy Bulk Package Cartons of 10 bottles 50419-328-11 6.5 mmol/65 mL (0.1 mmol/mL) Pharmacy Bulk Package Cartons of 10 bottles 50419-329-11 Storage and Handling Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].