Ambelvist Injection
FDA Label NDC 50419-323

Risk Associated with Intrathecal Use

Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. AMBELVIST is not approved for intrathecal use [see Warnings and Precautions (5.1)].

Nephrogenic Systemic Fibrosis

GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of AMBELVIST in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle, and internal organs.

The risk for NSF appears highest among patients with:

Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m²), orAcute kidney injury.

Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example, age > 60 years, hypertension, or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.

For patients at highest risk for NSF, do not exceed the recommended AMBELVIST dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.2)].

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)

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.

• 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.

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.

• 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 disposables for the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) should be discarded.

• AMBELVIST Pharmacy Bulk Package (PBP) is not for direct infusion.
• The PBP is for use with an appropriate transfer device for filling empty sterile syringes.
• Perform the transfer of AMBELVIST from the PBP in an aseptic work area, such as a laminar flow hood, using aseptic technique.
• Penetrate the closure only one time. Once the PBP is punctured, do not remove it from the aseptic work area.
• Use each individual dose of AMBELVIST promptly following withdrawal from the PBP.
• Withdraw the contents of the PBP within 6 hours after puncture at 20°C to 25°C (68°F to 77°F). Discard any unused portion after 6 hours.

Injection: 0.1 mmol/mL of gadoquatrane as a clear and colorless to pale yellow solution available as:

AMBELVIST is contraindicated in patients with a history of severe hypersensitivity reactions to AMBELVIST.

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

GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of AMBELVIST among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73 m²) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73 m²) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73 m²). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle, and internal organs. Report any diagnosis of NSF following AMBELVIST administration to Bayer HealthCare (1- 888-842-2937) 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 > 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 degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administrated to a patient. For patients at highest risk for NSF, do not exceed the recommended AMBELVIST 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. The usefulness of hemodialysis in the prevention of NSF is unknown.

With GBCAs, serious hypersensitivity reactions have occurred. In most cases, initial symptoms occurred within half an hour of GBCA administration and resolved with prompt emergency treatment.

• Before AMBELVIST 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 AMBELVIST.
• AMBELVIST is contraindicated in patients with history of severe hypersensitivity reactions to AMBELVIST [see Contraindications (4)].
• Administer AMBELVIST 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 AMBELVIST administration, observe patients for signs and symptoms of hypersensitivity reactions.

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 gadodiamide causing greater retention than other linear agents such as gadoxetate disodium and gadobenate dimeglumine. Retention is lowest and similar among the macrocyclic GBCAs such as gadoterate meglumine, gadobutrol, gadoteridol, gadopiclenol, and gadoquatrane.

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.

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.

In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses.

As with other GBCAs, AMBELVIST may obscure certain lesions that are visible on non-contrast MRI. When available, non-contrast MRI images should be reviewed during the interpretation of AMBELVIST MRI scans.

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)]

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.

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)].

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

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.

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 present in breast milk, and there is limited GBCA gastrointestinal absorption in the breast-fed infant. Gadoquatrane is present in rat milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AMBELVIST and any potential adverse effects on the breastfed infant from AMBELVIST or from the underlying maternal condition.

Data

In lactating rats that received intravenous gadoquatrane at up to 1.56 mmol Gd/kg/day (39 times the recommended human dose), small amounts of gadoquatrane were excreted in rat milk. The concentration of gadolinium in animal milk does not necessarily predict the concentration of gadolinium in human milk.

The safety and effectiveness of AMBELVIST for use with MRI to detect and visualize lesions with abnormal vascularity in the CNS (brain, spine, and associated tissues) and the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system) have been established in pediatric patients, including term neonates. Use of AMBELVIST in this age group is supported by evidence from adequate and well-controlled studies of AMBELVIST in adults, with additional pharmacokinetic and safety data from 93 pediatric patients aged 28 days to less than 18 years who received one 0.01 mmol/kg dose of AMBELVIST and underwent MRI of any body region [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2, 14.3)].

Adverse reactions in pediatrics included an episode of apnea in a 4-week-old patient with a history of cerebral vein thrombosis, seizures, and cerebral hemorrhage, occurring one minute after receiving AMBELVIST 0.01 mmol/kg (0.44 mL) at a rate of 0.8 mL/sec. The patient experienced sudden blood oxygen desaturation to 65% which returned to 100% within 11 minutes after the inhaled oxygen flow rate increased [see Adverse Reactions (6.1)].

The safety of AMBELVIST has not been established in preterm neonates.

Of the total number of patients in clinical studies of AMBELVIST, 238 (28%) of patients were 65 years of age and older, and 75 (9%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

This drug is known to be excreted by the kidney, and the risk of adverse reactions to this drug 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 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

In patients with renal impairment, the exposure of gadoquatrane is increased compared to patients with normal renal function. This may increase the risk of adverse reactions such as nephrogenic systemic fibrosis (NSF). Avoid use of AMBELVIST among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. No dose adjustment of AMBELVIST is recommended for patients with renal impairment. AMBELVIST can be removed from the body by hemodialysis [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

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.

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 C₈₁H₁₂₈Gd₄N₂₄O₃₂ and a molecular weight of 2,579.1 g/mol. The structural formula of gadoquatrane is:

Chemical Structure (Gadoquatrane 01)

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:

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.

In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with:

• differences in proton density
• differences of the spin-lattice or longitudinal relaxation times (T₁).
• differences in the spin-spin or transverse relaxation time (T₂).

Gadoquatrane alters the T₁ and T₂ relaxation times in tissues in the magnetic field of an MRI scanner. The extent to which a contrast agent can affect the relaxation rate (1/T₁ or 1/T₂) of tissue water is termed relaxivity (r₁ or r₂).

The relaxivity (r1) of gadoquatrane is presented in Table 3.

Table 3: Relaxivity (r₁) of Gadoquatrane

Each molecule of gadoquatrane contains 4 chelated gadolinium ions [see Description (11)].

in Human Plasma at 37°C

Magnetic Field Strength	Relaxivity (r1) (L/mmol/sec)
1.5 T	47
3.0 T	41

Cardiac Electrophysiology

At 5 times the recommended dose of gadoquatrane, clinically significant QTc interval prolongation was not observed.

The peak plasma concentration (C_max) and area under the concentration time curve (AUC) of gadolinium (Gd) increased proportionally over a dose range from 0.0025 to 0.05 mmol/kg of gadoquatrane (0.25 to 5 times the recommended dose). At the recommended dose, the median (5th, 95th percentile) C_max and AUC_inf were 394 (249, 628) µmol Gd/L and 462 (315, 766) µmol Gd*h/L, respectively. The pharmacokinetic (PK) parameters of gadolinium by age group are shown in Table 4.

Distribution

After intravenous administration, gadoquatrane is distributed from the vascular to the extracellular space.

The median (5th, 95th percentile) volume of distribution over body weight of gadolinium at steady state (Vss/BW) is 0.205 (0.157, 0.252) L/kg.

Plasma protein binding is < 1%.

Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.4)]. It is unknown whether the recommended dose of AMBELVIST results in similar or different levels of gadolinium retention relative to those of other approved macrocyclic GBCAs at their recommended doses.

Elimination

The median (5th, 95th percentile) effective elimination half-life (t_{1/2, eff}) of gadolinium is 1.6 (1.2, 2.6) hours.

The median (5th, 95th percentile) total body clearance over body weight (CL/BW) is 0.087 (0.052, 0.13) L/h/kg.

Metabolism

Gadoquatrane is not metabolized.

Excretion

Gadoquatrane is mainly eliminated through the kidneys by glomerular filtration. On average, 91% (CV 13%) of the dose was excreted in the urine within 12 hours after intravenous administration. Extrarenal elimination is negligible; less than 1% of the dose was detectable in feces.

Specific Populations

No clinically significant differences in PK of gadolinium were observed based on age (geriatric vs. younger patients) or sex (male vs. female).

Pediatric Patients

The PK profile of gadolinium in pediatric patients is generally comparable to and within range of that observed in adults. See Table 4 for the PK parameters of gadolinium at the recommended dose of gadoquatrane by age.

Patients with Renal Impairment

Gadolinium distributes into the extracellular space and is mainly eliminated by the kidney. Gadolinium clearance decreased as the severity of renal impairment increased, leading to higher total drug exposure (AUC) and prolonged excretion time. Despite the effects on total exposure, early plasma concentrations of gadolinium were not affected by the subjects' level of renal function [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

Table 5 presents the pharmacokinetic parameters of gadolinium at the recommended dose of gadoquatrane in adults with varying degrees of renal function (normal, mild, and moderate impairment) and for virtual patients representing severe renal impairment.

In patients with mild or moderate renal impairment, about 90% of the administered gadoquatrane was recovered in urine within 24 hours. In patients with severely impaired renal function, recovery of a similar amount is anticipated in urine within 5 to 7 days.

Gadoquatrane has been shown to be dialyzable in an in vitro hemodialysis study. After 1 hour of in vitro hemodialysis, approximately 97% of gadoquatrane was removed from the plasma.

Carcinogenicity

Carcinogenicity studies in animals have not been conducted with gadoquatrane.

Mutagenesis

Gadoquatrane was not mutagenic or clastogenic with or without metabolic activation in five strains of the Ames bacterial mutagenicity assay (TA100, TA98, TA1535, TA1537, and TA102), or in vitro and in vivo micronucleus assays.

Impairment of Fertility

No adverse effects on reproductive performance or pregnancy outcome were observed in parental rats following daily intravenous administration of gadoquatrane before and during gestation at up to 0.54 mmol Gd/kg/day (corresponding to 4 times the human exposure). At 1.54 mmol Gd/kg/day (12 times the human exposure), a slight increase in the number of dead embryos and the percentage of post-implantation loss (4 of the 20 females in the treatment group each having at least 3 dead embryos) was observed and considered potentially related to gadoquatrane.

The safety and effectiveness of AMBELVIST were investigated in two randomized, multicenter, double-blind, active comparator, crossover studies, Study 1 (NCT05915702) and Study 2 (NCT05915728). Study 1 focused on central nervous system (CNS) pathologies, while Study 2 addressed pathologies in non-CNS body regions.

In a random order separated by a 2- to 14-day period, each patient received AMBELVIST and an active comparator. AMBELVIST was administered at a dose of 0.01 mmol/kg, which delivers 0.04 mmol gadolinium (Gd)/kg. The active comparator was a macrocyclic GBCA (gadobutrol, gadoterate, or gadoteridol) administered at a standard dose of 0.1 mmol Gd/kg.

For each drug, pre-contrast (unenhanced) and paired (pre-contrast and post-contrast) image sets were separately evaluated by three independent central readers who were blinded to clinical information and identity of the contrast agent. Each reader assessed up to five lesions per patient on three visualization scores: contrast enhancement (4-point scale), delineation (4-point scale), and morphology (3-point scale). The number of lesions was also analyzed. An additional independent central reader performed lesion tracking to allow matching of lesions between pre-contrast and paired images.

Study 1 included 305 patients scheduled for MRI with known or suspected pathology of the CNS. Of these, 237 patients had assessable MR image sets and at least one matching lesion between paired AMBELVIST and pre-contrast MRI. These patients had a mean age of 56 years (range: 20 to 84 years), with 58% being female. Of the study population, 67% were White, 29% Asian, 1% Black or African American, <1% of multiple racial background, and 3% of unspecified race.

The blinded readers' scores of paired pre- and post-AMBELVIST images and pre-contrast images alone for all lesion visualization criteria are presented in Table 6.

AMBELVIST visualization scores and number of lesions identified per patient were similar to those of other tested GBCAs in descriptive analyses.

Study 2 included 410 patients with known or suspected pathology in non-CNS body regions, including head and neck, thorax, abdomen, pelvis, and extremities. Of these, 312 patients had assessable MR image sets and at least one matching lesion between paired AMBELVIST and pre-contrast MRI. These patients had a mean age of 58 years (range: 20 to 84), with 48% being female. Of the study population, 70% were White, 28% Asian, <1% Black or African American, and 2% of unspecified race.

A total of nine readers were divided into three specialization groups of three readers each for breast (N=32), cardiovascular (N=24), and other non-CNS body (N=256) imaging.

AMBELVIST demonstrated similar increases in lesion visualization scores across different reader groups (breast, cardiovascular, and other non-CNS body). Within the other non-CNS body group, scores also increased consistently across different anatomic regions. Lesion visualization scores for other non-CNS body imaging are summarized in Table 7.

AMBELVIST visualization scores and number of lesions identified per patient were similar to those of other tested GBCAs in descriptive analyses.

How Supplied

AMBELVIST (gadoquatrane) injection is a clear and colorless to pale yellow solution available in the following presentations:

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].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Nephrogenic Systemic Fibrosis

Inform the patient that AMBELVIST may increase the risk of NSF among patients with impaired elimination of the drug and that NSF may result in fatal or debilitating fibrosis affecting the skin, muscle, and internal organs.

Instruct the patient to contact their physician if they develop signs or symptoms of NSF following AMBELVIST 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 [see Warnings and Precautions (5.2)].

Gadolinium Retention

Advise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs following AMBELVIST administration even 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)].

Pregnancy

Advise pregnant women of the potential risk of fetal exposure to AMBELVIST [see Use in Specific Populations (8.1)].

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981

© 2026, Bayer HealthCare Pharmaceuticals Inc., All rights reserved.

NDC 50419-321-11

BAYER

Ambelvist^®
(gadoquatrane) injection

0.2 mmol/2 mL
(0.1 mmol/mL)

For Intravenous Administration
Single-dose vials.
Discard unused portion.

Dispense the enclosed Medication Guide to each patient

3 x 2 mL
Rx only
sterile solution

Principal Display Panel (2 mL Vial Carton)

NDC 50419-322-11

BAYER

Ambelvist^®
(gadoquatrane) injection

0.75 mmol/7.5 mL
(0.1 mmol/mL)

For Intravenous Administration
Single-dose vials.
Discard unused portion.

Dispense the enclosed Medication Guide to each patient

10 x 7.5 mL
Rx only
sterile solution

Principal Display Panel (7.5 mL Vial Carton)

NDC 50419-323-11

BAYER

Ambelvist^®
(gadoquatrane) injection

0.1 mmol/10 mL
(0.1 mmol/mL)

For Intravenous Administration
Single-dose vials.
Discard unused portion.

Dispense the enclosed Medication Guide to each patient

10 x 10 mL
Rx only
sterile solution

Principal Display Panel (10 mL Vial Carton)

NDC 50419-324-11

BAYER

Ambelvist^®
(gadoquatrane) injection

1.5 mmol/15 mL
(0.1 mmol/mL)

For Intravenous Administration
Single-dose vials.
Discard unused portion.

Dispense the enclosed Medication Guide to each patient

10 x 15 mL
Rx only
sterile solution

Principal Display Panel (15 mL Vial Carton)

NDC 50419-326-11

BAYER

Ambelvist^®
(gadoquatrane) injection

3 mmol/30 mL
(0.1 mmol/mL)

Imaging Bulk Package -
Not for Direct Infusion

Discard 6 hours after initial puncture.

Dispense the enclosed Medication Guide to each patient

10 x 30 mL
Rx only
sterile solution

Principal Display Panel (30 mL Vial Carton)

NDC 50419-327-11

BAYER

Ambelvist^®
(gadoquatrane) injection

6.5 mmol/65 mL
(0.1 mmol/mL)

Imaging Bulk Package -
Not for Direct Infusion

For Intravenous Use Only

Discard 6 hours after initial puncture.

Dispense the enclosed Medication Guide to
each patient

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 Imaging Bulk Package.

See drug and device labeling for information
on devices indicated for use with this Imaging
Bulk Package and techniques to help assure safe use.

Recommended Dosage:
See Prescribing Information.

Each mL contains 257.9 mg (0.1 mmol) of
gadoquatrane (containing 0.4 mmol of
gadolinium), 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.

Ambelvist contains no antimicrobial preservative.

Store at 25°C (77°F); excursions permitted to
15°C to 30°C (59°F to 86°F)
[See USP Controlled Room Temperature].

Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany

91629385

10 x 65 mL
Rx only
sterile solution

LOT

EXP

Bayer

Principal Display Panel (65 mL Bottle Label)

NDC 50419-329-11

BAYER

Ambelvist^®
(gadoquatrane) injection

6.5 mmol/65 mL
(0.1 mmol/mL)

Pharmacy Bulk Package -
Not for Direct Infusion

For Intravenous Use Only

Discard 6 hours after initial puncture.

Dispense the enclosed Medication Guide to
each patient

Recommended Dosage:
See Prescribing Information.

Each mL contains 257.9 mg (0.1 mmol) of
gadoquatrane (containing 0.4 mmol of
gadolinium), 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.

Ambelvist contains no antimicrobial preservative.

Store at 25°C (77°F); excursions permitted to
15°C to 30°C (59°F to 86°F)
[See USP Controlled Room Temperature].

Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany

91940293

10 x 65 mL
Rx only
sterile solution

LOT

EXP

Bayer

Principal Display Panel (65 mL Bottle Label)

NDC 50419-328-11

BAYER

Ambelvist^®
(gadoquatrane) injection

3 mmol/30 mL
(0.1 mmol/mL)

Imaging Bulk Package -
Not for Direct Infusion

Discard 6 hours after initial puncture.

Dispense the enclosed Medication Guide to each patient

10 x 30 mL
Rx only
sterile solution

Principal Display Panel (30 mL Bottle Carton)

NDC 50419-330-11

BAYER

Ambelvist^®
(gadoquatrane) injection

0.75 mmol/7.5 mL
(0.1 mmol/mL)

Pre-filled Disposable 7.5 mL Syringe
For Intravenous Administration
Single-dose syringe.
Discard unused portion and syringe.
MEDICATION AND FLUID PATHWAY ARE STERILE.
OUTSIDE OF SYRINGE IS NOT STERILE.

Dispense the enclosed Medication Guide to each patient

5 x 7.5 mL
pre-filled syringes
Rx only
sterile solution

Principal Display Panel (7.5 mL Syringe Carton)

NDC 50419-331-11

BAYER

Ambelvist^®
(gadoquatrane) injection

1 mmol/10 mL
(0.1 mmol/mL)

Pre-filled Disposable 10 mL Syringe
For Intravenous Administration
Single-dose syringe.
Discard unused portion and syringe.
MEDICATION AND FLUID PATHWAY ARE STERILE.
OUTSIDE OF SYRINGE IS NOT STERILE.

Dispense the enclosed Medication Guide to each patient

5 x 10 mL
pre-filled syringes
Rx only
sterile solution

Principal Display Panel (10 mL Syringe Carton)

NDC 50419-332-11

BAYER

Ambelvist^®
(gadoquatrane) injection

1.5 mmol/15 mL
(0.1 mmol/mL)

Pre-filled Disposable 15 mL Syringe
For Intravenous Administration
Single-dose syringe.
Discard unused portion and syringe.
MEDICATION AND FLUID PATHWAY ARE STERILE.
OUTSIDE OF SYRINGE IS NOT STERILE.

Dispense the enclosed Medication Guide to each patient

5 x 15 mL
pre-filled syringes
Rx only
sterile solution

Principal Display Panel (15 mL Syringe Carton)