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    MRI Agents

    BOXED WARNING

    Diabetes mellitus, dialysis, geriatric, hypertension, nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy), renal disease, renal failure, renal impairment

    Serious adverse reactions, including nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) (NSF/NFD), have been reported in patients with renal impairment after receiving gadolinium-based contrast agents (GBCAs), such as gadobutrol. NSF may result in fatal or debilitating systemic fibrosis affecting the internal organs, muscle, and skin. Patients at highest risk for NSF are those with chronic, severe renal disease or renal failure (glomerular filtration rate, GFR < 30 mL/min/1.73m2) and patients with acute renal injury. Avoid use of GBCAs in patients with impaired drug elimination unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. Use of higher than recommended doses or repeated administration may increase the risk for NSF; therefore, administer the lowest dose necessary for adequate imaging and, if needed, only repeat the dose after a sufficient period of time has passed for elimination of the agent from the body. Gadobutrol is removed by hemodialysis. For patients receiving hemodialysis, it may be prudent to dialyze patients after receiving the contrast agents, although a relationship between dialysis and prevention of NSF has not been determined. Of note, hemodialysis is the preferred method of dialysis as continuous ambulatory peritoneal dialysis does not appear to be as effective in eliminating GBCAs. All patients should be screened for evidence of renal dysfunction by obtaining a medical history and/or laboratory results prior to the administration of GBCAs. Acute renal injury occurs commonly after surgery, severe infection, injury, or drug-induced renal toxicity. In patients with acute renal injury, serum creatinine concentrations and estimated GFR may not reliably assess renal function; therefore, obtaining a medical history in these patients is of utmost importance. For patients at risk of chronic renal disease (e.g., patients with hypertension, diabetes mellitus, or geriatric patients [> 60 years of age]), estimate the GFR through laboratory testing. Counsel patients on the signs and symptoms of NSF/NFD. Report possible cases of NSF to the FDA through the FDA Medwatch program at 800-FDA-1088 and to the manufacturer at 888—842—2937.

    DEA CLASS

    Rx

    DESCRIPTION

    Paramagnetic gadolinium-based contrast agent
    For use during MRI of the central nervous system vasculature and to identify malignant breast disease; also used in MRA to evaluate known or suspected supra-aortic or renal artery disease
    May be associated with nephrogenic systemic fibrosis

    COMMON BRAND NAMES

    Gadavist

    HOW SUPPLIED

    Gadavist Intravenous Inj Sol: 1mMole, 1mL

    DOSAGE & INDICATIONS

    For use with magnetic resonance imaging (MRI) to enhance visualization of abnormal vascularity within the central nervous system (CNS), detect blood-brain barrier disruptions, and assess the presence and/or extent of malignant breast disease.
    For MRI of the CNS.
    Intravenous dosage
    Adults

    0.1 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection manually or by power injector at a rate of approximately 2 mL/second. Imaging may begin immediately after administration. The manufacturer provides weight-based dose volumes as follow: 35 kg: 3.5 mL; 40 kg: 4 mL; 45 kg: 4.5 mL; 50 kg: 5 mL; 60 kg: 6 mL; 70 kg: 7 mL; 80 kg: 8 mL; 90 kg: 9 mL; 100 kg: 10 mL; 110 kg: 11 mL; 120 kg: 12 mL; 130 kg: 13 mL; 140 kg: 14 mL.

    Neonates, Infants, Children, and Adolescents

    0.1 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection manually. Imaging may begin immediately after administration. The manufacturer provides weight-based dose volumes as follow: 2.5 kg: 0.25 mL; 5 kg: 0.5 mL; 10 kg: 1 mL; 15 kg: 1.5 mL; 20 kg: 2 mL; 25 kg: 2.5 mL; 30 kg: 3 mL; 35 kg: 3.5 mL; 40 kg: 4 mL; 45 kg: 4.5 mL; 50 kg: 5 mL; 60 kg: 6 mL; 70 kg: 7 mL; 80 kg: 8 mL; 90 kg: 9 mL; 100 kg: 10 mL; 110 kg: 11 mL; 120 kg: 12 mL; 130 kg: 13 mL; 140 kg: 14 mL.

    For MRI of the breast.
    Intravenous dosage
    Adults

    0.1 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection by power injector. Imaging may begin after administration and then repeat sequentially to determine peak intensity and wash-out. The manufacturer provides weight-based dose volumes as follow: 35 kg: 3.5 mL; 40 kg: 4 mL; 45 kg: 4.5 mL; 50 kg: 5 mL; 60 kg: 6 mL; 70 kg: 7 mL; 80 kg: 8 mL; 90 kg: 9 mL; 100 kg: 10 mL; 110 kg: 11 mL; 120 kg: 12 mL; 130 kg: 13 mL; 140 kg: 14 mL.

    For use in magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease.
    Intravenous dosage
    Adults

    0.1 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection by power injector at a rate of approximately 1.5 mL/second. Imaging should coincide with peak arterial concentration, which varies among patients. The manufacturer provides weight-based dose volumes as follow: 35 kg: 3.5 mL; 40 kg: 4 mL; 45 kg: 4.5 mL; 50 kg: 5 mL; 60 kg: 6 mL; 70 kg: 7 mL; 80 kg: 8 mL; 90 kg: 9 mL; 100 kg: 10 mL; 110 kg: 11 mL; 120 kg: 12 mL; 130 kg: 13 mL; 140 kg: 14 mL.

    Neonates, Infants, Children, and Adolescents

    0.1 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection by power injector or manually. Imaging should coincide with peak arterial concentration, which varies among patients. The manufacturer provides weight-based dose volumes as follow: 2.5 kg: 0.25 mL; 5 kg: 0.5 mL; 10 kg: 1 mL; 15 kg: 1.5 mL; 20 kg: 2 mL; 25 kg: 2.5 mL; 30 kg: 3 mL; 35 kg: 3.5 mL; 40 kg: 4 mL; 45 kg: 4.5 mL; 50 kg: 5 mL; 60 kg: 6 mL; 70 kg: 7 mL; 80 kg: 8 mL; 90 kg: 9 mL; 100 kg: 10 mL; 110 kg: 11 mL; 120 kg: 12 mL; 130 kg: 13 mL; 140 kg: 14 mL.

    MAXIMUM DOSAGE

    Adults

    0.1 mL/kg (0.1 mmol/kg) IV single dose.

    Geriatric

    0.1 mL/kg (0.1 mmol/kg) IV single dose.

    Adolescents

    0.1 mL/kg (0.1 mmol/kg) IV single dose.

    Children

    0.1 mL/kg (0.1 mmol/kg) IV single dose.

    Infants

    0.1 mL/kg (0.1 mmol/kg) IV single dose.

    Neonates

    0.1 mL/kg (0.1 mmol/kg) IV single dose.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    No dosage adjustments are recommended. Do not exceed the recommended dose and allow sufficient time for elimination prior to any repeat administration. Avoid use in patients with chronic, severe renal disease (GFR < 30 mL/min/1.73m2) and in patients with acute kidney injury unless the diagnostic information is essential and not available with non-contrast imaging or other modalities; these patients are at highest risk for nephrogenic systemic fibrosis.
    Intermittent hemodialysis
    Gadobutrol is removed from the body by hemodialysis. For patients receiving hemodialysis, consider initiating a hemodialysis session after drug administration in order to enhance clearance of the contrast agent.

    ADMINISTRATION

     
    NOTE: Hypersensitivity reactions may occur. Prior to administration, assess all patients for previous reactions to contrast media. Trained personnel and therapies used to treat hypersensitivity reactions (epinephrine, antihistamines, and corticosteroids) should be readily available. Observe patient for signs and symptoms of hypersensitivity reactions during and after administration.

    Injectable Administration

    Visually inspect for particulate matter and discoloration prior to administration. Solution is clear, colorless to pale yellow. Do not use if discolored or if particulate matter is present.
    Do not mix with other medications. Do not administer other medications in the same intravenous line.

    Intravenous Administration

    For single dose vials: Using aseptic technique, draw solution into a sterile syringe. Administer immediately after opening.
    For prefilled syringes: Remove tip cap immediately before administration.
    Ensure catheter and venous patency prior to the injection. Extravasation may result in tissue irritation.
    The product contains no antimicrobial preservatives. Discard any unused product.
     
    MRI of the Central Nervous System
    Administer as an intravenous injection, manually or by power injector, at a flow rate of approximately 2 mL/second.
    Follow with a 0.9% Sodium Chloride Injection flush to ensure complete administration of the contrast.
    Post contrast MRI can begin immediately following contrast administration.
     
    MRI of the Breast
    Administer as an intravenous bolus by power injector.
    Follow with a 0.9% Sodium Chloride Injection flush to ensure complete administration of the contrast.
    Start image acquisition following contrast administration and then repeat sequentially to determine peak intensity and wash-out.
     
    MRA
    Image acquisition should coincide with peak arterial concentration, which varies among patients. 
    Adults: Administer by power injector, at a flow rate of approximately 1.5 mL/second; follow with a 30 mL 0.9% Sodium Chloride Injection flush at the same rate to ensure complete administration of the contrast.
    Pediatrics: Administer by power injector or manually; follow with a 0.9% Sodium Chloride Injection flush to ensure complete administration of the contrast.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Gadavist:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Magnetic resonance imaging (MRI)

    Diagnostic procedures that involve use of contrast agents, such as gadobutrol, should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. As with any paramagnetic contrast agent, use of gadobutrol during contrast enhanced magnetic resonance imaging (MRI) could impair visualization of lesions seen on non-contrast MRI. Caution must be used when contrast-enhanced imaging is interpreted without a companion non-contrast image. Healthcare providers are also advised of the potential for a MRI of the breast to overestimate the degree of malignant disease present; gadobutrol-enhanced MRIs overestimated the histologically confirmed extent of malignant breast disease in up to 50% of patients. Repeated use (4 MRI scans or more) of gadolinium-based contrast agents (GBCA) has resulted in gadolinium deposits in the brain that remain long after drug receipt. No adverse health effects with gadolinium retention in the brain have been identified. Limit use of GBCA to situations in which the information provided is considered necessary, and assess the necessity of repetitive GBCA MRIs.

    Asthma, atopy, radiopaque contrast media hypersensitivity

    Administration of gadobutrol to patients with a history of gadolinium-based radiopaque contrast media hypersensitivity is contraindicated. The drug has been associated with serious, and sometimes fatal, anaphylactoid/anaphylactic reactions involving cardiovascular, respiratory, and/or cutaneous manifestations. In most cases, these reactions developed within 30 minutes of drug administration; however, delayed reactions may occur up to several days after administration. Prior to administration, assess hypersensitivity risk factors in all potential drug recipients. According to the American College of Radiology (ACR), the risk of adverse reactions is approximately 8-times higher in patients with a previous reaction to gadolinium-based contrast media; the subsequent reactions have the potential to be more severe than the first. Other individuals at increased risk include those with a history of asthma, atopy (including hay fever, food allergies, and drug allergies) or other allergic disorders. The manufacturer recommends appropriate facilities (trained personnel and therapies) be available for coping with the emergency treatment of severe reactions, and patients be closely observed for signs and symptoms of a hypersensitivity reaction during and after drug administration. One group of authors recommends taking similar precautions to those that are taken in patients who have previously reacted to iodinated radiopaque contrast media that require subsequent doses. First, the necessity of contrast enhancement during MRI should be determined. If it is determined that contrast enhancement outweighs any potential risk, the intensity of a previous reaction (to either iodinated or gadolinium-based contrast media) should guide precautionary measures. If the previous reaction to contrast media was mild or nonallergic, use of a different or low-osmolar (i.e., gadoteridol or gadodiamide) agent is recommended. If the previous reaction to contrast media was moderate or severe, premedication with steroids (e.g., prednisone or equivalent given 13, 7, and 1 hour prior to the exam; adult dose, 50 mg PO; pediatric dose, 0.5—0.7 mg/kg PO, up to 50 mg) and antihistamines (e.g., diphenhydramine given 1 hour prior to the exam; adult dose 50 mg IV/IM/PO; pediatric dose 1.25 mg/kg PO, up to 50 mg) along with the use of a different or low-osmolar contrast agent is recommended.

    Diabetes mellitus, dialysis, geriatric, hypertension, nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy), renal disease, renal failure, renal impairment

    Serious adverse reactions, including nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) (NSF/NFD), have been reported in patients with renal impairment after receiving gadolinium-based contrast agents (GBCAs), such as gadobutrol. NSF may result in fatal or debilitating systemic fibrosis affecting the internal organs, muscle, and skin. Patients at highest risk for NSF are those with chronic, severe renal disease or renal failure (glomerular filtration rate, GFR < 30 mL/min/1.73m2) and patients with acute renal injury. Avoid use of GBCAs in patients with impaired drug elimination unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. Use of higher than recommended doses or repeated administration may increase the risk for NSF; therefore, administer the lowest dose necessary for adequate imaging and, if needed, only repeat the dose after a sufficient period of time has passed for elimination of the agent from the body. Gadobutrol is removed by hemodialysis. For patients receiving hemodialysis, it may be prudent to dialyze patients after receiving the contrast agents, although a relationship between dialysis and prevention of NSF has not been determined. Of note, hemodialysis is the preferred method of dialysis as continuous ambulatory peritoneal dialysis does not appear to be as effective in eliminating GBCAs. All patients should be screened for evidence of renal dysfunction by obtaining a medical history and/or laboratory results prior to the administration of GBCAs. Acute renal injury occurs commonly after surgery, severe infection, injury, or drug-induced renal toxicity. In patients with acute renal injury, serum creatinine concentrations and estimated GFR may not reliably assess renal function; therefore, obtaining a medical history in these patients is of utmost importance. For patients at risk of chronic renal disease (e.g., patients with hypertension, diabetes mellitus, or geriatric patients [> 60 years of age]), estimate the GFR through laboratory testing. Counsel patients on the signs and symptoms of NSF/NFD. Report possible cases of NSF to the FDA through the FDA Medwatch program at 800-FDA-1088 and to the manufacturer at 888—842—2937.

    Extravasation

    Ensure the patency and integrity of the intravenous line prior to administering gadobutrol. Further, appropriate surveillance of the dosing limb for development of local injection site reactions is recommended. Take care to avoid extravasation as tissue irritation (pain, burning, swelling, blistering, and necrosis) may occur. According to the American College of Radiology (ACR), the risk of significant injury from gadolinium-based contrast agents (GBCA) is extremely low, with GBCAs being much less toxic to the skin/subcutaneous tissue than equal volumes of iodinated contrast media.

    Sickle cell disease

    Deoxygenated sickle erythrocytes have been shown in vitro to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by gadolinium-based contrast agents (GBCAs), such as gadobutrol, may possibly potentiate sickle erythrocyte alignment. Although the use of gadobutrol in patients with sickle cell disease and other hemoglobinopathies has not been studied, the American College of Radiology (ACR) manual on contrast media considers any special risk to sickle cell patients from administration of GBCAs to be extremely low; no restrictions for use of GBCAs are recommended by the ACR.

    Pregnancy

    Data for gadobutrol use in pregnant women to assess the drug-associated risk are unavailable. In animal studies, the drug was not found to be teratogenic; however, at doses of 8- to 12-times the recommended human dose, gadobutrol was lethal to the embryo when administered to pregnant rats, rabbits, and monkeys. The American College of Radiology (ACR) manual on contrast media acknowledges that a standard gadolinium-based contrast agent (GBCA) crosses the primate placenta; however, the risk to the human fetus is unknown. Therefore, the ACR advises against GBCA routine use in pregnant women; GBCA should only be administered during pregnancy if absolutely necessary and only after informed consent is obtained. The Guidelines for Computed Tomography and Magnetic Resonance Imaging in Pregnancy and Lactation state that because of the potential for fetal toxicity, the drug should only be used during pregnancy if deemed absolutely essential.

    Breast-feeding

    It is unknown if gadobutrol is excreted in human milk. An analysis of 18 lactating women receiving 0.1 mmol/kg of another gadolinium-based contrast agent (GBCA) found < 0.04% of the administered gadolinium was excreted into breast milk within 24-hours; for a 70-kg woman, this correlates to < 3 micromol of gadolinium. The overall duration of excretion into breast milk, the extent of oral absorption by the breast-fed infant, and the drug's potential effect on the infant remains unknown. The manufacturer recommends breast-feeding be discontinued prior to gadobutrol administration and not restarted for at least 18 hours following administration. However, the American Academy of Pediatrics (AAP) considers GBCAs compatible with breast-feeding. Additionally, the Guidelines for Computed Tomography and Magnetic Resonance Imaging Use During Pregnancy and Lactation and the American College of Radiology (ACR) manual on contrast media state that lactating women receiving GBCAs can continue to breast-feed without interruption. The reasoning for this recommendation is based on estimates of limited systemic exposure in the breast-fed infant and reviews that conclude maternally administered drug pose no risk to the nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    Aortic stenosis, renal artery stenosis

    Gadobutrol use in magnetic resonance angiography (MRA) has low sensitivity (55% or less) for detecting significant aortic stenosis, defined as more than 70% supra-aortic, or renal artery stenosis, defined as more than 50%. Therefore, a negative MRA study alone should not be used to rule out significant stenosis.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / 0.1-0.1
    nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    cyanosis / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    pulmonary edema / Early / Incidence not known
    cardiac arrest / Early / Incidence not known

    Moderate

    erythema / Early / 0.2-0.2
    dyspnea / Early / 0.1-0.1
    hypotension / Rapid / 0.1-0.1
    sinus tachycardia / Rapid / 0-0.1
    palpitations / Early / 0-0.1
    chest pain (unspecified) / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    hypertension / Early / Incidence not known

    Mild

    headache / Early / 1.5-1.5
    nausea / Early / 1.2-1.2
    dizziness / Early / 0.5-0.5
    injection site reaction / Rapid / 0.4-0.4
    dysgeusia / Early / 0.4-0.4
    vomiting / Early / 0.4-0.4
    rash (unspecified) / Early / 0.3-0.3
    pruritus / Rapid / 0.2-0.2
    urticaria / Rapid / 0.1-0.1
    flushing / Rapid / 0.1-0.1
    malaise / Early / 0-0.1
    tremor / Early / 0-0.1
    paresthesias / Delayed / 0.1-0.1
    parosmia / Delayed / 0-0.1
    xerostomia / Early / 0-0.1
    pallor / Early / Incidence not known
    cough / Delayed / Incidence not known
    sneezing / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir Alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tenofovir Alafenamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.

    PREGNANCY AND LACTATION

    Pregnancy

    Data for gadobutrol use in pregnant women to assess the drug-associated risk are unavailable. In animal studies, the drug was not found to be teratogenic; however, at doses of 8- to 12-times the recommended human dose, gadobutrol was lethal to the embryo when administered to pregnant rats, rabbits, and monkeys. The American College of Radiology (ACR) manual on contrast media acknowledges that a standard gadolinium-based contrast agent (GBCA) crosses the primate placenta; however, the risk to the human fetus is unknown. Therefore, the ACR advises against GBCA routine use in pregnant women; GBCA should only be administered during pregnancy if absolutely necessary and only after informed consent is obtained. The Guidelines for Computed Tomography and Magnetic Resonance Imaging in Pregnancy and Lactation state that because of the potential for fetal toxicity, the drug should only be used during pregnancy if deemed absolutely essential.

    It is unknown if gadobutrol is excreted in human milk. An analysis of 18 lactating women receiving 0.1 mmol/kg of another gadolinium-based contrast agent (GBCA) found < 0.04% of the administered gadolinium was excreted into breast milk within 24-hours; for a 70-kg woman, this correlates to < 3 micromol of gadolinium. The overall duration of excretion into breast milk, the extent of oral absorption by the breast-fed infant, and the drug's potential effect on the infant remains unknown. The manufacturer recommends breast-feeding be discontinued prior to gadobutrol administration and not restarted for at least 18 hours following administration. However, the American Academy of Pediatrics (AAP) considers GBCAs compatible with breast-feeding. Additionally, the Guidelines for Computed Tomography and Magnetic Resonance Imaging Use During Pregnancy and Lactation and the American College of Radiology (ACR) manual on contrast media state that lactating women receiving GBCAs can continue to breast-feed without interruption. The reasoning for this recommendation is based on estimates of limited systemic exposure in the breast-fed infant and reviews that conclude maternally administered drug pose no risk to the nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Gadobutrol, a paramagnetic agent, is used to enhance lesion detection and characterization during magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). In magnetic resonance, the visualization of normal and pathological tissue depends on changes in the radiofrequency signal intensity that occur with: differences in proton density; differences of the spin-lattice or longitudinal relaxation time (T1); and differences in the spin-spin or transverse relaxation time (T2). Gadobutrol causes increased signal intensity by developing a magnetic moment when placed in a magnetic field. This magnetic moment causes the T1 and T2 relaxation times to shorten in target tissues. The extent by which gadobutrol decreases the T1 and T2 relaxation times, and subsequently enhances the signal, depends on the concentration of the drug within the tissue, field strength within the magnetic resonance system, and the relative ratio of T1 and T2. When administered at the manufacturer recommended dose, effects on T1 relaxation time are observed with the greatest sensitivity in T1-weighted magnetic resonance sequences.

    PHARMACOKINETICS

    Gadobutrol is administered intravenously. Following administration, the drug does not bind to any particular plasma protein; it rapidly distributes into the extracellular space. Gadobutrol does not undergo metabolism. It is excreted in the urine, via glomerular filtration, as an unchanged drug. The elimination half-life is approximately 2 hours, with > 90% of the administered dose eliminated within 12 hours.
     
    Affected cytochrome P450 isoenzymes: none