Gadobutrol Injection
FDA Label NDC 42337-005

Risk Associated with Intrathecal Use

Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. Gadobutrol Injection 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 Gadobutrol Injection 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:

o  Chronic, severe kidney disease (GFR < 30 mL/min/1.73m ²), or

o  Acute 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 Gadobutrol Injection 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)].

Gadobutrol Injection is indicated for:

• Magnetic resonance imaging (MRI) of the central nervous system (CNS) to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity in adult and pediatric patients including term neonates
• MRI of the breast to assess the presence and extent of malignant breast disease in adult patients
• Magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients including term neonates
• Cardiac MRI (CMRI) to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD)

The recommended dose of Gadobutrol Injection for adult and pediatric patients, including term neonates, is 0.1 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered intravenously. 

For CMRI, the dose is divided into two separate, equal injections [see Dosage and Administration (2.2)] .

Refer to Table 1 for volumes to be administered for example body weights.

General

• Gadobutrol Injection is formulated at a higher concentration (1 mmol/mL) compared to certain other gadolinium-based contrast agents, resulting in a lower volume of administration [see Dosage and Administration (2.1)] .
• Gadobutrol Injection is for intravenous use only and must not be administered intrathecally [see Warnings and Precautions (5.1)] .
• Use aseptic technique when preparing and administering Gadobutrol Injection.
• Visually inspect Gadobutrol Injection for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored, if particulate matter is present, or if the container appears damaged.
• If solidification occurs due to cold exposure, bring Gadobutrol Injection to room temperature before use and inspect to ensure that the solution is clear and colorless to pale yellow.
• Do not mix Gadobutrol Injection with other medications and do not administer Gadobutrol Injection in the same intravenous line simultaneously with other medications.

MRI of the CNS in Adult and Pediatric Patients Including Term Neonates

• Administer Gadobutrol Injection as an intravenous injection, manually or by power injector, at a flow rate of approximately 2 mL/sec.
• Follow Gadobutrol Injection with a flush of 0.9% Sodium Chloride Injection to ensure complete administration of the contrast.
• Post contrast MRI can commence immediately following contrast administration.

MRI of the Breast in Adults

• Administer Gadobutrol Injection as an intravenous bolus by power injector, followed by a flush of 0.9% Sodium Chloride Injection to ensure complete administration of the contrast.
• Start image acquisition following Gadobutrol Injection administration and then repeat sequentially to determine peak intensity and wash-out.

MR Angiography in Adult and Pediatric Patients Including Term Neonates

• Image acquisition should coincide with peak arterial concentration, which varies among patients.
• For adults, administer Gadobutrol Injection as an intravenous injection by power injector, at a flow rate of approximately 1.5 mL/sec, followed by a 30 mL flush of 0.9% Sodium Chloride Injection at the same rate to ensure complete administration of the contrast.
• For pediatric patients including term neonates, administer Gadobutrol Injection as an intravenous injection by power injector or manually, followed by a flush of 0.9% Sodium Chloride Injection to ensure complete administration of the contrast.

Cardiac MRI in Adults

• Administer Gadobutrol Injection through a separate intravenous line in the contralateral arm if concomitantly providing a continuous infusion of a pharmacologic stress agent.
• Administer Gadobutrol Injection as two separate bolus injections: 0.05 mmol/kg actual body weight (equivalent to 0.05 mL/kg) at peak pharmacologic stress followed by 0.05 mmol/kg (equivalent to 0.05 mL/kg) at rest.
• Administer Gadobutrol Injection via a power injector at a flow rate of approximately 4 mL/sec and follow each injection with a 20 mL flush of 0.9% Sodium Chloride Injection at the same flow rate.

Single-Dose Vials

• Draw Gadobutrol Injection into the syringe immediately before use.
• Pierce the rubber stopper only once.
• Discard any unused vial contents.

Injection: 1 mmol/mL of gadobutrol as a clear and colorless to pale yellow solution available in the following strengths:

Gadobutrol Injection is contraindicated in patients with history of severe hypersensitivity reactions to Gadobutrol Injection [see Warnings and Precautions (5.3)] .

Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of Gadobutrol Injection have not been established with intrathecal use. Gadobutrol Injection is not approved for intrathecal use [see Dosage and Administration (2.2)] .

GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of Gadobutrol Injection 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/1.73m ²) 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/1.73m ²) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m ²). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following Gadobutrol Injection administration to Zydus Pharmaceuticals (USA) Inc. (1-877-993-8779) 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 administered to a patient. For patients at highest risk for NSF, do not exceed the recommended Gadobutrol Injection dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, 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.

Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, have occurred following Gadobutrol Injection administration [see Adverse Reactions (6.1, 6.2)] . There have been reports of life-threatening and fatal outcomes from these adverse reactions. Most hypersensitivity reactions to Gadobutrol Injection have occurred within half an hour after administration. Delayed reactions can occur up to several days after administration.

• Before Gadobutrol Injection 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 Gadobutrol Injection.
• Gadobutrol Injection is contraindicated in patients with history of hypersensitivity reactions to Gadobutrol Injection [see Contraindications (4)] .
• Administer Gadobutrol Injection only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation.
• Observe patients for signs and symptoms of hypersensitivity reactions during and following Gadobutrol Injection administration.

Acute respiratory distress syndrome (ARDS) has been reported in patients administered Gadobutrol Injection and may be characterized by severe
hypoxemia requiring oxygen support and mechanical ventilation. These manifestations may resemble an immediate hypersensitivity reaction with onset of respiratory distress within <30 minutes to 24 hours after Gadobutrol Injection administration. For patients demonstrating respiratory distress after Gadobutrol Injection administration, assess oxygen requirement and monitor for worsening respiratory function.

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 (for example, 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 retention [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.

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.

Injection site reactions have been reported in clinical studies with Gadobutrol Injection [see Adverse Reactions (6.1)] . Extravasation into tissues during Gadobutrol Injection administration may result in moderate irritation [see Nonclinical Toxicology (13.2)] . Ensure catheter and venous patency before the injection of Gadobutrol Injection.

Gadobutrol Injection MRI of the breast overestimated the histologically confirmed extent of malignancy in the diseased breast in up to 50% of the patients [see Clinical Studies ( 14.2)].

The performance of Gadobutrol Injection MRA for detecting arterial segments with significant stenosis (>50% renal, >70% supra-aortic) has not been shown to exceed 55%. Therefore, a negative MRA study alone should not be used to rule out significant stenosis [see Clinical Studies ( 14.3)].

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)]
• Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.4)]

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 Gadobutrol Injection was evaluated in 7,713 subjects (including 184 pediatric population, ages 0 to 17 years) who received Gadobutrol Injection in clinical trials. Approximately 52% of the subjects were male and the racial and ethnic distribution was 62% White, 28% Asian, 5% Hispanic or Latino, 2.5% Black or African American, and 2.5% other ethnic groups. The average age was 56 years (range from 1 week to 93 years).

Table 2 lists adverse reactions that occurred in ≥ 0.1% subjects who received Gadobutrol Injection.

Adverse reactions that occurred with a frequency of < 0.1% in subjects who received Gadobutrol Injection include: hypersensitivity/anaphylactic reaction, loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold.

Adverse Reactions in Pediatric Patients

The frequency, type, and severity of adverse reactions observed in pediatric patients from the clinical studies were similar to adverse reactions in adults [see Use in Specific Populations (8.4)] .

The following additional adverse reactions have been identified during postmarketing use of Gadobutrol Injection or other GBCAs. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders:Cardiac arrest

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 (5.5)]

Immune System Disorders:Hypersensitivity reactions (anaphylactic shock, circulatory collapse, respiratory arrest, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor).

Renal Disorders:Nephrogenic systemic fibrosis

Respiratory, Thoracic, and Mediastinal Disorders:Acute respiratory distress syndrome, pulmonary edema

Skin Disorders:Gadolinium associated plaques

Risk Summary

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, although teratogenicity was not observed, embryolethality was observed in monkeys, rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 times and above the recommended human dose. Retardation of embryonal development was observed in rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 and 12 times, respectively, the recommended human dose (see  Data) . Because of the potential risks of gadolinium to the fetus, use Gadobutrol Injection 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 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 is 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/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

Embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 8 times the recommended single human dose (based on body surface area); gadobutrol was not maternally toxic or teratogenic at this dose. Embryolethality and retardation of embryonal development also occurred in pregnant rats receiving maternally toxic doses of gadobutrol (≥ 7.5 mmol/kg body weight; equivalent to 12 times the human dose based on body surface area) and in pregnant rabbits (≥ 2.5 mmol/kg body weight; equivalent to 8 times the recommended human dose based on body surface area). In rabbits, this finding occurred without evidence of pronounced maternal toxicity and with minimal placental transfer (0.01% of the administered dose detected in the fetuses). Because pregnant animals received repeated daily doses of Gadobutrol Injection, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.

Risk Summary

There are no data on the presence of gadobutrol 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. Gadobutrol 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 Gadobutrol Injection and any potential adverse effects on the breastfed infant from Gadobutrol Injection or from the underlying maternal condition.

Data

In lactating rats receiving 0.5 mmol/kg of intravenous [ ¹⁵³Gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk within 3 hours after administration, and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine).

The safety and effectiveness of Gadobutrol Injection have been established in pediatric patients, including term neonates, for use with MRI to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the CNS and for use in MRA to evaluate known or suspected supra-aortic or renal artery disease. Use of Gadobutrol Injection for these indications is supported by adequate and well-controlled studies in adults and by additional imaging, pharmacokinetic, and safety data from two studies (i.e., Trials 1 and 2) in a total of 182 pediatric patients aged less than 18 years, including term neonates, with CNS and non-CNS lesions. Trial 1 included 138 patients aged 2 to less than 18 years and Trial 2 included 44 patients aged less than 2 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.3)] .

The safety and effectiveness of Gadobutrol Injection have not been established in preterm neonates for any indication or in pediatric patients of any age for use with MRI to assess the presence and extent of malignant breast disease, or for use in CMRI to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in patients with known or suspected coronary artery disease (CAD).

In clinical studies of Gadobutrol Injection, 1,377 patients were 65 years of age and over, while 104 patients were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences between the elderly 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 gadobutrol is increased compared to patients with normal renal function. This may increase the risk of adverse reactions such as NSF. Prior to administration of Gadobutrol Injection, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. For patients receiving hemodialysis, consider the prompt initiation of hemodialysis following the administration of Gadobutrol Injection in order to enhance elimination of gadobutrol [see Warnings and Precautions (5.2)and Clinical Pharmacology (12.3)] .

In the event of an overdose with Gadobutrol Injection, the substance can be removed by hemodialysis [see Clinical Pharmacology (12.3)] .

For additional overdose management recommendations, consider contacting the Poison Help line at 1-800-222-1222 or consulting a medical toxicologist.

Gadobutrol Injection is a paramagnetic macrocyclic gadolinium-based contrast agent for intravenous use.

The chemical name for gadobutrol is 10–[(1SR,2RS)–2,3–dihydroxy–1–hydroxymethylpropyl]–1,4,7,10–tetraazacyclododecane–1,4,7–triacetic acid, gadolinium complex. Gadobutrol is a water-soluble, hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of 0.006,and has a molecular formula of C ₁₈H ₃₁GdN ₄O ₉and a molecular weight of 604.72.The structural formula of gadobutrol is:

Structural Formula (1)

Gadobutrol Injection is a sterile, clear, colorless to pale yellow solution. Each mL contains 604.72 mg (1 mmol) of gadobutrol (containing 1 mmol of gadolinium) and the following inactive ingredients: 0.513 mg of calcobutrol sodium, 1.211 mg of trometamol, hydrochloric acid (for pH adjustment), and water for injection. Gadobutrol Injection contains no preservatives.

The main physicochemical properties of Gadobutrol Injection are listed in Table 3.

The thermodynamic stability constants for gadobutrol (log Ktherm and log Kcond at pH 7.4) are 21.8 and 15.3, respectively.

Gadobutrol 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.

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

• Differences in proton density
• Differences of the spin-lattice or longitudinal relaxation times (T ₁)
• Differences in the spin-spin or transverse relaxation time (T ₂)

When placed in a magnetic field, gadobutrol shortens the T ₁and T ₂relaxation times in targeted tissues. The extent to which a contrast agent can affect the relaxation rate of tissue water (1/T ₁or 1/T ₂) is termed relaxivity (r ₁or r ₂). The relaxivity of GBCAs is presented in Table 4.

Table 4: Relaxivity (r ₁) of GBCAs in Human Plasma at 1.5 T and 37 °C

Gadolinium-Chelate	r 1(L·mmol -1·s -1)
Gadobenate	6.3
Gadobutrol	5.2
Gadodiamide	4.3
Gadopiclenol	12.8
Gadoterate	3.6
Gadoteridol	4.1
Gadoxetate	6.9

Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Gadobutrol Injection results in half the volume of administration and a more compact contrast bolus injection. At the site of imaging, the relative height and width of the time intensity curve for Gadobutrol Injection varies as a function of imaging location and multiple patient, injection, and device-specific factors.

 After intravenous administration of 0.1 mmol/kg Gadobutrol Injection, average plasma levels of gadobutrol are 0.59 mmol/L at 2 minutes after injection and 0.3 mmol/L at 60 minutes after injection, with an AUC of 1,072 μmol∙h/L. Values for further PK parameters are given in Table 5 below.

Distribution

After intravenous administration, gadobutrol is distributed in the extracellular space. Gadobutrol does not display any particular protein binding. Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.5)] .

Elimination

The average elimination half-life (t _1/2) of gadobutrol is 1.8 hours.

Metabolism

Gadobutrol is not metabolized.

Excretion

Gadobutrol is excreted in an unchanged form through the kidneys by glomerular filtration. In healthy subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(min∙kg) and thus comparable to the renal clearance of inulin.

Within 2 hours after intravenous administration more than 50% and within 12 hours more than 90% of the given dose is eliminated via the urine. Extra-renal elimination is negligible.

Specific Populations

Geriatric Patients

A single intravenous dose of 0.1 mmol/kg Gadobutrol Injection was administered to 15 elderly and 16 non-elderly subjects. AUC was slightly higher (43%) and clearance slightly lower (31%) in elderly subjects as compared to non-elderly subjects [see Use in Specific Populations (8.5)] .

Pediatric Patients

The pharmacokinetics of gadobutrol were evaluated in a total of 173 pediatric patients aged less than 18 years (including term neonates) who received a single intravenous dose of 0.1 mmol/kg of Gadobutrol Injection. Table 5 shows the pharmacokinetic parameters of gadobutrol by age group. The pharmacokinetic profile of gadobutrol in pediatric patients is similar to that in adults, resulting in similar values for AUC, body weight normalized plasma clearance, as well as elimination half-life. Approximately 99% (median value) of the dose was recovered in urine within 6 hours (this information was derived from the 2 to less than 18 year-old age group).

Male and Female Patients

Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol.

Patients with Renal Impairment

In patients with renal impairment, the serum half-life of gadobutrol is prolonged and correlated with the reduction in creatinine clearance.

After intravenous injection of Gadobutrol Injection 0.1 mmol/kg, the elimination half-life was 5.8 ± 2.4 hours in patients with mild to moderate renal impairment (80 > CL _CR> 30 mL/min) and 17.6 ± 6.2 hours in patients with severe renal impairment not on dialysis (CL _CR< 30 mL/min). The average AUC of gadobutrol in patients with normal renal function was 1.1 ± 0.1 mmol∙h/L, compared to 4.0 ± 1.8 mmol∙h/L in patients with mild to moderate renal impairment and 11.5 ± 4.3 mmol∙h/L in patients with severe renal impairment.

Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function about 80% of the administered dose was recovered in the urine within 5 days.

For patients receiving hemodialysis, 68% of gadobutrol is removed from the body after the first dialysis, 94% after the second dialysis, and 98% after the third dialysis session. [see Warnings and Precautions (5.2)and Use in Specific Populations (8.6)] .

Carcinogenesis

No carcinogenicity studies of gadobutrol have been conducted.

Mutagenesis

Gadobutrol was not mutagenic in in vitroreverse mutation tests in bacteria, in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test using cultured Chinese hamster V79 cells, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivomicronucleus test in mice after intravenous injection of 0.5 mmol/kg.

Impairment of Fertility

Gadobutrol had no effect on fertility and general reproductive performance of male and female rats when given in doses 12.2 times the human equivalent dose (based on body surface area).

Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells was observed after paravenous administration to rabbits, suggesting the possibility of occurrence of local irritation if the contrast medium leaks around veins in a clinical setting [see Warnings and Precautions (5.7)].

The effectiveness of Gadobutrol Injection for the visualization of lesions was evaluated in two clinical trials (i.e., Studies 1 and 2) in patients who were referred for MRI of the CNS with contrast. In both studies, patients underwent a baseline, pre-contrast MRI prior to administration of Gadobutrol Injection at a dose of 0.1 mmol/kg, followed by a post-contrast MRI. In Study 1, patients also underwent an MRI before and after the administration of gadoteridol. The studies were designed to demonstrate superiority of Gadobutrol Injection MRI to non-contrast MRI for lesion visualization. For both studies, pre-contrast and pre-plus-post contrast images (paired images) were independently evaluated by three readers for contrast enhancement and border delineation using a scale of 1 to 4, and for internal morphology using a scale of 1 to 3 (Table 6). Lesion counting was also performed to demonstrate non-inferiority of paired Gadobutrol Injection image sets to pre-contrast MRI. Readers were blinded to clinical information.

A total of 657 patients were evaluated. The average age was 49 years (range 18 to 85 years) and 42% were male. The racial and ethnic representations were 39% White, 4% Black or African American, 16% Hispanic or Latino, 38% Asian, and 3% of other ethnic groups.

Table 7 shows a comparison of visualization results between paired images and pre-contrast images. Gadobutrol Injection provided a statistically significant improvement for each of the three lesion visualization parameters when averaged across three independent readers for each study.

Performances of Gadobutrol Injection and gadoteridol for visualization parameters were similar. Regarding the number of lesions detected, Study 2 met the prespecified noninferiority margin of -0.35 for paired read versus pre-contrast read while in Study 1, Gadobutrol Injection and gadoteridol did not.

For the visualization endpoints contrast enhancement, border delineation, and internal morphology, the percentage of patients scoring higher for paired images compared to pre-contrast images ranged from 93% to 99% for Study 1, and 95% to 97% for Study 2. For both studies, the mean number of lesions detected on paired images exceeded that of the pre-contrast images; 37% for Study 1 and 24% for Study 2. There were 29% and 11% of patients in which the pre-contrast images detected more lesions for Study 1 and Study 2, respectively.

The percentage of patients whose average reader mean score changed by ≤0, up to 1, up to 2, and ≥2 scoring categories presented in Table 6 is shown in Table 8. The categorical improvement of (≤0) represents higher (< 0) or identical (= 0) scores for the pre-contrast read, the categories with scores > 0 represent the magnitude of improvement seen for the paired read.

For both studies, the improvement of visualization endpoints in paired Gadobutrol Injection images compared to pre-contrast images resulted in improved assessment of normal and abnormal CNS anatomy.

The effectiveness of Gadobutrol Injection for the ability to assess the presence and extent of malignant breast disease was evaluated in two identical clinical trials (i.e., Studies 3 and 4) in patients with recently diagnosed breast cancer prior to surgery. Patients underwent non-contrast breast MRI (BMR) prior to Gadobutrol Injection (0.1 mmol/kg) breast MRI. BMR images and Gadobutrol Injection BMR (combined contrast plus non-contrast) images were independently evaluated in each study by three readers blinded to clinical information. In separate reading sessions the BMR images and Gadobutrol Injection BMR images were also interpreted together with X-ray mammography images (XRM).

A total of 787 patients were evaluated: Study 3 enrolled 390 female patients with an average age of 56 years and racial distribution of 74% White, 25% Asian, 0.5% Black or African American, and 0.5% other; Study 4 enrolled 396 female patients and 1 male patient with an average age of 57 years and racial distribution of 71% White, 24% Asian, 3% Black or African American, and 2% other.

The readers assessed 5 regions per breast for the presence of malignancy using each reading modality. The readings were compared to an independent standard of truth (SoT) consisting of histopathology for all regions where excisions were made and tissue evaluated. XRM plus ultrasound was used for all other regions.

The assessment of malignant disease was performed using a region based within-subject sensitivity. Sensitivity for each reading modality was defined as the mean of the percentage of malignant breast regions correctly interpreted for each subject. The within-subject sensitivity of Gadobutrol Injection BMR was superior to that of BMR. The lower bound of the 95% Confidence Interval (CI) for the difference in within-subject sensitivity ranged from 19% to 42% for Study 3 and from 12% to 27% for Study 4. The within-subject sensitivity for Gadobutrol Injection BMR and BMR as well as for Gadobutrol Injection BMR plus XRM and BMR plus XRM is presented in Table 9.

Specificity was defined as the percentage of non-malignant breasts correctly identified as non-malignant. The lower limit of the 95% confidence interval for specificity of Gadobutrol Injection BMR was greater than 80% for 5 of 6 readers. (Table 10)

Three additional readers in each study read XRM alone. For these readers over both studies, sensitivity ranged from 68% to 73% and specificity in non-malignant breasts ranged from 86% to 94%.

In breasts with malignancy, a false positive detection rate was calculated as the percentage of subjects for which the readers assessed a region as malignant which could not be verified by SoT. The false positive detection rates for Gadobutrol Injection BMR ranged from 39% to 53% (95% CI Upper Bounds ranged from 44% to 58%).

The effectiveness of Gadobutrol Injection for the ability to evaluate known or suspected supra-aortic or renal artery disease was evaluated in two clinical trials (i.e., Studies 5 and 6). Study 5 enrolled patients with known or suspected disease of the supra-aortic arteries (for evaluation up to but excluding the basilar artery), and Study 6 enrolled patients with known or suspected disease of the renal arteries.. In both studies, non-contrast, 2D time-of-flight (ToF) magnetic resonance angiography (MRA) was performed prior to Gadobutrol Injection MRA using a single intravenous injection of 0.1 mmol/kg. The injection rate of 1.5 mL/second was selected to extend the injection duration to at least half of the imaging duration. Imaging was performed with parallel-channel, 1.5T MRI devices and an automatic bolus tracking technique to trigger the image acquisition following Gadobutrol Injection administration using elliptically encoded, T1-weighted, 3D gradient-echo image acquisition and single breath hold. Three central readers blinded to clinical information interpreted the ToF and Gadobutrol Injection MRA images. Three additional central readers interpreted separately acquired computed tomographic angiography (CTA) images, which were used as the standard of reference (SoR) in each study.

A total of 749 patients were evaluated. The 457 patients in Study 5 had an average age of 68 years (range 25 to 93 years) and were 64% male with a racial distribution of 80% White, 28% Black or African American, and 16% Asian. The 292 patients in Study 6 had an average age of 55 years (range 18 to 88 years) and were 54% male with a racial distribution of 68% White, 7% Black or African American, and 22% Asian.

Efficacy was evaluated based on anatomical visualization and performance for distinguishing between normal and abnormal anatomy. The visualization metric depended on whether readers selected, "Yes, it can be visualized along its entire length..." when responding to the question, "Is this segment assessable?" Twenty-one segments in Study 5 and six segments in Study 6 were presented per subject to each reader. The performance metrics, sensitivity and specificity, depended on digital caliper-based quantitation of arterial narrowing in visualized, non-occluded, abnormal-appearing segments. Significant stenosis was defined as at least 70% in Study 5 and 50% in Study 6. Performance of Gadobutrol Injection MRA compared to ToF MRA was calculated using an imputation method for non-visualized segments by assigning them as a 50% match with SoR and a 50% mismatch. Performance of Gadobutrol Injection MRA compared to a pre-specified threshold of 50% was calculated after excluding non-visualized segments. Measurement variability and visualization of accessory renal arteries was also evaluated.

Results were analyzed for each of the three central readers.

GAD MRA = Post-contrast Gadobutrol Injection Magnetic Resonance Angiography, ToF = Non-contrast 2D-Time of Flight.

For all three supra-aortic artery readers in Study 5, the lower bound of confidence for the sensitivity of Gadobutrol Injection MRA did not exceed 54%. For all three renal artery readers in Study 6, the lower bound of confidence for the sensitivity of Gadobutrol Injection MRA did not exceed 46%.

Measurement Variability

For both MRA and CTA, readers varied in the quantity of narrowing they assigned to the same arterial segments. Table 12 shows the percentage of patients in whom the measurement range was 30% or greater for the left or right internal carotid and proximal renal artery segments. There were approximately four measurements per patient segment, one from the site and three central readers. Measurement variability was high for both CTA and MRA, but numerically lower for Gadobutrol Injection compared to non-contrast ToF MRA.

Visualization of Accessory Renal Arteries for Surgical Planning and Renal Donor Evaluation (Study 6 only)

Of 1,752 main arteries visualized by the central CTA readers, 266 (15%) were also associated with positive visualization of at least one accessory (duplicate) artery. With the central MRA readers, the comparable rates were 232 of 1752 (13%) for Gadobutrol Injection MRA compared to 53 of 1,752 (3%) for ToF MRA.

The effectiveness of Gadobutrol Injection for detection of coronary artery disease (CAD) was evaluated in two multi-center, open-label clinical trials (i.e., Studies 7 and 8) in adult patients with known or suspected CAD. Patients were excluded from study if they had a history of coronary artery bypass grafting, or if it was known in advance that they were unable to hold their breath, or had atrial fibrillation or other arrhythmia likely to prevent electrocardiogram-gated CMRI.

A total of 764 patients were evaluated. The 376 patients in Study 7 had an average age of 59 years (range 20 to 84 years) and were 69% male with a racial distribution of 74% White, 1% Black or African American, and 25% Asian. The 388 patients in Study 8 had an average age of 59 years (range 23 to 82 years) and were 61% male with a racial distribution of 67% White, 17% Black or African American, and 12% Asian.

All subjects underwent dynamic first-pass Gadobutrol Injection imaging during vasodilator stress, followed ~10 minutes later by dynamic first-pass Gadobutrol Injection imaging at rest, followed ~5 minutes later with imaging during a period of gradual Gadobutrol Injection washout from the myocardium (late gadolinium enhancement, LGE). Imaging was performed on 1.5 T or 3.0 T MRI devices equipped with multichannel surface coils to support accelerated acquisitions with parallel imaging, T1-weighted, 2D gradient-echo, dynamic acquisition of perfusion with at least 3 slices per heartbeat. Gadobutrol Injection was administered intravenously at a rate of ~4 mL/second as two separate bolus injections (0.05 mmol/kg each), the first at peak pharmacologic stress (~3 minutes after start of ongoing adenosine infusion, or immediately after completion of regadenoson administration, at approved doses). No additional Gadobutrol Injection was administered for LGE imaging.

Images were read by three independent readers blinded to clinical information. Reader detection of CAD depended on visually detecting defective perfusion or scar on Gadobutrol Injection CMRI (stress, rest, LGE) imaging. Quantitative coronary angiography (QCA) was used to measure intraluminal narrowing and served as the standard of reference (SoR).

Computed tomographic angiography (CTA) was used as the SoR if disease could be unequivocally excluded, and no coronary angiography (CA) was available. The left ventricular myocardium was divided into six regions. Readers provided per-region (CMRI, CTA) and per-artery (QCA) interpretations for each subject. Subject-level endpoints reflected each subject's most abnormal localized finding.

The sensitivity results for Gadobutrol Injection CMRI to detect CAD defined as either maximum stenosis ≥50% or ≥70% by QCA are presented in Table 13. For each reader, sensitivity of Gadobutrol Injection CMRI larger than 60% can be concluded if the lower 95% confidence limit of the sensitivity estimate exceeds the pre-specified threshold of 60%.

The specificity results for Gadobutrol Injection CMRI to detect CAD defined as either maximum stenosis ≥50% or ≥70% by QCA are presented in Table 14. For each reader, specificity of Gadobutrol Injection CMRI larger than 55% can be concluded if the lower 95% confidence limit of the specificity estimate exceeds the pre-specified threshold of 55%.

In Study 7, among the 33 patients with maximum stenosis by QCA between 50% and <70%, the proportion of Gadobutrol Injection- CMRI positive detections of CAD ranged from 15% to 33%. In Study 8, among the 45 patients with maximum stenosis by QCA between 50% and < 70%, the proportion of Gadobutrol Injection-CMRI positive detections of CAD ranged from 20% to 35%. The results of Gadobutrol Injection-CMRI reads to detect CAD in patients with maximum stenosis between 50% and < 70% are summarized in Table 15.

Left Mainstem Stenosis

The studies did not include sufficient numbers of subjects to characterize the performance of Gadobutrol Injection CMRI for detection of left mainstem stenosis (LMS), a subgroup at high risk from false negative reads. In Studies E and F, only three subjects had isolated LMS stenosis >50%. In two of the three cases, the CMRI was interpreted as normal by at least two of the three readers (false negative). Sixteen subjects had LMS stenosis >50% (including subjects with isolated LMS stenosis and subjects with LMS stenosis in addition to stenoses elsewhere). In five of these sixteen cases, the CMR was interpreted as normal by at least two of the three readers (false negative).

How Supplied

Gadobutrol Injection is supplied at a concentration of 1 mmol/mL of gadobutrol as a clear and colorless to pale yellow solution available in the following strengths:

• NDC 42337-005-02: 7.5 mmol/7.5 mL (1 mmol/mL) single-dose vials (42337-005-01) rubber stoppered in cartons of 10.
• NDC 42337-006-02: 10 mmol/10 mL (1 mmol/mL) single-dose vials (42337-006-01) rubber stoppered in cartons of 10.
• NDC 42337-007-02: 15 mmol/15 mL (1 mmol/mL) single-dose vials (42337-007-01) rubber stoppered in cartons of 10.

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].

If solidification occurs due to cold exposure, bring Gadobutrol Injection to room temperature before use and inspect to ensure that the solution is clear and colorless to pale yellow.

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

Nephrogenic Systemic Fibrosis

Inform the patient that Gadobutrol Injection 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 patients to contact their physician if they develop signs or symptoms of NSF following Gadobutrol Injection 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)] .

Acute Respiratory Distress Syndrome

Advise patients that acute respiratory distress syndrome (ARDS) has occurred with Gadobutrol Injection. Inform patients on the symptoms of the observed ARDS cases, and instruct patients to inform their healthcare provider if they experience these symptoms [see Warnings and Precautions (5.4)] .

Gadolinium Retention

Advise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs following Gadobutrol Injection 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 (5.5)] .

Pregnancy

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

Manufactured by:

Viwit Pharmaceutical Co., Ltd.

Zaozhuang, Shandong, China

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

                                                                                                                                                                                 Revised: 05/2026

Gadobutrol Injection 7.5 mL Vial Label

NDC 42337-005-01
7.5 mL

Rx only

Sterile Solution

Gadobutrol Injection

1 mmol/mL

For Intravenous Administration.
Single-Dose Vial.

Discard Unused Portion.

7.5 mL Single-dose Vial Label (Proposed Viwit Vial 7 5ml)

Gadobutrol Injection 10 mL Vial Label

NDC 42337-006-01
10 mL

Rx only

Sterile Solution

Gadobutrol Injection

1 mmol/mL

For Intravenous Administration.
Single-Dose Vial.

Discard Unused Portion.

10 mL Single-dose Vial Label (Proposed Viwit Vial 10ml)

Gadobutrol Injection 15 mL Vial Label

NDC 42337-007-01
15 mL

Rx only

Sterile Solution

Gadobutrol Injection

1 mmol/mL

For Intravenous Administration.
Single-Dose Vial.

Discard Unused Portion.

15 mL Single-dose Vial Label (Proposed Viwit Vial 15ml)

Gadobutrol Injection 7.5 mL Carton Label

NDC 42337-005-02
7.5 mL

Rx only

Sterile Solution

Gadobutrol Injection

1 mmol/mL

For Intravenous Administration.
Single-Dose Vial.

Discard Unused Portion.

7.5 mL Single-dose Carton Label (Proposed Viwit Carton 7 5ml)

Gadobutrol Injection 10 mL Carton Label

NDC 42337-006-02
10 mL

Rx only

Sterile Solution

Gadobutrol Injection

1 mmol/mL

For Intravenous Administration.
Single-Dose Vial.

Discard Unused Portion.

10 mL Single-dose Carton Label (Proposed Viwit Carton 10ml)

Gadobutrol Injection 15 mL Carton Label

NDC 42337-007-02
15 mL

Rx only

Sterile Solution

Gadobutrol Injection

1 mmol/mL

For Intravenous Administration.
Single-Dose Vial.

Discard Unused Portion.

15 mL Single-dose Carton Label (Proposed Viwit Carton 15ml)