Gadobutrol

FDA Drug Information • Also known as: Gadavist, Gadobutrol

Brand Names: Gadavist, Gadobutrol
Drug Class: Gadolinium-based Contrast Agent [EPC]
Route: INTRAVENOUS
Dosage Form: INJECTION
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS Risk Associated with Intrathecal Use Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. GADAVIST 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 GADAVIST 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: Chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ), or 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 GADAVIST 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) ]. WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS See full prescribing information for complete boxed warning. Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. GADAVIST is not approved for intrathecal use. ( 5.1 ) GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GADAVIST in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. The risk for NSF appears highest among patients with: Chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ), or 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. ( 5.2 )

Description

11 DESCRIPTION GADAVIST (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: GADAVIST 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. GADAVIST contains no preservatives. The main physicochemical properties of GADAVIST are listed in Table 3. Table 3: Physicochemical Properties of GADAVIST 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. Chemical Structure

What Is Gadobutrol Used For?

1 INDICATIONS AND USAGE GADAVIST 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) GADAVIST 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 To assess the presence and extent of malignant breast disease in adult patients To evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients including term neonates To assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD) ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Recommended dose for adults and pediatric patients, including term neonates, is 0.1 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered by intravenous bolus injection. ( 2.1 , 2.2 ) See Full Prescribing Information for administration, imaging, and handling. ( 2.2 , 2.3 ) 2.1 Recommended Dose The recommended dose of GADAVIST 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. Table 1: Volume of GADAVIST for Example Body Weights 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 and Imaging Instructions General GADAVIST 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) ]. GADAVIST is for intravenous use only and must not be administered intrathecally [see Warnings and Precautions (5.1) ] . Use aseptic technique when preparing and administering GADAVIST. Visually inspect GADAVIST 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 GADAVIST to room temperature before use and inspect to ensure that the solution is clear and colorless to pale yellow. Do not mix GADAVIST with other medications and do not administer GADAVIST in the same intravenous line simultaneously with other medications. MRI of the CNS in Adult and Pediatric Patients Including Term Neonates Administer GADAVIST as an intravenous injection, manually or by power injector, at a flow rate of approximately 2 mL/sec. Follow GADAVIST 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 GADAVIST 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 GADAVIST 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 GADAVIST 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...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS 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) ] Most common adverse reactions (incidence ≥ 0.5%) are headache, nausea, and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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 GADAVIST was evaluated in 7,713 subjects (including 184 pediatric population, ages 0 to 17 years) who received GADAVIST 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 GADAVIST. Table 2: Adverse Reactions Reported in ≥0.1% Subjects who Received GADAVIST in Clinical Trials Adverse Reaction GADAVIST n=7,713 Rate (%) 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 GADAVIST 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 [ s ee Use in Specific Populations (8.4) ] . 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of GADAVIST 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

Contraindications

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

Pregnancy and Breastfeeding

8.1 Pregnancy 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 GADAVIST 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...

Overdosage

10 OVERDOSAGE In the event of an overdose with GADAVIST, 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied GADAVIST (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: 30 mmol/30 mL (1 mmol/mL) in pharmacy bulk package, rubber stoppered in boxes of 2 cartons containing 5 bottles each (10 total) (NDC 50419-325-14) 65 mmol/65 mL (1 mmol/mL) in pharmacy bulk package, rubber stoppered, in boxes of 10 bottles (NDC 50419-325-15) 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 GADAVIST to room temperature before use and inspect to ensure that the solution is clear and colorless to pale yellow.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.