GADOVIST

Gadobutrol is a second-generation extracellular non-ionic macrocyclic GBCA (gadolinium-based contrast agent) used in magnetic resonance imaging (MRI) in adults and children older than 2 years of age. formulated at twice the gadolinium ion concentration compared to other GBCA and thus requires a lesser injection volume.

Like other

GBCA, gadobutrol usage carries the risk of nephrogenic systemic fibrosis (NSF) due to the dissociation of gadolinium from the chelates, although gadobutrol tends to have a lower risk of NSF thanks to the macrocyclic structures that limit dechelation of gadolinium.

Gadobutrol is indicated for use with magnetic resonance imaging for the following diagnostic processes: 6 To detect and visualize areas with disrupted blood-brain barrier and/or abnormal vascularity of the central nervous system in adult and pediatric patients, including term neonates.

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

Gadobutrol leads to distinct shortenings of relaxation times even in low concentrations. relaxivity (r1).

• determined from the influence on the relaxation times (T1) of protons in plasma.

• is 5.2 L/(mmol-sec)

the relaxivity (r2).

• determined from the influence on the relaxation times (T2).

• is 6.1 L/(mmol-sec). display only slight dependence on the strength of the magnetic field.

In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with differences in proton density, the spin-lattice or longitudinal relaxation times (T1), and the spin-spin or transverse relaxation time (T2).

When placed in a magnetic field, gadobutrol shortens the T1 and T2 relaxation times.

The extent of decrease of

T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from gadobutrol, is based upon several factors including the concentration of gadobutrol in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times.

At the recommended dose, the T1 shortening effect is observed with the greatest sensitivity in T1-weighted magnetic resonance sequences.

In T2*-weighted sequences, the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease.

After intravenous administration, gadobutrol is rapidly distributed in the extracellular space.

After a gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured in plasma 2 minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection.

Gadobutrol does not display any particular protein binding.

GBCA administration, gadolinium is present for months or years in the brain, bone, skin, and other organs.

The mean

AUC of gadobutrol in patients with normal renal function was 1.1 ± 0.1 mmol∙h/L, compared to 4.0 ± 1.8 mmol∙h/L in patients with mild to moderate renal impairment and 11.5 ± 4.3 mmol∙h/L in patients with severe renal impairment.

In children aged 2-17, the body weight-normalized median total volumes of distribution (L/kg) were estimated to be 0.20 for all ages, 0.24 in the 2-6-year, 0.19 in the 7-11 year and 0.18 in the 12-17 year.

Gadobutrol is excreted in an unchanged form via the kidneys.

Within two hours after intravenous administration more than 50% and within 12 hours more than 90% of the given dose is eliminated via the urine.

For adult patients, the half-life was estimated to be 1.80 hours.

For pediatric aged to <2 years, 2-6 years, 7-11 years, and to < 18 years, the half-life was calculated to be 2.91, 1.91, 1.66, and 1.68 hours respectively.

In healthy subjects, renal clearance is 1.1-1.7 mL/(min-kg).

Clearance was observed to be slightly lower in elderly subjects, when using a 0.1 mmol/kg dose.

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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.

In animal reproduction studies, although teratogenicity was not observed, embryo-lethality 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 and 12 times, respectively, the recommended human dose.

Because of the potential risks of gadolinium to the fetus, use Gadavist only if imaging is essential during pregnancy and cannot be delayed.

The maximum dose of gadobutrol tested in healthy volunteers, 1.5 mL/kg body weight (1.5 mmol/kg; 15 times the recommended dose), was tolerated in a manner similar to lower doses.

Gadobutrol can be removed by hemodialysis [ No carcinogenicity studies of gadobutrol have been conducted.

Gadobutrol was not mutagenic in in vitro reverse mutation tests in bacteria, in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test using cultured Chinese hamster V79 cells, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of 0.5 mmol/kg.

Gadobutrol had no effect on fertility and general reproductive performance of male and female rats when given in doses 12.2 times the human equivalent dose (based on body surface area).

Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells was observed after paravenous administration to rabbits, suggesting the possibility of occurrence of local irritation if the contrast medium leaks around veins in a clinical setting.

Gadobutrol injection is contraindicated in patients with history of severe hypersensitivity reactions to gadobutrol injection.

History of severe hypersensitivity reaction to gadobutrol injection.

• Recommended dose for adults and pediatric patients (including term neonates) is 0.1 mL/kg body weight.

• Administer as an intravenous bolus injection.

• Follow injection with a normal saline flush 2.1 Recommended Dose The recommended dose of gadobutrol injection for adult and pediatric patients (including term neonates) is 0.1 mL/kg body weight (0.1 mmol/kg).

Refer to

Table to determine the volume to be administered.

Table 1: Volume of Gadobutrol Injection by Body Weight Body Weight (kg) Volume to be Administered (mL) 2.5 0.25 5 0.5 10 1 15 1.5 20 2 25 2.5 30 3 35 3.5 40 4 45 4.5 50 5 60 6 70 7 80 8 90 9 100 10 110 11 120 12 130 13 140 14 for Cardiac MRI, the dose is divided into 2 separate, equal injections 2.2 Administration Guidelines.

• Gadobutrol injection is formulated at a higher concentration (1 mmol/mL) compared to certain other gadolinium based contrast agents, resulting in a lower volume of administration.

• Use sterile technique when preparing and administering gadobutrol injection.

• Administer gadobutrol injection as an intravenous injection, manually or by power injector, at a flow rate of approximately 2 mL/second.

• Follow gadobutrol injection with a normal saline flush to ensure complete administration of the contrast.

• Post contrast MRI can commence immediately following contrast administration.

MRI of the

• Administer gadobutrol injection as an intravenous bolus by power injector, followed by a normal saline 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.

Image acquisition should coincide with peak arterial concentration, which varies among patients.

• Administer gadobutrol injection by power injector, at a flow rate of approximately 1.5 mL/second, followed by a 30 mL normal saline flush at the same rate to ensure complete administration of the contrast.

Pediatric patients.

• Administer gadobutrol injection by power injector or manually, followed by a normal saline flush to ensure complete administration of the contrast.

• Administer gadobutrol injection through a separate intravenous line in the contralateral arm if concomitantly providing a continuous infusion of a pharmacologic stress agent.

• Administer gadobutrol injection as two separate bolus injections: 0.05 mL/kg (0.05 mmol/kg) body weight at peak pharmacologic stress followed by 0.05 mL/kg (0.05 mmol/kg) body weight at rest.

• Administer gadobutrol injection via a power injector at a flow rate of approximately 4 mL/second and follow each injection with a normal saline flush of 20 mL at the same flow rate. 2.3 Drug Handling.

• Visually inspect gadobutrol injection for particulate matter and discoloration prior to administration.

Do not use the solution if it is discolored, if particulate matter is present or if the container appears damaged.

• Do not mix gadobutrol injection with other medications and do not administer gadobutrol injection in the same intravenous line simultaneously with other medications because of the potential for chemical incompatibility.

• Draw gadobutrol injection into the syringe immediately before use.

• Do not pierce the rubber stopper more than once.

Discard any unused vial contents.

Gadobutrol injection is a sterile, clear and colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol gadobutrol) per mL.

Gadobutrol injection is supplied in the following sizes: Product Code Unit of Sale Each 281202 NDC 65219-281-02 Packaged in a Box of 5 Cartons containing 3 vials each. (15 total vials) NDC 65219-281-00 2 mL Single-Dose Vial with rubber stopper.

NDC 65219-281-07 Packaged in a Box of 2 Cartons containing 10 vials each. (20 total vials) NDC 65219-281-03 7.5 mL Single-Dose Vial with rubber stopper.

NDC 65219-281-10 Packaged in a Box of 2 Cartons containing 10 vials each. (20 total vials) NDC 65219-281-08 10 mL Single-Dose Vial with rubber stopper.

NDC 65219-281-15 Packaged in a Box of 2 Cartons containing 10 vials each. (20 total vials) NDC 65219-281-05 15 mL Single-Dose Vial with rubber stopper. 16.2 Storage and Handling Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Should freezing occur, gadobutrol injection should be brought to room temperature before use.

If allowed to stand at room temperature, gadobutrol injection should return to a clear and colorless to pale yellow solution.

Visually inspect gadobutrol injection for particulate matter and discoloration prior to administration.

Do not use the solution if it is discolored, if particulate matter is present or if the container appears damaged.

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.

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 and 12 times, respectively, the recommended human dose.

Because of the potential risks of gadolinium to the fetus, use gadobutrol injection 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 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 gadobutrol injection, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.

The safety and effectiveness of gadobutrol injection 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 gadobutrol injection in these indications is supported by adequate and well-controlled studies in adults and supportive imaging data in two studies in 135 patients 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 to less than 18 years of age and 43 patients less than 2 years of age, including term neonates.

The frequency, type, and severity of adverse reactions in pediatric patients were similar to adverse reactions in adults.

No dose adjustment according to age is necessary in pediatric patients.

The safety and effectiveness of gadobutrol injection 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).

NSF Risk No case of

NSF associated with gadobutrol injection or any other GBCA has been identified in pediatric patients ages 6 years and younger.

Pharmacokinetic studies suggest that clearance of gadobutrol injection 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/1.73m 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/1.73m 2 (age to 7 days), 38 mL/min/1.73m 2 (age to 28 days), 62 mL/min/1.73m 2 (age to 6 months), and 83 mL/min/1.73m 2 (age 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 gadobutrol injection, 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 gadobutrol injection 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.