GADOBUTROL: 4,045 Adverse Event Reports & Safety Profile

Gadobutrol injection is a paramagnetic macrocyclic contrast agent administered intravenously for magnetic resonance imaging. 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 has a molecular formula of C 18 H 31 GdN 4 O 9 and a molecular weight of 604.72. Gadobutrol injection is a sterile, clear, colorless to pale yellow solution containing 604.72 mg (1.0 mmol) of gadobutrol per mL as the active ingredient with 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 (1 mmol/mL solution for injection) are listed below: 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. gadob-struc-01.jpg

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).

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 approved or cleared for use with this contrast agent in this Imaging Bulk Package. Please see drug and device labeling for information on devices indicated for use with this Imaging Bulk Package and techniques to help assure safe use. 1.

The

Gadobutrol injection Imaging Bulk Package is to be used only in a room designated for radiological procedures that involve intravascular administration of a contrast agent. 2. Utilize aseptic technique for penetrating the container closure of the Gadobutrol injection Imaging Bulk Package and transferring Gadobutrol injection. 3. The container closure must be penetrated only one time with a suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) approved or cleared for use with this contrast agent in this Imaging Bulk Package. 4. Once the Gadobutrol injection Imaging Bulk Package is punctured, do not remove it from the work area during the entire period of use. Storage temperature of Gadobutrol injection Imaging Bulk Package after the closure has been entered is 20°C to 25°C (68°F to 77°F). 5. A maximum use time of 24 hours from initial puncture is permitted to complete fluid transfer. Discard any unused Gadobutrol injection 24 hours after initial puncture of the Imaging Bulk Package. 6. After the container closure is punctured, if the integrity of the Imaging Bulk Package and the delivery system cannot be assured through direct continuous supervision, the Imaging Bulk Package and all associated disposables for the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) should be discarded.

Gadobutrol injection is contraindicated in patients with history of severe hypersensitivity reactions to gadobutrol injection. History of severe hypersensitivity reaction to gadobutrol injection ( 4 )

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

AND PRECAUTIONS

• Hypersensitivity Reactions: Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have occurred. Monitor patients closely during and after administration of gadobutrol injection. ( 5.3 )
• Acute Respiratory Distress Syndrome: For Patients demonstrating respiratory distress after administration, assess oxygen requirement and monitor for worsening respiratory function. ( 5.4 )
• Gadolinium Retention: Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.5 )

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 Gadobutrol injection have not been established with intrathecal use. Gadobutrol injection is not approved for intrathecal use <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

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 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 &lt; 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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 &gt; 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span>. The usefulness of hemodialysis in the prevention of NSF is unknown <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

5.3 Hypersensitivity Reactions Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following gadobutrol injection administration <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> .

• 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.
• 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. Most hypersensitivity reactions to gadobutrol injection have occurred within half an hour after administration. Delayed reactions can occur up to several days after administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following gadobutrol injection administration.

5.4 Acute Respiratory Distress Syndrome 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 &lt;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.

5.5 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 (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 Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadobutrol injection (gadobutrol), ProHance (gadoteridol)]. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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.

5.6 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.

5.7 Extravasation and Injection Site Reactions Ensure catheter and venous patency before the injection of gadobutrol injection. Extravasation into tissues during gadobutrol injection administration may result in moderate irritation <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.2 )]</span> .

5.8 Overestimation of Extent of Malignant Disease in MRI of the Breast Gadobutrol injection MRI of the breast overestimated the histologically confirmed extent of malignancy in the diseased breast in up to 50% of the patients <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span>.

5.9 Low Sensitivity for Significant Arterial Stenosis The performance of gadobutrol injection MRA for detecting arterial segments with significant stenosis (&gt;50% renal, &gt;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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.3 )]</span>.