Gadopiclenol

Vueway ® 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) Vueway 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 )

Injection: 0.5 mmol/mL of gadopiclenol as a clear, colorless to yellow aqueous solution available as: Strength Packaging 1.5 mmol/3 mL (0.5 mmol/mL) 3.75 mmol/7.5 mL (0.5 mmol/mL) 5 mmol/10 mL (0.5 mmol/mL) 7.5 mmol/15 mL (0.5 mmol/mL) Single-dose vials (glass) 3.75 mmol/7.5 mL (0.5 mmol/mL) 5 mmol/10 mL (0.5 mmol/mL) 7.5 mmol/15 mL (0.5 mmol/mL) Single-dose prefilled syringes (plastic) 15 mmol/30 mL (0.5 mmol/mL) 25 mmol/50 mL (0.5 mmol/mL) 50 mmol/100 mL (0.5 mmol/mL) Pharmacy bulk package (glass) 15 mmol/30 mL (0.5 mmol/mL) 25 mmol/50 mL (0.5 mmol/mL) 50 mmol/100 mL (0.5 mmol/mL) Imaging Bulk Package (glass) Injection: 0.5 mmol/mL of gadopiclenol in single-dose vials, single-dose prefilled syringes, pharmacy bulk packages, and imaging bulk packages ( 3 )

Vueway is contraindicated in patients with history of hypersensitivity reactions to Vueway. History of hypersensitivity reactions to Vueway ( 4 )

Hypersensitivity Reactions: Serious hypersensitivity reactions have occurred with GBCAs. Monitor patients closely for need of emergency cardiorespiratory support. ( 5.3 ) Gadolinium Retention: Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.4 )

5.1 Risk Associated with Intrathecal Use Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of Vueway have not been established with intrathecal use. Vueway 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 Vueway among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73 m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73 m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73 m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle, and internal organs. Report any diagnosis of NSF following Vueway administration to Bracco Diagnostics Inc. (1-800-257-5181) 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 (e.g., 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 the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended Vueway 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 minutes of GBCA administration and resolved with prompt emergency treatment. Before Vueway 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 Vueway. Vueway is contraindicated in patients with history of hypersensitivity reactions to Vueway [see Contraindications ( 4 )] . Administer Vueway 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 Vueway 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, and gadopiclenol. 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 [see Adverse Reactions ( 6.2 )] . 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 chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent. Do not exceed the recommended dose.

5.6 Extravasation and Injection Site Reactions Injection site reactions such as injection site pain have been reported in the clinical studies with Vueway [see Adverse Reactions ( 6.1 )]. Extravasation during Vueway administration may result in tissue irritation [see Nonclinical Toxicology ( 13.2 )]. Ensure catheter and venous patency before the injection of Vueway.

5.7 Interference with Visualization of Lesions Visible with Non-Contrast MRI As with any GBCA, Vueway may impair the visualization of lesions seen on non-contrast MRI. Therefore, caution should be exercised when Gadopiclenol MRI scans are interpreted without a companion non-contrast MRI scan.

The following clinically significant adverse reactions are discussed elsewhere in labeling: Nephrogenic Systemic Fibrosis [see Warnings and Precautions ( 5.2 )] Hypersensitivity Reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] Most common adverse reactions (incidence >0.2%) are injection site pain, headache, nausea, injection site warmth and coldness, dizziness, localized swelling, and erythema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS contact Bracco Diagnostics Inc. at 1-800-257-5181 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 Vueway was evaluated in 1,083 patients who received Vueway at doses ranging from 0.025 mmol/kg (one half the recommended dose) to 0.3 mmol/kg (six times the recommended dose). A total of 744 patients (including 116 pediatric patients) received the recommended dose of 0.05 mmol/kg. Among patients who received the recommended dose, the average age was 49 years (range from less than one month to 88 years) and 55% were female. The race distribution was 80% White, 10% Asian, 6% American Indian or Alaska native, 2% Black, and 2% patients of other or unspecified race groups. Overall, approximately 4.6% of subjects receiving the labeled dose reported one or more adverse reactions. Table 1 lists adverse reactions that occurred in > 0.2% of patients who received 0.05 mmol/kg Vueway. Table 1. Adverse Reactions Reported in > 0.2% of Patients Receiving Vueway in Clinical Trials Adverse Reaction Vueway 0.05 mmol/kg (n=744) (%) Injection site pain

0.7 Headache

0.7 Nausea

0.4 Injection site warmth

0.4 Injection site coldness

0.3 Dizziness

0.3 Localized swelling

0.3 Erythema

0.3 Adverse reactions that occurred with a frequency ≤ 0.2% in patients who received 0.05 mmol/kg Vueway included: maculopapular rash, vomiting, worsened renal impairment, feeling hot, pyrexia, oral paresthesia, dysgeusia, diarrhea, pruritus, allergic dermatitis, injection site paresthesia, Cystatin C increase, and blood creatinine increase. Adverse Reactions in Pediatric Patients The overall safety profile observed in pediatric patients was similar to the safety profile of adult patients [see Use in Specific Populations ( 8.4 )] .

6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of Vueway or other 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

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 Vueway 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 Vueway during organogenesis (see Data ) . Because of the potential risks of gadolinium to the fetus, use Vueway only if imaging is essential during pregnancy and cannot be delayed. The 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 Human Data Available data regarding exposure to GBCAs during pregnancy from published epidemiological studies are not sufficient to assess the potential 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/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 Animal reproduction studies conducted with gadopiclenol showed some signs of maternal toxicity in rats at 10 mmol/kg and rabbits at 5 mmol/kg (corresponding to 52 times and 57 times the recommended human dose, respectively). This maternal toxicity was characterized in both species by swelling, decreased activity, and lower gestation weight gain and food consumption. No effect on embryo-fetal development was observed in rats at 10 mmol/kg (corresponding to 52 times the recommended human dose). In rabbits, a lower mean fetal body weight was observed at 5 mmol/kg (corresponding to 57 times the recommended human dose) and this was attributed as a consequence of the lower gestation weight gain.

8.2 Lactation Risk Summary There are no data on the presence of gadopiclenol 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 excreted in breast milk. Additionally, there is limited GBCA gastrointestinal absorption in the breast-fed infant. Gadopiclenol is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Vueway and any potential adverse effects on the breastfed infant from Vueway or from the underlying maternal condition. Data In lactating rats receiving single intravenous injection of [ 153 Gd]-gadopiclenol, 0.3% and 0.2% of the total administered radioactivity was transferred to the pups via maternal milk at 6 hours and 24 hours after administration, respectively. Furthermore, in nursing rat pups, oral absorption of gadopiclenol was 3.6%.

8.4 Pediatric Use The safety and effectiveness of Vueway 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 Vueway in this age group is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data from two open-label, single-arm, multicenter, single dose studies (i.e., Trials 1 and 2) of Vueway (0.05 mmol/kg) in 116 pediatric patients who underwent CNS and body MRI. Trial 1 (NCT03749252) included 80 pediatric patients aged 2 to 17 years, and Trial 2 (NCT05590884) included 36 pediatric patients aged 25 days to less than 2 years [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 , 14.3 )] . The safety of Vueway has not been established in preterm neonates.

8.5 Geriatric Use Of the total number of Vueway-treated patients in clinical studies, 270 (26%) patients were 65 years of age and over, while 62 (6%) patients were 75 years of age and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects. This drug is known to be substantially 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.

8.6 Renal Impairment In patients with renal impairment, the exposure of gadopiclenol 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 Vueway among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. No dose adjustment of Vueway is recommended for patients with renal impairment. Vueway can be removed from the body by hemodialysis [see Warnings and Precautions ( 5.2 , 5.4 , 5.5 ) and Clinical Pharmacology ( 12.3 )] .

Gadopiclenol is a paramagnetic molecule (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 signal intensity (brightness) of tissues.