Clariscan

• RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS 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.
• Clariscan 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 Clariscan 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/1.73 m 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 ).
• Risk Associated with Intrathecal Use Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures.
• Clariscan 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 Clariscan 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/1.73 m 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 (e.g., age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.2) .
• For patients at highest risk for NSF,
• do not exceed the recommended Clariscan 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) ].

History of clinically important hypersensitivity reactions to Clariscan [see Warnings and Precautions (5.3) ]. Clinically important hypersensitivity reactions to Clariscan. ( 4 )

• Hypersensitivity Reactions:
• Anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred.
• Monitor patients closely for need of emergency cardiorespiratory support.
• ( 5.3 ) Gadolinium Retention:
• Gadolinium is retained for months or years in brain, bone, and other organs.
• ( 5.4 )
• 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 Clariscan have not been established with intrathecal use.
• Clariscan is not approved for intrathecal use [see Dosage and Administration (2.1) ].
• 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 Clariscan 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/1.73 m 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/1.73 m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73 m 2 ).
• Report any diagnosis of NSF following Clariscan administration to GE HealthCare at (1-800-654-0118) or FDA at (1-800-FDA-1088 or www.fda.gov/medwatch).
• 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 (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.
• The factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA, and the degree of renal impairment at the time of exposure.
• Record the specific GBCA and the dose administered to a patient.
• do not exceed the recommended Clariscan dose and allow a sufficient period of time for elimination of the drug prior to re-administration.
• For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination.
• The usefulness of hemodialysis in the prevention of NSF is unknown [see Dosage and Administration (2) and Clinical Pharmacology (12) ].
• 5.3 Hypersensitivity Reactions Anaphylactic and anaphylactoid reactions have been reported with gadoterate meglumine, involving cardiovascular, respiratory, and/or cutaneous manifestations.
• Some patients experienced circulatory collapse and died.
• In most cases, initial symptoms occurred within minutes of gadoterate meglumine administration and resolved with prompt emergency treatment [see Adverse Reactions (6) ].
• Before Clariscan 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 Clariscan.
• Administer Clariscan only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation.
• During and following Clariscan administration, observe patients for signs and symptoms of hypersensitivity reactions.
• 5.4 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 (e.g., 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 [Clariscan (gadoterate meglumine), Dotarem (gadoterate meglumine), Gadavist (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 [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.
• 5.5 Acute Kidney Injury In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs.
• The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging.
• Screen all patients for renal impairment by obtaining a history and/or laboratory tests.
• Consider follow-up renal function assessments for patients with a history of renal dysfunction.
• 5.6 Extravasation and Injection Site Reactions Ensure catheter and venous patency before the injection of Clariscan.
• Extravasation into tissues during Clariscan administration may result in tissue irritation [see Nonclinical Toxicology (13.2) ].

• Risk Summary GBCAs cross the human 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, there were no adverse developmental effects observed in rats or rabbits with intravenous administration of gadoterate meglumine during organogenesis at doses of 16 and 10 times, respectively, the recommended human dose (see Data ) .
• Because of the potential risks of gadolinium to the fetus, use Clariscan 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(s) are 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 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 material 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 Gadoterate meglumine was administered in intravenous doses of 0, 2, 4 and 10 mmol/kg/day [3, 7 and 16 times the recommended human dose (RHD) based on body surface area (BSA)] to female rats for 14 days before mating, throughout the mating period and until gestation day (GD) 17.
• Pregnant rabbits were administered gadoterate meglumine in intravenous doses of 0, 1, 3 and 7 mmol/kg/day (3, 10 and 23 times the RHD based on BSA) from GD6 to GD19.
• No effects on embryo-fetal development were observed at doses up to 10 mmol/kg/day in rats and 3 mmol/kg/day in rabbits.
• Maternal toxicity was observed in rats at 10 mmol/kg/day and in rabbits at 7 mmol/kg/day.
• This maternal toxicity was characterized in rats by a slightly lower litter size and gravid uterus weight compared to the control group, and in rabbits by a reduction in body weight and food consumption.
• 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 human 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, there were no adverse developmental effects observed in rats or rabbits with intravenous administration of gadoterate meglumine during organogenesis at doses of 16 and 10 times, respectively, the recommended human dose (see Data ) .
• Because of the potential risks of gadolinium to the fetus, use Clariscan 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(s) are 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 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 material 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 Gadoterate meglumine was administered in intravenous doses of 0, 2, 4 and 10 mmol/kg/day [3, 7 and 16 times the recommended human dose (RHD) based on body surface area (BSA)] to female rats for 14 days before mating, throughout the mating period and until gestation day (GD) 17.
• Pregnant rabbits were administered gadoterate meglumine in intravenous doses of 0, 1, 3 and 7 mmol/kg/day (3, 10 and 23 times the RHD based on BSA) from GD6 to GD19.
• No effects on embryo-fetal development were observed at doses up to 10 mmol/kg/day in rats and 3 mmol/kg/day in rabbits.
• Maternal toxicity was observed in rats at 10 mmol/kg/day and in rabbits at 7 mmol/kg/day.
• This maternal toxicity was characterized in rats by a slightly lower litter size and gravid uterus weight compared to the control group, and in rabbits by a reduction in body weight and food consumption.
• 8.2 Lactation Risk Summary There are no data on the presence of gadoterate 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.
• Additionally, there is limited GBCA gastrointestinal absorption in the breastfed infant.
• Gadoterate is present in goat milk ( see Data ).
• The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Clariscan and any potential adverse effects on the breastfed infant from Clariscan or from the underlying maternal condition.
• Data Nonclinical data demonstrate that gadoterate is detected in goat milk in amounts of < 0.1% of the dose intravenously administered.
• Furthermore, in rats, absorption of gadoterate via the gastrointestinal tract is poor (1.2% of the administered dose was absorbed and eliminated in urine).
• 8.4 Pediatric Use The safety and efficacy of gadoterate meglumine at a single dose of 0.1 mmol/kg have been established in pediatric patients from birth (term neonates ≥ 37 weeks gestational age) to 17 years of age based on clinical data in 133 pediatric patients 2 years of age and older, and clinical data in 52 pediatric patients birth to less than 2 years of age that supported extrapolation from adult data [see Clinical Studies (14) ] .
• Adverse reactions in pediatric patients were similar to those reported in
• adults [see Adverse Reactions (6.1) ] .
• No dose adjustment according to age is necessary in pediatric patients [see Dosage and Administration (2.1) , Pharmacokinetics (12.3) ] .
• The safety of gadoterate meglumine has not been established in preterm neonates.
• No cases of NSF associated with gadoterate meglumine or any other GBCA have been identified in pediatric patients age 6 years and younger [see Warnings and Precautions (5.2) ] .
• Normal estimated GFR (eGFR) is approximately 30 mL/minute/1.73 m 2 at birth and increases to adult values by 2 years of age.
• Juvenile Animal Data Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants.
• 8.5 Geriatric Use In clinical studies of gadoterate meglumine, 900 patients were 65 years of age and over, and 304 patients were 75 years of age and over.
• No overall differences in safety or efficacy were observed between these subjects and younger subjects.
• In general, use of Clariscan in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy.
• No age-related dosage adjustment is necessary.
• 8.6 Renal Impairment No Clariscan dosage adjustment is recommended for patients with renal impairment.
• Gadoterate can be removed from the body by hemodialysis [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ].

Gadoterate does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Specific drug interaction studies with gadoterate meglumine have not been conducted.

• Clariscan administered to healthy volunteers and to adult patients at cumulative doses up to 0.3 mmol/kg was tolerated in a manner similar to lower doses.
• Adverse reactions to overdosage with gadoterate meglumine have not been reported.
• Gadoterate can be removed from the body by hemodialysis [see Clinical Pharmacology (12.3) ].