ProHance (Page 3 of 5)

8  USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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.

8.2 Lactation

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.

DataProHance 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).

8.4 Pediatric Use

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).

8.5 Geriatric Use

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.

8.6 Renal Impairment

No ProHance dosage adjustment is recommended for patients with renal impairment. Gadoteridol can be removed from the body by hemodialysis [see Warning and Precautions (5.1) and Clinical Pharmacology (12.3)].

10  OVERDOSAGE

Clinical consequences of overdose with ProHance have not been reported. The safety of ProHance has been tested in clinical studies using doses up to 0.3 mmol/kg and no clinical consequences related to increasing dose have been observed to date. ProHance can be removed by hemodialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

11  DESCRIPTION

ProHance, a gadolinium-based paramagnetic MRI contrast agent, is a colorless to slightly yellow aqueous, sterile, nonpyrogenic injectable solution. Each mL contains 279.3 mg (0.5 mmol/mL) gadoteridol, 0.23 mg calteridol calcium, 1.21 mg tromethamine and water for injection. ProHance contains no antimicrobial preservative.

Gadoteridol is the gadolinium complex of 10-(2-hydroxy-propyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid with a molecular weight of 558.7, an empirical formula of C17 H29 N4 O7 Gd and has the following structural formula:

ProHance Structure

ProHance has a pH of 6.5 to 8.0. Pertinent physiochemical parameters are provided below:

Osmolality630 mOsmol/kg water at 37 °C
Viscosity1.3 cP at 37 °C
Density1.137 g/mL at 25 °C

ProHance has an osmolality that is 2.2 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use.

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