gadobutrol

RECENT MAJOR CHANGES Warnings and Precautions, Acute Respiratory Distress Syndrome ( 5.4 ) 3/2025

1 INDICATIONS AND USAGE Gadobutrol injection is a gadolinium-based contrast agent indicated for use with magnetic resonance imaging (MRI): • To detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system in adult and pediatric patients (including term neonates) ( 1.1 ) • To assess the presence and extent of malignant breast disease in adult patients ( 1.2 ) • To evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients (including term neonates) ( 1.3 ) • To assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD). ( 1.4 ). 1.1 Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS) Gadobutrol injection is indicated for use with magnetic resonance imaging (MRI) in adult and pediatric patients, including term neonates, to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system. 1.2 MRI of the Breast Gadobutrol injection is indicated for use with MRI in adult patients to assess the presence and extent of malignant breast disease. 1.3 Magnetic Resonance Angiography (MRA) Gadobutrol injection is indicated for use in magnetic resonance angiography (MRA) in adult and pediatric patients, including term neonates, to evaluate known or suspected supra-aortic or renal artery disease. 1.4 Cardiac MRI Gadobutrol injection is indicated for use in cardiac MRI (CMRI) to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD).

2 DOSAGE AND ADMINISTRATION • Recommended dose for adults and pediatric patients (including term neonates) is 0.1 mL/kg body weight ( 2.1 ) • Administer as an intravenous bolus injection ( 2.2 ) • Follow injection with a normal saline flush ( 2.2 ) 2.1 Recommended Dose The recommended dose of gadobutrol injection for adult and pediatric patients (including term neonates) is 0.1 mL/kg body weight (0.1 mmol/kg). Refer to Table 1 to determine the volume to be administered. Table 1: Volume of Gadobutrol Injection by Body Weight *For Cardiac MRI , the dose is divided into 2 separate, equal injections Body Weight (kg) Volume to be Administered (mL) 2.5 0.25 5 0.5 10 1 15 1.5 20 2 25 2.5 30 3 35 3.5 40 4 45 4.5 50 5 60 6 70 7 80 8 90 9 100 10 110 11 120 12 130 13 140 14 2.2 Administration Guidelines 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. Use Table 1 to determine the volume to be administered. Use sterile technique when preparing and administering gadobutrol injection. MRI of the Central Nervous System • Administer gadobutrol injection as an intravenous injection, manually or by power injector, at a flow rate of approximately 2 mL/second. • Follow gadobutrol injection with flush of 0.9% Sodium Chloride Injection, USP to ensure complete administration of the contrast. • Post contrast MRI can commence immediately following contrast administration. MRI of the Breast • Administer gadobutrol injection as an intravenous bolus by power injector, followed by a flush of 0.9% Sodium Chloride Injection, USP to ensure complete administration of the contrast. • Start image acquisition following contrast administration and then repeat sequentially to determine peak intensity and wash-out. MR Angiography Image acquisition should coincide with peak arterial concentration, which varies among patients. Adults • Administer gadobutrol injection by power injector, at a flow rate of approximately 1.5 mL/second, followed by a 30 mL flush of 0.9% Sodium Chloride Injection, USP at the same rate to ensure complete administration of the contrast. Pediatric patients • Administer gadobutrol injection by power injector or manually, followed by a flush of 0.9% Sodium Chloride Injection, USP to ensure complete administration of the contrast. Cardiac MRI • 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 (2) separate bolus injections: 0.05 mL/kg (0.05 mmol/kg) body weight at peak pharmacologic stress followed by 0.05 mL/kg (0.05 mmol/kg) body weight at rest. • Administer gadobutrol injection via a power injector at a flow rate of approximately 4 mL/second and follow each injection with a flush of 20 mL of 0.9% Sodium Chloride Injection, USP at the same flow rate. 2.3 Drug Handling • 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. • Do not mix gadobutrol injection with other medications and do not administer gadobutrol injection in the same intravenous line simultaneously with other medications because of the potential for chemical incompatibility. • Instructions of the device manufacturer must be followed. 2.4 Imaging Bulk Package Preparation Instructions Gadobutrol injection Imaging Bulk Package (IBP) is a container of a sterile preparation for parenteral use that contains many single doses of gadobutrol for use with a medical imaging device. Gadobutrol injection Imaging Bulk Package is for intravenous use and not for direct infusion. Gadobutrol injection Imaging Bulk Package is for use only with an automated contrast injection system, contrast management system, or contrast media transfer set ap …

3 DOSAGE FORMS AND STRENGTHS Gadobutrol injection is a sterile, clear, and colorless to pale yellow solution for injection containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol gadobutrol/mL) supplied in single-dose vials. Gadobutrol injection contains 604.72 mg gadobutrol/mL (equivalent to 1 mmol gadobutrol/mL) and is available in vials ( 3 )

4 CONTRAINDICATIONS Gadobutrol Injection is contraindicated in patients with history of severe hypersensitivity reactions to Gadobutrol Injection [see Warnings and Precautions (5.3) ] . History of severe hypersensitivity reaction to Gadobutrol Injection ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in labeling: • Nephrogenic Systemic Fibrosis (NSF) [see Boxed Warning and 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 )] . • Gadolinium Retention [see Warnings and Precautions ( 5.5 )] . Most common adverse reactions (incidence ≥ 0.5%) are headache, nausea, and dizziness ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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 adverse reactions described in this section reflect gadobutrol injection exposure in 7,713 subjects (including 184 pediatric patients, ages 0 to 17 years) with the majority receiving the recommended dose. Approximately 52% of the subjects were male and the ethnic distribution was 62% Caucasian, 28% Asian, 5% Hispanic, 2.5% Black, and 2.5% patients of other ethnic groups. The average age was 56 years (range from 1 week to 93 years). Overall, approximately 4% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after gadobutrol injection administration. Adverse reactions associated with the use of gadobutrol injection were usually mild to moderate in severity and transient in nature. Table 2 lists adverse reactions that occurred in ≥ 0.1% subjects who received gadobutrol injection. Table 2: Adverse Reactions Reaction Rate (%) n=7,713 Headache 1.7 Nausea 1.2 Dizziness 0.5 Dysgeusia 0.4 Feeling Hot 0.4 Injection site reactions 0.4 Vomiting 0.4 Rash (includes generalized, macular, papular, pruritic) 0.3 Erythema 0.2 Paresthesia 0.2 Pruritus (includes generalized) 0.2 Dyspnea 0.1 Urticaria 0.1 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. 6.2 Postmarketing Experience 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 arrest • Nephrogenic Systemic Fibrosis (NSF) • 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) • Respiratory, Thoracic, and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema • General Disorders and Administration Site Conditions: Adverse reactions with variable onset and duration have been reported after GBCA administration These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems . • Skin: Gadolinium associated plaques • Gastrointestinal Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration

8 USE IN SPECIFIC POPULATIONS Pregnancy: Use only if imaging is essential during pregnancy and cannot be delayed. ( 8.1 ) 8.1 Pregnancy Risk Summary GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive (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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA administration. Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, 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. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy. 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. 8.2 Lactation 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 breastfe …

12.1 Mechanism of Action 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 injection shortens the T 1 and T 2 relaxation times. The extent of decrease of T 1 and T 2 relaxation times, and therefore the amount of signal enhancement obtained from gadobutrol injection, is based upon several factors including the concentration of gadobutrol injection in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. At the recommended dose, the T 1 shortening effect is observed with greatest sensitivity in T 1 -weighted magnetic resonance sequences. In T 2 *-weighted sequences the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease.

11 DESCRIPTION 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 18 H 31 GdN 4 O 9 and a molecular weight of 604.72.The structural formula of gadobutrol is: 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. Table 3: Physicochemical Properties of Gadobutrol Injection Parameter Value Density (g/mL at 37°C) 1.3 Osmolarity at 37°C (mOsm/L solution) 1117 Osmolality at 37°C (mOsm/kg H 2 O) 1603 Viscosity at 37°C (mPa·s) 4.96 pH 6.6 to 8 The thermodynamic stability constants for gadobutrol (log Ktherm and log Kcond at pH 7.4) are 21.8 and 15.3, respectively. Structural Formula

10 OVERDOSAGE The maximum dose of gadobutrol injection tested in healthy volunteers, 1.5 mL/kg body weight (1.5 mmol/kg; 15 times the recommended dose), was tolerated in a manner similar to lower doses. Gadobutrol injection can be removed by hemodialysis [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Gadobutrol injection is a sterile, clear and colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol gadobutrol per mL). Gadobutrol injection is supplied in the following Multiple-Dose container sizes: Product Code Unit of Sale Each 287230 NDC 65219-287-30 Packaged in cartons of 10. NDC 65219-287-10 30 mL Imaging Bulk Package with rubber stopper. 287265 NDC 65219-289-65 Packaged in cartons of 10. NDC 65219-289-10 65 mL Imaging Bulk Package with rubber stopper. 16.2 Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Should freezing occur, gadobutrol injection should be brought to room temperature before use. If allowed to stand at room temperature, gadobutrol injection should return to a clear and colorless to pale yellow solution. 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.

16.1 How Supplied Gadobutrol injection is a sterile, clear and colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol gadobutrol per mL). Gadobutrol injection is supplied in the following Multiple-Dose container sizes: Product Code Unit of Sale Each 287230 NDC 65219-287-30 Packaged in cartons of 10. NDC 65219-287-10 30 mL Imaging Bulk Package with rubber stopper. 287265 NDC 65219-289-65 Packaged in cartons of 10. NDC 65219-289-10 65 mL Imaging Bulk Package with rubber stopper.