Gadoteridol Injection Solution

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:

Storage

ProHance (Gadoteridol) Injection should be stored at 25°C (77°F) excursions permitted to 1530°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.

Manufactured for: Bracco Diagnostics Inc. Monroe Township, NJ 08831 by BIPSO GmbH 78224 Singen (Germany). Revised: Sep 2017

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. 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.

Clinical Trials

ProHance was evaluated in two blinded read trials in a total of 133 adults who had an indication for head and neck extracranial or extraspinal magnetic resonance imaging. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and < 1% other. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, approximately 75-82% of the scans were enhanced. 45-48% of the scans provided additional diagnostic information, and 8-25% of the diagnoses were changed. The relevance of the findings to disease sensitivity and specificity has not been fully evaluated. ProHance was evaluated in a multicenter clinical trial of 103 children who had an indication for a brain or spine MRI. These 103 children, (54 boys and 49 girls) had a mean age of 8.7 years with an age range of 2 to 20 years. Of these 103 children, 54 were between 2 and 12 years of age. Also, of these 103 children, 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2% other. The results of the non-contrast and gadoteridol MRI scans were compared. ProHance was given in one single 0.1 mmol/kg dose. Repeat dosing was not studied. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30-95% of the scans.

Patients scheduled to receive ProHance should be instructed to inform their physician if the patient;

1. is pregnant or breast feeding
2. has anemia or diseases that affect the red blood cells
3. has a history of renal or hepatic disease, seizure, hemoglobinopathies, asthma or allergic respiratory diseases
4. has recently received a GBCA.

GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF:

• Describe the clinical manifestations of NSF
• Describe procedures to screen for the detection of renal impairment Instruct the patients to contact their physician if they develop signs or symptoms of NSF following ProHance administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness.

Directions for Use of the ProHance® (Gadoteridol) Injection single dose syringe*

1. Screw the threaded tip of the plunger rod clockwise into the cartridge plunger and push forward a few millimeters to break any friction between the cartridge plunger and syringe barrel.
2. Holding syringe erect, unscrew the plastic tip cap from the tip of the syringe and attach either a sterile, disposable needle or tubing with a compatible luer lock using a push-twist action.
3. Hold the syringe erect and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual aspiration procedure, complete the injection. To ensure complete delivery of the contrast medium, the injection should be followed by a normal saline flush.
4. Properly dispose of the syringe and any other materials used.

*The syringe assembly is a HYPAK SCF® single dose syringe supplied by Becton Dickinson.

Gadoteridol can cause a life-threatening condition in people with advanced kidney disease. The symptoms of this condition include:

• burning, itching, swelling, scaling, and tightening or hardening of your skin;
• muscle weakness;
• joint stiffness in your arms, hands, legs, or feet;
• deep bone pain in your ribs or your hips;
• trouble moving; or
• skin redness or discoloration.

Before receiving this medication, tell your doctor if you have kidney disease or if you are on dialysis. You may not be able to receive gadoteridol. Also tell your doctor if you have recently received any contrast agents similar to gadoteridol.

To make sure you can safely receive this medication, tell your doctor if you have any of these other conditions:

• diabetes;
• high blood pressure;
• liver disease (or liver transplant);
• a heart rhythm disorder;
• anemia or other red blood cell disorder;
• a history of seizures (convulsions);
• asthma, hay fever, or a history of food or drug allergies;
• if you are over 60 years old;
• if you have ever had any type of reaction to a contrast agent; or
• if you have recently had an injury, surgery, or severe infection.

FDA pregnancy category C. It is not known whether gadoteridol will harm an unborn baby. Before you receive this medication, tell your doctor if you are pregnant.

It is not known whether gadoteridol passes into breast milk or if it could harm a nursing baby. Do not receive this medication without telling your doctor if you are breast-feeding a baby.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Your doctor or pharmacist can provide more information about gadoteridol.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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