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PROHANCE INJECTION

Active substance(s): GADOTERIDOL / GADOTERIDOL / GADOTERIDOL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
ProHance 279.3 mg/ml, solution for injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Gadoteridol 279.3mg/ml (0.5M)

3

PHARMACEUTICAL FORM
Sterile solution for intravenous injection

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
This medicinal product is for diagnostic use only.
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.

4.2

Posology and method of administration
Posology
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.
Paediatric population
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.
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).
Method of administration
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.
Caution during injection of any contrast media is necessary to avoid extravasation.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1 or to other gadolinium-based contrast.
ProHance is contraindicated in children under 6 months of age.

4.4

Special warnings and precautions for use

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.
In patients suffering from epilepsy or brain lesions the likelihood of convulsions
during the examination may be increased. Precautions are necessary when examining
these patients (e.g. monitoring of the patient) and the equipment and medicinal
products needed for the rapid treatment of possible convulsions should be 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.
Caution during injection of any contrast media is necessary to avoid
extravasation.
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.

4.5

Interaction with other medicinal products and other forms of interaction
There are no known drug interactions with Gadoteridol. No clinically significant
changes or trends in laboratory tests were seen in clinical trials with ProHance®.

4.6

Fertility, pregnancy and lactation
Fertility
There are no fertility data.
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.

4.7

Effects on Ability to Drive and Use Machines
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.

4.8

Undesirable effects
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%.

System Organ
Class

Adverse Reactions
Common
(≥1/100 <1/10)

Immune system
disorders
Psychiatric
disorders
Nervous system
disorders

Skin and
subcutaneous tissue
disorders
Musculoskeletal
and connective
tissue disorders
Renal and urinary
system
General disorders
and administration
site conditions
Investigations

Rare
(≥1/10,000 - <1/1000)

Not known
( cannot be
estimated from
the available data)

Anaphylactic/anaphylactoid
reactions***
anxiety
headache,
paraesthesia,
dizziness, taste
disturbance

Eye disorders
Ear and labyrinth
disorders
Cardiac disorders
Vascular disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Uncommon
(≥1/1000 - <1/100)

mental impairment,
abnormal coordination,
convulsion

loss of
consciousness,
coma,
vasovagal
reactions*

increased lacrimation
tinnitus
nodal arrhythmia

cardiac arrest

laryngospasm, dyspnoea,
rhinitis, cough, apnea,
wheezing

respiratory arrest ,
pulmonary
oedema

flushing,
hypotension

nausea

dry mouth, vomiting

pruritus, rash,
urticaria

abdominal pain, tongue
oedema, oral pruritus,
gingivitis, loose stools
oedema face

musculoskeletal stiffness

acute renal
failure**
injection site pain,
injection site
reaction****,
asthenia
heart rate increased

chest pain, pyrexia

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.
**** Injection site reactions are mainly characterised by local pain, erythema
or swelling, and in some cases they are a consequence of an extravasation.
Isolated cases of nephrogenic systemic fibrosis (NSF) have been reported with
ProHance, most of which were in patients co-administered other gadoliniumcontaining contrast agents (see section 4.4).
Paediatric Patients
The ProHance safety profile is similar in children and adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme.
Website: www.mhra.gov.uk/yellowcard
4.9

Overdose
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).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: magnetic resonance imaging contrast media, ATC
code: V08CA04

Mechanism of action 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.
Pharmacodynamic effects
However, disruption of the blood-brain barrier or normal vascularity allows
penetration of gadoteridol into lesions such as neoplasms, abscesses, and
subacute infarcts.
5.2

Pharmacokinetic properties
Distribution
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.
Elimination
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.

5.3

Preclinical safety data
Preclinical data indicate no additional risks for humans based on conventional studies
of safety pharmacology, repeated dose toxicity or genotoxicity. Carcinogenicity
studies have not been conducted.
Reproduction toxicity studies gave no indication of teratogenic potential. Rats and
rabbits that received gadoteridol for 12-13 days during gestation showed an increase
in post-implantation loss / abortion at doses 20-33 times the maximum human dose of
0.3mmol/kg/day. The offspring of rats treated at this dose also showed an increased
spontaneous motor activity.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Calteridol Calcium
Tromethamine
Hydrochloric Acid
Sodium Hydroxide
Water for Injections

6.2

6.3

Incompatibilities

ProHance® should not be admixed with any other drug.

Shelf life
36 months

6.4

Special precautions for storage
Store at room temperature (15-30°C.), protect from light. ProHance should not be
frozen.

6.5

Nature and contents of container
Vials: Type 1 glass vials with grey butyl stoppers and aluminium seals containing
5,10, 15 or 20ml.

6.6

Special precautions for disposal
The peel-off tracking label on the vials should be stuck onto the patient record
to enable accurate recording of the gadolinium contrast agent used. The dose
used should also be recorded. . If electronic patient records are used, the name of
the product, the batch number and the dose should be entered into the patient
record.
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Bracco International B.V.
Strawinskylaan 3051
1077 ZX Amsterdam
The Netherlands

8

MARKETING AUTHORISATION NUMBER(S)
PL 14447/0001

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29 October 1992 / 24 April 2001

10

DATE OF REVISION OF THE TEXT
02/06/2016

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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