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bayer healthcare pharmaceuticals inc. - gadoxetate disodium (unii: hoy74vze0m) (gadolinium cation (3+) - unii:azv954tz9n) - gadoxetate disodium 181.43 mg in 1 ml - eovist is indicated for intravenous use in magnetic resonance imaging (mri) of the liver to detect and characterize lesions in patients with known or suspected focal liver disease. eovist is contraindicated in patients with history of severe hypersensitivity reactions to eovist [see warnings and precautions ( 5.3 )] . gbcas have been shown to 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, no teratogenicity was observed with repeated daily intravenous administration of gadoxetate disodium to rats during organogenesis at doses up to 32 times the recommended single human dose; however, an increase in preimplantation loss was noted at doses 3.2 times the single human dose. post implantation loss was observed with repeated daily intravenous administration of gadoxetate disodium to rabbits on gestation days 6 through 18 at doses 26 times the recommended single human dose (see data) . because of the potential risks of gadolinium to the fetus, use eovist only if imaging is essential during pregnancy and cannot be delayed. the background risk in the u.s. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. 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 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, 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. animal reproductive and developmental toxicity studies were done in rats and rabbits. gadoxetate disodium was not teratogenic when given intravenously during organogenesis to pregnant rats at doses up to 32 times the recommended single human dose (mmol/m2 basis). however, an increase in preimplantation loss was noted at 3.2 times the human dose (mmol/m2 basis). compared to untreated controls, rates of postimplantation loss and absorption increased and litter size decreased when pregnant rabbits received gadoxetate disodium at doses 26 times the recommended human single dose (mmol/m2 basis). this occurred without evidence of maternal toxicity. because pregnant animals received repeated daily doses of gadoxetate disodium, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans. risk summary there is no information regarding the presence of gadoxetate disodium in human milk, the effects of the drug in a breastfed infant, or the effects of the drug on milk production. however, published lactation data on other gbcas report 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 breastfed infant. in rat lactation studies with [153 gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the nursing pup. clinical considerations a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for up to 10 hours after eovist administration in order to minimize exposure to a breastfed infant. data animal data in lactating rats given 0.1 mmol/kg [153 gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the neonates via maternal milk, mostly within 2 hours. adequate and well-controlled studies of eovist in pediatric patients have not been conducted. an observational study with eovist was performed in 52 patients (aged > 2 months and < 18 years) referred for evaluation of suspected or known focal liver lesions. eovist improved border delineation and increased contrast of the primary lesion in the majority of patients when compared to non-contrast images. no safety issues were identified. no dose adjustment according to age is necessary in pediatric patients. the safety and effectiveness of eovist have not been established in premature infants. nsf risk no case of nsf associated with eovist or any other gbca has been identified in pediatric patients ages 6 years and younger. 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. in clinical studies of eovist, 674 (34%) patients were 65 years of age and over, while 20 (1%) were 80 years of age and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, use of eovist in an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. in a clinical pharmacology study, slight to moderate differences in pharmacokinetic parameters of gadoxetate disodium (increased auc and terminal half-life, decreased total clearance) were found in a group of geriatric volunteers in comparison to non-geriatric volunteers. no clinically relevant differences in liver contrast enhancement were found. in a clinical pharmacology study in a group of patients with moderate renal impairment, a moderate increase in auc and terminal half-life was observed in comparison to healthy volunteers with normal renal function. hepatic contrast did not differ among the groups. end-stage renal failure may impair eovist imaging performance [see warnings and precautions (5.6)]. in a study of patients with end-stage renal failure, the terminal half-life was prolonged about 12-fold and the auc was increased about 6-fold. hepatic contrast was markedly reduced in these patients, which was attributed to significantly elevated serum ferritin levels [see warnings and precautions ( 5.2 )] . approximately 30% of the injected dose was removed by dialysis in a single 3-hour dialysis session, which started one hour after an eovist dose. eovist was almost completely eliminated via dialysis and biliary excretion within the observation period of 6 days, predominantly within the first 3 days. in a clinical pharmacology study in groups of patients with mild or moderate hepatic impairment, a slight to moderate increase in plasma auc, half-life and urinary excretion, as well as decrease in hepatobiliary excretion was observed in comparison to healthy subjects with normal liver function. hepatic contrast signal did not differ among the groups. severe hepatic impairment may impair eovist imaging performance [see warnings and precautions (5.6)] . in patients with severe hepatic impairment, especially in patients with abnormally high (> 3 mg/dl) serum bilirubin levels, the auc was increased up to 60% and the elimination half-life was increased up to 49%. the hepatobiliary excretion substantially decreased to about 5% of the administered dose and reduced hepatic contrast signal was observed. a dose adjustment is not necessary for patients with hepatic impairment. in clinical studies, 489 patients had a diagnosis of liver cirrhosis (child-pugh category a, n = 270; category b, n = 98; category c, n = 24; unknown category, n = 97). no difference in diagnostic performance and safety was observed among these patients.

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bayer healthcare pharmaceuticals inc. - gadobutrol (unii: 1bj477io2l) (gadolinium cation (3+) - unii:azv954tz9n) - gadobutrol 604.72 mg in 1 ml - gadavist 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. gadavist is indicated for use with mri in adult patients to assess the presence and extent of malignant breast disease. gadavist 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 . gadavist 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). gadavist is contraindicated in patients with history of severe hypersensitivity reactions to gadavist. 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 gadavist 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. 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. 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. 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 gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans 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 breastfeeding should be considered along with the mother’s clinical need for gadavist and any potential adverse effects on the breastfed infant from gadavist or from the underlying maternal condition. in lactating rats receiving 0.5 mmol/kg of intravenous [153 gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk within 3 hours after administration, and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine). the safety and effectiveness of gadavist have been established in pediatric patients, including term neonates, for use with mri to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system and for use in mra to evaluate known or suspected supra-aortic or renal artery disease. use of gadavist in these indications is supported by adequate and well-controlled studies in adults and supportive imaging data in two studies in 135 patients 2 to less than 18 years of age and 44 patients less than 2 years of age with cns and non-cns lesions, and pharmacokinetic data in 130 patients 2 to less than 18 years of age and 43 patients less than 2 years of age, including term neonates [see clinical pharmacology (12.3) and clinical studies (14.1) ]. the frequency, type, and severity of adverse reactions in pediatric patients were similar to adverse reactions in adults [see adverse reactions (6.1)] . no dose adjustment according to age is necessary in pediatric patients [see dosage and administration (2.1), clinical pharmacology (12.3), and clinical studies (14.1)] . the safety and effectiveness of gadavist have not been established in preterm neonates for any indication or in pediatric patients of any age for use with mri to assess the presence and extent of malignant breast disease, or for use in cmri to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in patients with known or suspected coronary artery disease (cad). no case of nsf associated with gadavist or any other gbca has been identified in pediatric patients ages 6 years and younger. pharmacokinetic studies suggest that clearance of gadavist is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. no increased risk factor for nsf has been identified in juvenile animal studies of gadobutrol. normal estimated gfr (egfr) is around 30 ml/min/1.73m2 at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum egfr: 31 ml/min/1.73m2 (age 2 to 7 days), 38 ml/min/1.73m2 (age 8 to 28 days), 62 ml/min/1.73m2 (age 1 to 6 months), and 83 ml/min/1.73m2 (age 6 to 12 months). 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. in clinical studies of gadavist, 1,377 patients were 65 years of age and over, while 104 patients  were 80 years of age and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, use of gadavist in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. no dose adjustment according to age is necessary in this population. prior to administration of gadavist, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests [see warnings and precautions (5.2)] . no dosage adjustment is recommended for patients with renal impairment. gadavist can be removed from the body by hemodialysis [see warnings and precautions (5.2) and clinical pharmacology (12.3)] .

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bracco diagnostics inc - gadobenate dimeglumine (unii: 3q6ppc19po) (gadolinium cation (3+) - unii:azv954tz9n) - gadobenate dimeglumine 529 mg in 1 ml - multihance is indicated for intravenous use in magnetic resonance imaging (mri) of the central nervous system (cns) in adults and pediatric patients (including term neonates), to visualize lesions with abnormal blood-brain barrier or abnormal vascularity of the brain, spine, and associated tissues. multihance is indicated for use in magnetic resonance angiography (mra) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease. multihance is contraindicated in patients with known allergic or hypersensitivity reactions to gadolinium-based contrast agents [see warnings and precautions (5.3)] . 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, gadobenate dimeglumine has been shown to be teratogenic in rabbits following repeated intravenous administration during organogenesis at doses up to 6 times the recommended human dose. there were no adverse developmental effects observed in rats with intravenous administration of gadobenate dimeglumine during organogenesis at doses up to three times the recommended human dose (see data) . because of the potential risks of gadolinium to the fetus, use multihance only if imaging is essential and cannot be delayed. the estimated 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 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 gadobenate dimeglumine has been shown to be teratogenic in rabbits when administered intravenously at 2 mmol/kg/day (6 times the recommended human dose based on body surface area) during organogenesis (day 6 to 18) inducing microphthalmia/small eye and/or focal retinal fold in 3 fetuses from 3 separate litters. in addition, multihance administered intravenously at 3 mmol/kg/day (10 times the recommended human dose based on body surface area) has been shown to increase intrauterine deaths in rabbits. there was no evidence that multihance induced teratogenic effects in rats at doses up to 2 mmol/kg/day (3 times the recommended human dose based on body surface area), however, rat dams exhibited no systemic toxicity at this dose. there were no adverse effects on the birth, survival, growth, development and fertility of the f1 generation at doses up to 2 mmol/kg in a rat peri- and post-natal (segment iii) study. risk summary limited literature reports that breastfeeding after gadobenate dimeglumine administration to the mother would result in the infant receiving an oral dose of 0.001%-0.04% of the maternal dose. there is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. additionally, there is limited gbca gastrointestinal absorption. the developmental and health benefits of breastfeeding should be considered together with the mother’s clinical need for multihance and any potential adverse effects on the breastfed infant from multihance or from the underlying maternal condition. multihance is approved for intravenous use for mri of the cns to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine, and associated tissues in pediatric patients from birth, including term neonates, to less than 17 years of age. pediatric use is based on evidence of effectiveness in adults and in 202 pediatric patients 2 years of age and older, in addition to experience in 105 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 two years of age and older. for pediatric patients, less than 2 years of age, the recommended dosage range is 0.1 to 0.2 ml/kg [see dosage and administration (2.1), pharmacokinetics (12.3)] . the safety of multihance has not been established in preterm neonates. of the total number of 4967 adult subjects in clinical studies of multihance, 33% were 65 or older. no overall differences in safety or effectiveness were observed between these elderly subjects and the younger subjects. the drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to multihance may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function it may be useful to monitor renal function.

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bracco diagnostics inc - gadoteridol (unii: 0199mv609f) (gadoteridol - unii:0199mv609f) - gadoteridol 279.3 mg in 1 ml - prohance is indicated for magnetic resonance imaging (mri) in adults and pediatric patients including term neonates to visualize lesions with disrupted blood brain barrier and/or abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. prohance is indicated for mri in adults to visualize lesions in the head and neck. prohance is contraindicated in patients with known allergic or hypersensitivity reactions to prohance [see warnings and precautions (5.3)]. 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) . because of the potential risks of gadolinium to the fetus, use prohance only if imaging is essential during pregnancy and cannot be delayed. in animal reproduction studies in rats, gadoteridol doubled the incidence of post-implantation loss at up to 16 times the recommended human dose (rhd). there were no adverse developmental effects observed in rabbits with intravenous administration of gadoteridol during organogenesis at doses up to 19 times the recommended human dose of 0.1 mmol/kg (see data) . the estimated 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 contrast agent 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. 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 gadoteridol was administered in intravenous doses of 0, 0.375, 1.5, 6.0, and 10 mmol/kg/day [0.6, 2.4, 9.7, and 16 times the recommended human dose (rhd) based on body surface area (bsa)] to female rats from gestational day (gd)6 until gd17. gadoteridol at 10 mmol/kg/day for 12 days during gestation doubled the incidence of post-implantation loss. when rats were administered 6.0 or 10.0 mmol/kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. pregnant rabbits were administered gadoteridol in intravenous doses of 0, 0.4, 1.5, and 6 mmol/kg/day (1.3, 4.8, and 19.4 times the rhd based on bsa) from gd6 to gd18. gadoteridol increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/kg/day for 13 days during gestation. risk summary there are no data on the presence of gadoteridol 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. gadoteridol is present in rat milk (see data). the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for prohance and any potential adverse effects on the breastfed infant from prohance or from the underlying maternal condition. data prohance excretion in the milk of lactating rats was evaluated at 30 minutes, 6 and 24 hours after intravenous administration of 0.1 mmol/kg of 153 gd-gadoteridol to nursing mothers. small amounts of compound were found in milk immediately after injection (0.14% of the id), with the amount declining to a low level 24 hours after injection (<0.01% of the id). the safety and effectiveness of prohance have been established for use with mri to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine, and associated tissues in pediatric patients from birth, including term neonates, to 17 years of age. pediatric use is based on evidence of effectiveness in adults and in 103 pediatric patients 2 years of age and older, in addition to experience in 125 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)] . the safety and efficacy of > 0.1 mmol/kg, and sequential and/or repeat procedures have not been studied in pediatric patients [see indications and usage (1) and dosage and administration (2)] . no case of nsf associated with prohance or any other gbca has been identified in pediatric patients ages 6 years and younger. pharmacokinetic studies suggest that weight normalized clearance of prohance is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. normal estimated gfr (egfr) is around 30 ml/min/1.73m2 at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum egrf; 59.37 ml/min/1.73m2 (age just after birth to < 30 days), 118.84 ml/min/1.73m2 (age 30 days to < 6 months), 140.44 ml/min/1.73m2 (age 6 to 12 months). of the total number of 2673 adult subjects in clinical studies of prohance, 22% were 65 and over. no overall differences in safety were observed between these elderly subjects and the younger subjects. prohance is known to be substantially excreted by the kidneys, and the risk of toxic reactions from prohance may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. no prohance dosage adjustment is recommended for patients with renal impairment. gadoteridol can be removed from the body by hemodialysis [see warning and precautions (5.2) and clinical pharmacology (12.3)] .

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guerbet llc - gadoterate meglumine (unii: l0nd3981ag) (gadolinium cation (3+) - unii:azv954tz9n) - gadolinium cation (3+) 376.9 mg in 1 ml - dotarem is a gadolinium-based contrast agent indicated for intravenous use with magnetic resonance imaging (mri) in brain (intracranial), spine and associated tissues in adult and pediatric patients (including term neonates) to detect and visualize areas with disruption of the blood brain barrier (bbb) and/or abnormal vascularity. history of clinically important hypersensitivity reactions to dotarem [see warnings and precautions (5.2)]. 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 dotarem 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 2-4% and 15-20% 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 on 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. 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 breast-fed 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 dotarem and any potential adverse effects on the breastfed infant from dotarem 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). the safety and efficacy of dotarem 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 dotarem has not been established in preterm neonates. no cases of nsf associated with dotarem 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/1.73m2 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. in clinical studies of dotarem, 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 dotarem 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. no dotarem 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)] .

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ge healthcare inc. - gadodiamide (unii: 84f6u3j2r6) (gadodiamide - unii:84f6u3j2r6) - gadodiamide 287 mg in 1 ml - omniscan is a gadolinium-based contrast agent indicated for intravenous use in mri to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues [see clinical studies (14.1)]. omniscan is a gadolinium-based contrast agent indicated for intravenous use in mri to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space [see clinical studies (14.2)]. omniscan is contraindicated in patients with: - chronic, severe kidney disease (glomerular filtration rate, gfr < 30 ml/min/1.73m2 ) or acute kidney injury - prior hypersensitivity to omniscan 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, no adverse

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ge healthcare inc. - gadodiamide (unii: 84f6u3j2r6) (gadodiamide - unii:84f6u3j2r6) - gadodiamide 287 mg in 1 ml - omniscan is a gadolinium-based contrast agent indicated for intravenous use in mri to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues [see clinical studies (14.1)]. omniscan is a gadolinium-based contrast agent indicated for intravenous use in mri to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space [see clinical studies (14.2)]. omniscan is contraindicated in patients with: - chronic, severe kidney disease (glomerular filtration rate, gfr < 30 ml/min/1.73m2 ) or acute kidney injury - prior hypersensitivity to omniscan 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. because of the potential risks of gadolinium to the fetus, use omniscan only if imaging is essential during pregnancy and cannot be delayed. contrast enhancement is visualized in the human 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. 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. omniscan has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). these adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to omniscan administration during pregnancy. in rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made. it is not known whether this drug is excreted in human milk. because many drugs are excreted in human milk, exercise caution when administering omniscan to a nursing woman. the safety and efficacy of omniscan at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of omniscan in adults, a pediatric cns imaging study, and safety data in the scientific literature. however, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients. pharmacokinetics of omniscan have not been studied in pediatrics. the glomerular filtration rate of neonates and infants is much lower than that of adults. the pharmacokinetics volume of distribution is also different. therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established. in clinical studies of omniscan, 243 patients were between 65 and 80 years of age while 15 were over 80. no overall differences in safety or effectiveness were observed between these patients and younger patients. other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. omniscan is excreted by the kidney, and the risk of toxic reactions to omniscan may be greater in patients with impaired renal function [see warnings and precautions (5.4)]. because elderly patients are more likely to have decreased renal function, select dose carefully and consider assessment of renal function before omniscan use. dose adjustments in renal or hepatic impairment have not been studied. caution should be exercised in patients with impaired renal insufficiency [see warnings and precautions (5.2, 5.5) ].

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bracco diagnostics inc - gadoteridol (unii: 0199mv609f) (gadoteridol - unii:0199mv609f) - prohance is indicated for magnetic resonance imaging (mri) in adults and pediatric patients including term neonates to visualize lesions with disrupted blood brain barrier and/or abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. prohance is indicated for mri in adults to visualize lesions in the head and neck. prohance is contraindicated in patients with known allergic or hypersensitivity reactions to prohance [see warnings and precautions (5.3)]. 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). because of the potential risks of gadolinium to the fetus, use prohance only if imaging is essential during pregnancy and cannot be delayed. in animal reproduction studies in rats, gadoteridol doubled the incidence of post-implantation loss at up to 16 times the recommended human dose (rhd). there were no adverse developmental effects observed in rabbits with intravenous administration of gadoteridol during organogenesis at doses up to 19 times the recommended human dose of 0.1 mmol/kg (see data) . the estimated 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 contrast agent 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. 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 gadoteridol was administered in intravenous doses of 0, 0.375, 1.5, 6.0, and 10 mmol/kg/day [0.6, 2.4, 9.7, and 16 times the recommended human dose (rhd) based on body surface area (bsa)] to female rats from gestational day (gd)6 until gd17. gadoteridol at 10 mmol/kg/day for 12 days during gestation doubled the incidence of post-implantation loss. when rats were administered 6.0 or 10.0 mmol/kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. pregnant rabbits were administered gadoteridol in intravenous doses of 0, 0.4, 1.5, and 6 mmol/kg/day (1.3, 4.8, and 19.4 times the rhd based on bsa) from gd6 to gd18. gadoteridol increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/kg/day for 13 days during gestation. risk summary there are no data on the presence of gadoteridol 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. gadoteridol is present in rat milk (see data). the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for prohance and any potential adverse effects on the breastfed infant from prohance or from the underlying maternal condition. data prohance excretion in the milk of lactating rats was evaluated at 30 minutes, 6 and 24 hours after intravenous administration of 0.1 mmol/kg of 153 gd-gadoteridol to nursing mothers. small amounts of compound were found in milk immediately after injection (0.14% of the id), with the amount declining to a low level 24 hours after injection (<0.01% of the id). the safety and effectiveness of prohance have been established for use with mri to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine, and associated tissues in pediatric patients from birth, including term neonates, to 17 years of age. pediatric use is based on evidence of effectiveness in adults and in 103 pediatric patients 2 years of age and older, in addition to experience in 125 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)] . the safety and efficacy of > 0.1 mmol/kg, and sequential and/or repeat procedures have not been studied in pediatric patients [see indications and usage (1) and dosage and administration (2)] . no case of nsf associated with prohance or any other gbca has been identified in pediatric patients ages 6 years and younger. pharmacokinetic studies suggest that weight normalized clearance of prohance is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. normal estimated gfr (egfr) is around 30 ml/min/1.73m2 at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum egrf; 59.37 ml/min/1.73m2 (age just after birth to < 30 days), 118.84 ml/min/1.73m2 (age 30 days to < 6 months), 140.44 ml/min/1.73m2 (age 6 to 12 months). of the total number of 2673 adult subjects in clinical studies of prohance, 22% were 65 and over. no overall differences in safety were observed between these elderly subjects and the younger subjects. prohance is known to be substantially excreted by the kidneys, and the risk of toxic reactions from prohance may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. no prohance dosage adjustment is recommended for patients with renal impairment. gadoteridol can be removed from the body by hemodialysis [see warning and precautions (5.2) and clinical pharmacology (12.3)] .

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bracco diagnostics inc - gadobenate dimeglumine (unii: 3q6ppc19po) (gadolinium cation (3+) - unii:azv954tz9n) - multihance is indicated for intravenous use in magnetic resonance imaging (mri) of the central nervous system (cns) in adults and pediatric patients (including term neonates), to visualize lesions with abnormal blood-brain barrier or abnormal vascularity of the brain, spine, and associated tissues. multihance is indicated for use in magnetic resonance angiography (mra) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease. multihance is contraindicated in patients with known allergic or hypersensitivity reactions to gadolinium-based contrast agents [see warnings and precautions (5.3) ]. 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, gadobenate dimeglumine has been shown to be teratogenic in rabbits following repeated intravenous administration during organogenesis at doses up to 6 times the recommended human dose. there were no adverse developmental effects observed in rats with intravenous administration of gadobenate dimeglumine during organogenesis at doses up to three times the recommended human dose (see data). because of the potential risks of gadolinium to the fetus, use multihance only if imaging is essential and cannot be delayed. the estimated 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 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 gadobenate dimeglumine has been shown to be teratogenic in rabbits when administered intravenously at 2 mmol/kg/day (6 times the recommended human dose based on body surface area) during organogenesis (day 6 to 18) inducing microphthalmia/small eye and/or focal retinal fold in 3 fetuses from 3 separate litters. in addition, multihance administered intravenously at 3 mmol/kg/day (10 times the recommended human dose based on body surface area) has been shown to increase intrauterine deaths in rabbits. there was no evidence that multihance induced teratogenic effects in rats at doses up to 2 mmol/kg/day (3 times the recommended human dose based on body surface area), however, rat dams exhibited no systemic toxicity at this dose. there were no adverse effects on the birth, survival, growth, development and fertility of the f1 generation at doses up to 2 mmol/kg in a rat peri- and post-natal (segment iii) study. risk summary limited literature reports that breastfeeding after gadobenate dimeglumine administration to the mother would result in the infant receiving an oral dose of 0.001%-0.04% of the maternal dose. there is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. additionally, there is limited gbca gastrointestinal absorption. the developmental and health benefits of breastfeeding should be considered together with the mother’s clinical need for multihance and any potential adverse effects on the breastfed infant from multihance or from the underlying maternal condition. multihance is approved for intravenous use for mri of the cns to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine, and associated tissues in pediatric patients from birth, including term neonates, to less than 17 years of age. pediatric use is based on evidence of effectiveness in adults and in 202 pediatric patients 2 years of age and older, in addition to experience in 105 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 two years of age and older. for pediatric patients, less than 2 years of age, the recommended dosage range is 0.1 to 0.2 ml/kg [see dosage and administration (2.1), pharmacokinetics (12.3)] . the safety of multihance has not been established in preterm neonates. of the total number of 4967 adult subjects in clinical studies of multihance, 33% were 65 or older. no overall differences in safety or effectiveness were observed between these elderly subjects and the younger subjects. the drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to multihance may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function it may be useful to monitor renal function.

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bayer healthcare pharmaceuticals inc. - gadobutrol (unii: 1bj477io2l) (gadolinium cation (3+) - unii:azv954tz9n) - gadavist 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. gadavist is indicated for use with mri in adult patients to assess the presence and extent of malignant breast disease. gadavist 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. gadavist 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). gadavist is contraindicated in patients with history of severe hypersensitivity reactions to gadavist. 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 gadavist 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. 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. 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. 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 gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans. 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 breastfeeding should be considered along with the mother’s clinical need for gadavist and any potential adverse effects on the breastfed infant from gadavist or from the underlying maternal condition. in lactating rats receiving 0.5 mmol/kg of intravenous [153 gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk within 3 hours after administration, and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine). the safety and effectiveness of gadavist have been established in pediatric patients, including term neonates, for use with mri to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system and for use in mra to evaluate known or suspected supra-aortic or renal artery disease. use of gadavist in these indications is supported by adequate and well-controlled studies in adults and supportive imaging data in two studies in 135 patients 2 to less than 18 years of age and 44 patients less than 2 years of age with cns and non-cns lesions, and pharmacokinetic data in 130 patients 2 to less than 18 years of age and 43 patients less than 2 years of age, including term neonates [see clinical pharmacology (12.3) and clinical studies (14.1)] . the frequency, type, and severity of adverse reactions in pediatric patients were similar to adverse reactions in adults [ see adverse reactions (6.1)] . no dose adjustment according to age is necessary in pediatric patients [see dosage and administration (2.1), clinical pharmacology (12.3), and clinical studies (14.1)] . the safety and effectiveness of gadavist have not been established in preterm neonates for any indication or in pediatric patients of any age for use with mri to assess the presence and extent of malignant breast disease, or for use in cmri to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in patients with known or suspected coronary artery disease (cad). no case of nsf associated with gadavist or any other gbca has been identified in pediatric patients ages 6 years and younger. pharmacokinetic studies suggest that clearance of gadavist is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. no increased risk factor for nsf has been identified in juvenile animal studies of gadobutrol. normal estimated gfr (egfr) is around 30 ml/min/1.73m2 at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum egfr: 31 ml/min/1.73m2 (age 2 to 7 days), 38 ml/min/1.73m2 (age 8 to 28 days), 62 ml/min/1.73m2 (age 1 to 6 months), and 83 ml/min/1.73m2 (age 6 to 12 months). 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. in clinical studies of gadavist, 1,377 patients were 65 years of age and over, while 104 patients were 80 years of age and over. no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, use of gadavist in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. no dose adjustment according to age is necessary in this population. prior to administration of gadavist, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests [see warnings and precautions (5.2)] . no dosage adjustment is recommended for patients with renal impairment. gadavist can be removed from the body by hemodialysis [see warnings and precautions (5.2) and clinical pharmacology (12.3)].