PROHANCE- gadoteridol injection, solution
BRACCO DIAGNOSTICS INC
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS
Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs.
The risk for NSF appears highest among patients with:
chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or
acute kidney injury.
Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.
For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration (see WARNINGS).
DESCRIPTION
ProHance (Gadoteridol) Injection is a nonionic contrast medium for magnetic resonance imaging (MRI), available as a 0.5M sterile clear colorless to slightly yellow aqueous solution in vials and syringes for intravenous injection.
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
Each mL of ProHance contains 279.3 mg gadoteridol, 0.23 mg calteridol calcium, 1.21 mg tromethamine and water for injection. ProHance contains no antimicrobial preservative.
ProHance has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below:
PARAMETER
Osmolality (mOsmol/kg water)
@ 37� C 630
Viscosity
(cP) @ 20� C 2.0
@ 37� C 1.3
Specific Gravity
@ 25� C 1.140
Density
(g/mL) @ 25� C 1.137
Octanol: H2 O coefficient -3.68 � 0.02
ProHance has an osmolality 2.2 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two-compartment open model with mean distribution and elimination half-lives (reported as mean � SD) of about 0.20 � 0.04 hours and 1.57 � 0.08 hours, respectively.
Gadoteridol is eliminated in the urine with 94.4 � 4.8% (mean � SD) of the dose excreted within 24 hours post-injection. It is unknown if biotransformation or decomposition of gadoteridol occur in vivo.
The renal and plasma clearance rates (1.41 � 0.33 mL/ min/kg and 1.50 � 0.35 mL/ min/kg, respectively) of gadoteridol are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (204 � 58 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular filtration.
It is unknown if protein binding of ProHance occurs in vivo.
Pharmacodynamics
Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent.
In magnetic resonance imaging (MRI), visualization of normal and pathologic brain tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.
Gadoteridol does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that have a normal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of ProHance in various lesions is not known.
INDICATIONS AND USAGE
Central Nervous System
ProHance (Gadoteridol) Injection is indicated for use in MRI in adults and children over 2 years of age to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues.
Extracranial/Extraspinal Tissues
ProHance is indicated for use in MRI in adults to visualize lesions in the head and neck.
CONTRAINDICATIONS
ProHance is contraindicated in patients with known allergic or hypersensitivity reactions to ProHance (see WARNINGS).
DOSAGE AND ADMINISTRATION
Central Nervous System
ADULTS: The recommended dose of ProHance (Gadoteridol) Injection is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). In patients with normal renal function suspected of having poorly enhancing lesions, in the presence of negative or equivocal scans, a supplementary dose of 0.2 mmol/kg (0.4 mL/kg) may be given up to 30 minutes after the first dose.
CHILDREN (2-18 years): The recommended dose of ProHance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min). The safety and efficacy of doses > 0.1 mmol/kg, and sequential and/or repeat procedures has not been studied.
Extracranial/Extraspinal Tissues
ADULTS: The recommended dose of ProHance is 0.1 mmol/kg (0.2 mL/kg) administered as a rapid intravenous infusion (10 mL/min-60 mL/min) or bolus (> 60 mL/min).
CHILDREN: Safety and efficacy for extracranial/extra-spinal tissues has not been established.
Dose adjustments in renal and liver impairment have not been studied.
To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush. The imaging procedure should be completed within 1 hour of the first injection of ProHance (Gadoteridol) Injection.
Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Any unused portion must be discarded in accordance with regulations dealing with the disposal of such materials.
HOW SUPPLIED
ProHance (Gadoteridol) Injection is a clear, colorless to slightly yellow solution containing 279.3 mg/mL of gadoteridol in rubber stoppered vials. ProHance is available in boxes of:
Five 5 mL fills in single dose 15 mL vials (NDC 0270-1111-04)
Five 10 mL fills in single dose 30 mL vials (NDC 0270-1111-01)
Five 15 mL fills in single dose 30 mL vials (NDC 0270-1111-02)
Five 20 mL fills in single dose 30 mL vials (NDC 0270-1111-03)
Five 10 mL fills in single dose 20 mL prefilled syringes (NDC 0270-1111-16)
Five 17 mL fills in single dose 20 mL prefilled syringes (NDC 0270-1111-45)
STORAGE
ProHance (Gadoteridol) Injection should be stored at 25� C (77� F) excursions permitted to 15-30� C (59-86� F) [See USP Controlled Room Temperature]. Protect from light. DO NOT FREEZE. Should freezing occur in the vial, ProHance should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 60 minutes, ProHance (Gadoteridol) Injection should return to a clear, colorless to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard vial. Frozen syringes should be discarded.