ENANTUM

Gadobutrol injection is a paramagnetic macrocyclic contrast agent administered for magnetic resonance imaging.

The chemical name for gadobutrol is 10–[(1SR,2RS)–2,3–dihydroxy–1–hydroxymethylpropyl]–1,4,7,10–tetraazacyclododecane–1,4,7–triacetic acid, gadolinium complex.

Gadobutrol has a molecular formula of

C 18 H 31 GdN 4 O and a molecular weight of 604.72.

Gadobutrol injection is a sterile, clear, colorless to pale yellow solution containing 604.72 mg (1.0 mmol) of gadobutrol per mL as the active ingredient with 0.513 mg of calcobutrol sodium, 1.211 mg of trometamol, hydrochloric acid (for pH adjustment) and water for injection.

Gadobutrol injection contains no preservatives.

The main physicochemical properties of gadobutrol injection (1 mmol/mL solution for injection) are listed below: Density (g/mL at 37°C) 1.3 Osmolarity at 37°C (mOsm/L solution) 1,117 Osmolality at 37°C (mOsm/kg H 2 O) 1,603 Viscosity at 37°C (mPa·s) 4.96 pH 6.6 to The thermodynamic stability constants for gadobutrol (log Ktherm and log Kcond at pH 7.4) are 21.8 and 15.3, respectively. gadob-struc-01.jpg.

• To detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system in adult and pediatric patients, including term neonates.

• To assess the presence and extent of malignant breast disease in adult patients.

• To evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients, including term neonates.

• To assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD). . 1.1 Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS) Gadobutrol injection 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. 1.2 MRI of the Breast Gadobutrol injection is indicated for use with MRI in adult patients to assess the presence and extent of malignant breast disease. 1.3 Magnetic Resonance Angiography (MRA) Gadobutrol injection 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. 1.4 Cardiac MRI Gadobutrol injection 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).

• Differences in proton density.

• Differences of the spin-lattice or longitudinal relaxation times (T 1 ).

• Differences in the spin-spin or transverse relaxation time (T 2 ) When placed in a magnetic field, gadobutrol shortens the T and T 2 relaxation times.

The extent of decrease of T and T 2 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 T 1 shortening effect is observed with greatest sensitivity in T 1 -weighted magnetic resonance sequences.

In T 2 *-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. 12.2 Pharmacodynamics Gadobutrol leads to distinct shortening of the relaxation times even in low concentrations.

At pH 7, 37°C and 1.5 T, the relaxivity (r 1 ).

• determined from the influence on the relaxation times (T 1 ) of protons in plasma.

• is 5.2 L/(mmol·sec) and the relaxivity (r 2 ).

• determined from the influence on the relaxation times (T 2 ).

• is 6.1 L/(mmol·sec).

These relaxivities display only slight dependence on the strength of the magnetic field.

T 1 shortening effect of paramagnetic contrast agents is dependent on concentration and r 1 relaxivity.

This may improve tissue visualization.

Table 3: Relaxivity (r 1 ) of Gadolinium Chelates at 1.5 T r 1 relaxivity in plasma at 37°C Gadolinium-Chelate r 1 (L·mmol -1 ·s -1 ) Gadobenate 6.3 Gadobutrol 5.2 Gadodiamide 4.3 Gadofosveset 16 Gadopentetate 4.1 Gadoterate 3.6 Gadoteridol 4.1 Gadoversetamide 4.7 Gadoxetate 6.9 Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of gadobutrol injection results in half the volume of administration and a more compact contrast bolus injection.

At the site of imaging, the relative height and width of the time intensity curve for gadobutrol injection varies as a function of imaging location and multiple patient, injection, and device-specific factors.

Gadobutrol is a water-soluble, hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006. 12.3 Pharmacokinetics Distribution 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 brain, bone, skin, and other organs.

Gadobutrol is not metabolized.

Elimination Values for

AUC, body weight normalized plasma clearance and half-life are given in Table 4, below.

Gadobutrol is excreted in an unchanged form via the kidneys.

In healthy subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(min∙kg) and thus comparable to the renal clearance of inulin, confirming that gadobutrol is eliminated by glomerular filtration.

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.

Extra-renal elimination is negligible.

Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol.

A single intravenous dose of 0.1 mmol/kg gadobutrol injection was administered to 15 elderly and 16 non-elderly subjects.

AUC was slightly higher and clearance slightly lower in elderly subjects as compared to non-elderly subjects.

The pharmacokinetics of gadobutrol were evaluated in two studies in a total of 130 patients age to less than 18 years and in 43 patients less than 2 years of age (including term neonates).

Patients received a single intravenous dose of 0.1 mmol/kg of gadobutrol injection.

The pharmacokinetic profile of gadobutrol in pediatric patients is similar to that in adults, resulting in similar values for AUC, body weight normalized plasma clearance, as well as elimination half-life.

Approximately 99% (median value) of the dose was recovered in urine within 6 hours (this information was derived from the to less than 18 year old ).

Table 4: Pharmacokinetics by (Median [Range]) 0 to < 2 years to 6 years to 11 years to < 18 years Adults N=43 N=45 N=39 N=46 N=93 AUC (µmolxh/L) 781 846 1,025 1,237 1,072 CL (L/h/kg) 0.128 0.119 0.099 0.081 0.094 t 1/2 (h) 2.91 1.91 1.66 1.68 1.80 C 20 (µmol/L) 367 421 462 511 441 Renal Impairment In patients with impaired renal function, the serum half-life of gadobutrol is prolonged and correlated with the reduction in creatinine clearance.

After intravenous injection of 0.1 mmol gadobutrol/kg body weight, the elimination half-life was 5.8 ± 2.4 hours in mild to moderately impaired patients (80 > CL CR > 30 mL/min) and 17.6 ± 6.2 hours in severely impaired patients not on dialysis (CL CR < 30 mL/min).

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.

Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours.

In patients with severely impaired renal function about 80% of the administered dose was recovered in the urine within 5 days.

For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of gadobutrol injection in order to enhance the contrast agent’s elimination.

Sixty-eight percent (68%) of gadobutrol is removed from the body after the first dialysis, 94% after the second dialysis, and 98% after the third dialysis session.

• Nephrogenic Systemic Fibrosis (NSF) .

• Hypersensitivity reactions.

Most common adverse reactions (incidence ≥ 0.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse reactions described in this section reflect gadobutrol injection exposure in 7,713 subjects (including 184 pediatric patients, ages to 17 years) with the majority receiving the recommended dose.

Approximately 52% of the subjects were male and the ethnic distribution was 62% Caucasian, 28% Asian, 5% Hispanic, 2.5% Black, and 2.5% patients of other ethnic groups.

The average age was 56 years (range from 1 week to 93 years).

Overall, approximately 4% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after gadobutrol injection administration.

Adverse reactions associated with the use of gadobutrol injection were usually mild to moderate in severity and transient in nature.

Table 2 lists adverse reactions that occurred in ≥ 0.1% subjects who received gadobutrol injection.

Table 2: Adverse Reactions Reaction Rate (%) n=7,713 Headache 1.7 Nausea 1.2 Dizziness 0.5 Dysgeusia 0.4 Feeling Hot 0.4 Injection site reactions 0.4 Vomiting 0.4 Rash (includes generalized, macular, papular, pruritic) 0.3 Erythema 0.2 Paresthesia 0.2 Pruritus (includes generalized) 0.2 Dyspnea 0.1 Urticaria 0.1 Adverse reactions that occurred with a frequency of < 0.1% in subjects who received gadobutrol injection include: hypersensitivity/anaphylactic reaction, loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of gadobutrol injection or other GBCAs.

Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Cardiac arrest.

• Nephrogenic Systemic Fibrosis (NSF).

• Hypersensitivity reactions (anaphylactic shock, circulatory collapse, respiratory arrest, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor).

Disorders: Acute respiratory distress syndrome, pulmonary edema.

Disorders and Administration Site Conditions: Adverse reactions with variable onset and duration have been reported after GBCA administration These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.

• Skin: Gadolinium associated plaques.

Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration.

The maximum dose of gadobutrol injection 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.

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.