ProHance

Gadoteridol 279.3mg/ml (0.5M)

Sterile solution for intravenous injection

Using Magnetic Resonance Imaging (MRI), ProHance provides contrast enhancement of the brain, spine and surrounding tissues resulting in improved visualization (compared with unenhanced MRI) of lesions with abnormal vascularity or those thought to cause a disruption of the normal blood-brain barrier.

ProHance can also be used for whole body MRI including the head, neck, liver, breast, muscoloskeletal system and soft tissue pathologies.

Adults

The recommended dose of ProHance for imaging most brain and spinal pathologies is 0.1 mmol/kg. However, doses of 0.3 mmol/kg have been shown to be useful in patients suspected of having cerebral metastases or other poorly enhancing lesions.

The recommended dose for whole body MRI is 0.1 mmol/kg.

Children (2 years and above)

The recommended dose of ProHance for brain imaging and spine pathologies is 0.1 mmol/kg (0.2 ml/kg).

ProHance has been used in only a limited number of children aged between 6 months and 2 years. If an MRI procedure must be performed in this group, particular caution should be exercised.

The safety and efficacy of doses higher than 0.1 mmol/kg and sequential or repeat procedures have not been established.

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 after injecting ProHance.

Special Populations

Impaired renal function

ProHance should only be used in patients with severe renal impairment (GFR < 30 ml/min/1.73m²) and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4). If it is necessary to use ProHance, the dose should not exceed 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, ProHance injections should not be repeated unless the interval between injections is at least 7 days.

Infants from 6 months to 1 year of age

Due to immature renal function in infants up to 1 year of age, ProHance should only be used in patients 6 to 12 months of age after careful consideration at a dose not exceeding 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, ProHance injections should not be repeated unless the interval between injections is at least 7 days.

Use of ProHance is not recommended in children less than 6 months of age.

Use for whole body MRI is not recommended in children less than 18 years of age

Elderly (aged 65 years and above)

No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).

ProHance is contra-indicated in patients with hypersensitivity to the active substance gadoteridol or any of its constituents or other gadolinium-based contrast.

ProHance is contraindicated in children under 6 months of age.

Patients with a history of allergy, drug reactions, or other hypersensitivity-like disorders should be closely observed during the procedure and the contrast medium administration, as well as for the time the physician deems useful given the patient condition.

As with other gadolinium chelates, there have been reports of anaphylactic/anaphylactoid/ hypersensitivity reactions with gadoteridol These reactions manifested with various degrees of severity, including anaphylactic shock or death. They involved one or more body systems, mostly respiratory, cardiovascular and/or mucocutaneous systems.

Anaphylactic shock has been very rarely been reported with the use of gadoteridol

Appropriate drugs and instruments for emergency measures must be readily available.

Transitory changes in serum iron (within normal range in the majority of cases) have been observed in some patients after administration of ProHance and these changes were shown not to be clinically significant.

Since Gadoteridol is renally cleared from the body, caution should be exercised in patients with severely impaired renal function.

Impaired renal function

Prior to administration of ProHance, it is recommended that all patients are screened for renal dysfunction by obtaining laboratory tests.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR < 30 ml/min/1.73m2). Patients undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group. As there is a possibility that NSF may occur with ProHance, it should therefore only be used in patients with severe renal impairment and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI.

Haemodialysis shortly after ProHance administration may be useful at removing ProHance from the body. There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis.

Infants from 6 months to 1 year of age

Due to immature renal function in infants up to 1 year of age, ProHance should only be used in patients 6 to 12 months of age after careful consideration.

Elderly

As the renal clearance of gadoteridol may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.

There are no known drug interactions with gadoteridol. No clinically significant changes or trends in laboratory tests were seen in clinical trials with ProHance.

Pregnancy

There are no data from the use of gadoteridol in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). ProHance should not be used during pregnancy unless the clinical condition of the woman requires use of gadoteridol.

Lactation

Gadolinium containing contrast agents are excreted into breast milk in very small amounts (see section 5.3). At clinical doses, no effects on the infant are anticipated due to the small amount excreted in milk and poor absorption from the gut. Continuing or discontinuing breast feeding for a period of 24 hours after administration of ProHance, should be at the discretion of the doctor and lactating mother.

On the basis of the pharmacokinetic and pharmacodynamic profiles, no or negligible influence is expected with the use of ProHance on the ability to drive or use machines.

The accepted safety considerations and procedures that are required for Magnetic Resonance Imaging are applicable when ProHance is used for contrast enhancement.

The following adverse reactions have been reported with ProHance. adverse reactions from clinical trials have been included with an indication of the frequency. Adverse reactions from spontaneous reporting are included with the frequency “not known”. There were no adverse reactions with an incidence greater than 2%.

Description of selected adverse reactions

*Vasovagal reactions

Vasovagal reactions, rarely leading to vasovagal syncope have been reported during or immediately after ProHance administration. The condition is often related to emotional distress or painful/unpleasant stimuli (e.g. needle puncture for IV placement). Symptoms commonly experienced include nausea, dizziness and diaphoresis.

In severe cases possibly leading to syncope, patients are usually pale and diaphoretic with altered state of consciousness and bradycardia. In addition patients could frequently experience apprehension, restlessness, faintness and salivary hypersecretion. Proper recognition of this reaction and differential diagnosis with hypersensitivity/anaphylactoid reaction is vital in order to apply the appropriate treatment measures to revert the vagal stimulation.

**Acute renal failure

Cases of acute renal failure have been reported in patients with pre-existing severe renal impairment.

***Anaphylactic/anaphylactoid reactions

As with other gadolinium chelates, there have been reports of anaphylactic/anaphylactoid/ hypersensitivity reactions with gadoteridol. These reactions manifested with various degrees of severity, including anaphylactic shock or death. They involved one or more body systems, mostly respiratory, cardiovascular and/or mucocutaneous systems. Commonly reported symptoms include throat tightness, throat irritation, dyspnoea, chest discomfort, feeling hot, dysphagia, burning sensation, oedema in pharynx or larynx, and hypotension.

Isolated cases of nephrogenic systemic fibrosis (NSF) have been reported with ProHance, most of which were in patients co-administered other gadolinium-containing contrast agents (see section 4.4).

There have been no cases of overdose reported to date, consequently, neither signs nor symptoms of overdosage have been identified. In the event of overdosage occurring, the patient should be observed and treated symptomatically.

ProHance can be removed by haemodialysis. However there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

Gadoteridol is a non-ionic paramagnetic contrast medium for Magnetic Resonance Imaging.

When placed in a magnetic field, gadoteridol decreases T1 relaxation times in targeted areas. 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 normal vascularity allows penetration of gadoteridol into lesions such as neoplasms, abscesses, and subacute infarcts.

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 ± 10.04 hours and 1.57 ± 10.08 hours, respectively.

Gadoteridol is exclusively eliminated in the urine with 94.4 ± 4.8% (mean ± SD) of the dose excreted within 24 hours post injection. There is no detectable biotransformation or decomposition of gadoteridol.

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 1 kg) is equal to that of extra cellular water, and clearance is similar to that of substances which are subject to glomerular filtration.

No serum protein binding was detected in rats.

Calteridol Calcium

Tromethamine USP

Hydrochloric Acid Ph Eur

Sodium Hydroxide Ph Eur

Water for Injections Ph Eur

ProHance should not be admixed with any other drug.

36 months

Store at room temperature (15-30°C.), protect from light. Frozen syringes should be discarded.

Syringes: Type I glass syringes with rubber stoppers and polypropylene plunger rods containing

5, 10, 15 or 17 ml.

a. 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.

b. Holding syringe erect, aseptically remove the rubber 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.

c. Hold the syringe erect and push plunger forward until all 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.

d. Properly dispose of the syringe and any other material used.

The peel-off tracking label on the syringes should be stuck onto the patient record to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded.

Bracco International B.V.

Strawinskylaan 3051

1077 ZX Amsterdam

The Netherlands

14447/0002

28 February 1997

23/03/2011