AMBELVIST Solution for injection Ref.[116696] Active ingredients: Gadoquatrane

5.1 Risks Associated with Intrathecal Use

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)].

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 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.

5.3 Hypersensitivity Reactions

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.

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, 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.

5.5 Acute Kidney Injury

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.

5.6 Interference with Lesion Visualization

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.

Table 1. Adverse Reactions Reported in ≥0.2% of Adult Patients Who Received AMBELVIST:

^* Injection site reactions include injection site pain, catheter site pain, injection site coldness, and injection site erythema.

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)].