Primovist 0.25 mmol/ml, solution for injection, pre-filled syringe.

BP24017, REC32745

Note

Text in blue = added text

Text in red strikethrough = deleted text

2. What you need to know before you are given Primovist

[...]

Pregnancy

Gadoxetate disodium can cross the placenta. It is not known whether it affects the baby. You must tell your doctor if you think you are or might become pregnant, as Primovist should not be used during pregnancy unless strictly necessary. 

6. Contents of the pack and other information

[...]

This leaflet was last revised in SeptemberApril 20242

BP24017, REC32745

Note

Text in blue = added text

Text in red strikethrough = deleted text

4.6    Pregnancy, lactation and fertility

Pregnancy

There are no dataData from the use of gadoxetateon gadolinium-based contrast agents in pregnant women is limited. Gadolinium can cross the placenta. It is unknown whether exposure to gadolinium is associated with adverse effects in the foetus. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3). Primovist should not be used during pregnancy unless the clinical condition of the woman requires use of gadoxetate.

10.    DATE OF REVISION OF THE TEXT

SeptemberApril 20242

BP22036, REC30610

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

6. Contents of the pack and other information

[…]

Marketing Authorisation Holder 

Bayer Limited, 1st Floor, The Grange Offices, The Grange, Brewery Road, Stillorgan, Co. Dublin, A94 H2K7, The Atrium, Blackthorn road, Dublin 18, Ireland

[…]

This leaflet was last revised: September 2022October2019

BP22036, REC30610

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

7. MARKETING AUTHORISATION HOLDER

Bayer Limited

1^st Floor

The Grange Offices

The Grange

Brewery Road

Stillorgan

Co. Dublin

A94 H2K7

The Atrium

Blackthorn Road

Dublin 18

Ireland

10. DATE OF REVISION OF THE TEXT

 October 2019September2022

Type II variation- Update of dossier to prepare for RUP

Type II variation- Update of dossier to prepare for RUP

In section 6.3: shelf life, the following text has been added:

5 years (glass prefilled syringe).

3 years (plastic prefilled syringe)

In section 6.5 the following text has been added:

Glass syringes: 10 ml prefilled syringes consisting of a colourless siliconized PhEur type I glass barrel, a siliconized chlorobutyl elastomer plunger stopper, a chlorobutyl elastomer rubber tip cap, a polysulfone Luer Lock adapter and a polypropylene safety cap.

Plastic syringes: 10 ml prefilled syringes consisting of a colourless cycloolefin polymer plastic barrel with a thermoplastic elastomer tip seal, closed with a siliconized bromobutyl plunger.

Package sizes:

1, 5 and 10 x 5 ml (in 10 ml prefilled syringe)

1, 5 and 10 x 7.5 ml (in 10 ml prefilled syringe) (glass only)

1, 5 and 10 x 10 ml (in 10 ml prefilled syringe)

Not all pack sizes may be marketed.

In section 6.3: shelf life, the following text has been added:

5 years (glass prefilled syringe).

3 years (plastic prefilled syringe)

In section 6.5 the following text has been added:

Glass syringes: 10 ml prefilled syringes consisting of a colourless siliconized PhEur type I glass barrel, a siliconized chlorobutyl elastomer plunger stopper, a chlorobutyl elastomer rubber tip cap, a polysulfone Luer Lock adapter and a polypropylene safety cap.

Plastic syringes: 10 ml prefilled syringes consisting of a colourless cycloolefin polymer plastic barrel with a thermoplastic elastomer tip seal, closed with a siliconized bromobutyl plunger.

Package sizes:

1, 5 and 10 x 5 ml (in 10 ml prefilled syringe)

1, 5 and 10 x 7.5 ml (in 10 ml prefilled syringe) (glass only)

1, 5 and 10 x 10 ml (in 10 ml prefilled syringe)

Not all pack sizes may be marketed.

[New Text; Deleted text]

Section 4.2:

‘Paediatric population

The safety and efficacy of Primovist have has not been established in patients under 18 years old. Therefore, use of Primovist in this patient group cannot be recommended. Currently available data are described in section 5.1’

Section 4.8:

‘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 HPRA IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517. Website: www.hpraimb.ie; Ee-mail: medsafety@hpra.ieimbpharmacovigilance@imb.ie.  ’

Section 5.1:

‘Paediatric population

An observational study was performed in 52 paediatric patients (aged > 2 months and < 18 years). Patients were referred for Primovist enhanced liver MRI to evaluate suspected or known focal liver lesions. Additional diagnostic information was obtained when combined unenhanced and enhanced liver MR images were compared with unenhanced MR images alone. Serious adverse events were reported, however none were assessed by the investigator to be related to Primovist. Due to the retrospective nature and small sample size of this study, no definitive conclusion can be made regarding efficacy and safety in this population.’

Section 6.6:

‘The peel-off tracking label on the pre-filled 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. If electronic patient records are used, the name of the product, the batch number and the dose should be entered into the patient record.’

Section 10;

The date of revision has been updated to ‘July 2015’

[New Text; Deleted text]

Section 4.2:

‘Paediatric population

The safety and efficacy of Primovist have has not been established in patients under 18 years old. Therefore, use of Primovist in this patient group cannot be recommended. Currently available data are described in section 5.1’

Section 4.8:

‘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 HPRA IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517. Website: www.hpraimb.ie; Ee-mail: medsafety@hpra.ieimbpharmacovigilance@imb.ie.  ’

Section 5.1:

‘Paediatric population

An observational study was performed in 52 paediatric patients (aged > 2 months and < 18 years). Patients were referred for Primovist enhanced liver MRI to evaluate suspected or known focal liver lesions. Additional diagnostic information was obtained when combined unenhanced and enhanced liver MR images were compared with unenhanced MR images alone. Serious adverse events were reported, however none were assessed by the investigator to be related to Primovist. Due to the retrospective nature and small sample size of this study, no definitive conclusion can be made regarding efficacy and safety in this population.’

Section 6.6:

‘The peel-off tracking label on the pre-filled 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. If electronic patient records are used, the name of the product, the batch number and the dose should be entered into the patient record.’

Section 10;

The date of revision has been updated to ‘July 2015’

{Deleted text; Inserted text}

Section 2: Qualitative and quantitative composition:

…………………

Excipients with known effect: Contains 11.7 mg sodium/ ml

For the a full list of excipients, see section 6.1.

Section 4.3: Special warnings and precautions for use:

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Section 4.6: Fertility, pPregnancy, and lactation and fertility

Pregnancy

There are no data from the use of gadoxetate in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3). Primovist should not be used during pregnancy unless the clinical condition of the woman requires use of gadoxetate.

LactationBreast-feeding

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 Primovist, should be at the discretion of the doctor and lactating mother.

Fertility

Animal studies did not indicate impairment of fertility.

Section 4.8: Undesirable effects

……………….

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 IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie.

Section 5.2: Pharmacokinetic properties:

……………….

MetabolismBiotransformation

Gadoxetate disodium is not metabolized.

……………….

Section 6.6: Special precautions for disposal and other handling:

……………….

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

……………….

The Date of last renewal (section 9) has been updated to “26^th March 2014”

The Date of revision of the text (section 10) has been updated to “June 2014”

In addition, a number of formatting updates were undertaken on sections 4.2, 4.4, 4.5, 5.1, 5.3 & 6.5.

{Deleted text; Inserted text}

Section 2: Qualitative and quantitative composition:

…………………

Excipients with known effect: Contains 11.7 mg sodium/ ml

For the a full list of excipients, see section 6.1.

Section 4.3: Special warnings and precautions for use:

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Section 4.6: Fertility, pPregnancy, and lactation and fertility

Pregnancy

There are no data from the use of gadoxetate in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3). Primovist should not be used during pregnancy unless the clinical condition of the woman requires use of gadoxetate.

LactationBreast-feeding

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 Primovist, should be at the discretion of the doctor and lactating mother.

Fertility

Animal studies did not indicate impairment of fertility.

Section 4.8: Undesirable effects

……………….

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 IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie.

Section 5.2: Pharmacokinetic properties:

……………….

MetabolismBiotransformation

Gadoxetate disodium is not metabolized.

……………….

Section 6.6: Special precautions for disposal and other handling:

……………….

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

……………….

The Date of last renewal (section 9) has been updated to “26^th March 2014”

The Date of revision of the text (section 10) has been updated to “June 2014”

In addition, a number of formatting updates were undertaken on sections 4.2, 4.4, 4.5, 5.1, 5.3 & 6.5.

Section 1: Qualitative and quantitative composition:

“1 Each ml solution for injection contains 0.25 mmol gadoxetate 181.43 mg gadoxetic acid, disodium (Gd‑EOB‑DTPA disodium), equivalent to 0.25 mmol Gd-EOB-DTPA disodium 181.43 mg gadoxetate disodium.

1 prefilled syringe with 5.0 ml contains 907 mg gadoxetic acid gadoxetate, disodium,

1 prefilled syringe with 7.5 ml contains 1361 mg gadoxetic acid gadoxetate, disodium,

1 prefilled syringe with 10.0 ml contains 1814 mg gadoxetic acid gadoxetate, disodium.

Contains 11.7 mg sodium/ ml.

For a full list of excipients, see section 6.1.”

{Deleted text; Inserted text}

Section 4.2: Posology and method of administration has been updated as follows:

Section 4.4: Special warnings and precautions for use:

“The usual safety precautions for MRI must be observed, e.g. exclusion of cardiac pacemakers and ferromagnetic implants.

Diagnostic procedures that involve the use of contrast agents should be carried out under the direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed.

The patient should refrain from eating for two hours prior to examination to reduce the risk of aspiration, as nausea and vomiting are known possible adverse reactions.

Whenever possible, the contrast agent should be administered with the patient lying down. After the injection, the patient should be kept under observation for at least 30 minutes, since experience with contrast media shows that the majority of undesirable effects occur within this time.

This medicinal product contains 11.7 mg sodium per ml, and the dosage is 0.1 ml/kg body weight. To be taken into consideration by patients on a controlled sodium diet.

·         Impaired renal function

Prior to administration of Primovist, 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< 30ml/min/1.73 m²). 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 Primovist, it should therefore be avoided in patients with severe renal impairment and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI.

Haemodialysis shortly after Primovist administration may be useful at removing Primovist 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.

·         Elderly

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

·         Patients with cardiovascular disease

Caution should be exercised when Primovist is administered to patients with severe cardiovascular problems because only limited data are available so far.

Gd-EOB-DTPA Primovist should not be used in patients with uncorrected hypokalemia.

Gd-EOB-DTPA Primovist should be used with special care in patients

- with known congenital long QT syndrome or a family history of congenital long QT syndrome

- with known previous arrhythmias when on drugs that prolong cardiac repolarisation

- who are currently taking a drug that is known to prolong cardiac repolarisation e.g. a class III antiarrhythmic, (e.g. amiodarone, sotalol).

Primovist may cause transient QT-prolongation in individual patients (see section 5.3).

·         Hypersensitivity

Allergy-like reactions, including shock, are known to be rare events after administration of gadolinium-based MRI contrast media. Most of these reactions occur within half an hour after administration of contrast media. However, as with other contrast media of this class, delayed reactions may occur after hours to days in rare cases.

Medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures are necessary.

The risk of hypersensitivity reactions is higher in case of:

- previous reaction to contrast media

- history of bronchial asthma

- history of allergic disorders.

In patients with an allergic disposition (especially with a history of the above mentioned conditions) the decision to use Primovist must be made after particularly careful evaluation of the risk-benefit ratio.

Hypersensitivity reactions can be more intense in patients on beta-blockers, particularly in the presence of bronchial asthma. It should be considered that patients on beta-blockers may be refractory to standard treatment of hypersensitivity reactions with beta-agonists.

If hypersensitivity reactions occur, injection of the contrast medium must be discontinued immediately.

·         Local intolerance

Intramuscular administration may cause local intolerance reactions including focal necrosis and should must therefore be strictly avoided (see section5.3).

• Excipients

This medicinal product contains 11.7 mg sodium per ml, and the dosage is 0.1 ml/kg body weight. To be taken into consideration by patients on a controlled sodium diet.”

Section 4.5: Interaction with other medicinal products and other forms of interaction

“As transport of gadoxetate to the liver may be mediated by OATP transporters it cannot be excluded that potent OATP inhibitors could cause drug interactions reducing the hepatic contrast effect. However, no clinical data have been presented to support that theory. No interaction studies have been performed in man. But in general, anionic drugs primarily excreted into the bile (such as rifampicin) may compete with the hepatic contrast enhancement and the biliary excretion of Primovist. Animal studies demonstrated that compounds belonging to the class of rifamycins block the hepatic uptake of Primovist thus reducing the hepatic contrast effect. In this case the expected benefit of an injection of Primovist might be limited. No further interactions with other medicinal products are known. An interaction study in healthy subjects demonstrated that the co-administration of erythromycin did not influence efficacy and pharmacokinetics of Primovist. No further clinical interaction studies with other medicinal products have been performed.

·         Interference from elevated bilirubin or ferritin levels in patients

Elevated levels of bilirubin or ferritin can reduce the hepatic contrast effect of Primovist (see section 5.1).

·         Interference with diagnostic tests

Serum iron determination using complexometric methods (e.g. Ferrocine complexation method) may result in false values for up to 24 hours after the examination with Primovist because of the free complexing agent contained in the contrast medium solution.”

Section 4.6: Pregnancy and lactation

·         Pregnancy

There are no data from the use of gadoxetic acid gadoxetate in pregnant women.. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3). Primovist should not be used during pregnancy unless the clinical condition of the woman requires use of gadoxetic acid gadoxetate.

·         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 Primovist, should be at the discretion of the doctor and lactating mother.

Section 4.8: Undesirable effects has been updated as follows:

BEFORE:

“During the clinical development phase the overall incidence of adverse reactions which were classified as related was below 5 %. Most of the undesirable effects were transient and of mild to moderate intensity.

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs)

No individual adverse reaction reached a frequency greater than 1/100. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

*Pruritus (generalized pruritus, eye pruritus)

**Injection site reactions (various kinds) comprise the following terms: Injection site extravasation, injection site burning, injection site coldness, injection site irritation, injection site pain

*** Since the reactions were not observed during clinical trials with more than 1,700 patients, best estimate is that they occur rarely (<1/1,000)

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions

Laboratory changes as elevated serum iron, elevated bilirubin, increases in liver transaminases, decrease of hemoglobin, elevation of amylase, leucocyturia, hyperglycemia, elevated urine albumin, hyponatremia, elevated inorganic phosphate, decrease of serum protein, leucocytosis, hypokalemia, elevated LDH were reported in clinical trials. ECGs were regularly monitored during clinical studies and transient QT prolongation was observed in some patients without any associated adverse clinical events.

In very rare cases anaphylactoid reactions leading to shock may occur.

Cases of nephrogenic systemic fibrosis (NSF) have been reported with other gadolinium-containing contrast agents (see section 4.4).”

AFTER:

·      “Summary of the safety profile

The overall safety profile of Primovist is based on data from more than 1,900 patients in clinical trials, and from post-marketing surveillance.

The most frequently observed adverse drug reactions (³ 0.5 %) in patients receiving Primovist are nausea, headache, feeling hot, blood pressure increased, back pain and dizziness.

The most serious adverse drug reaction in patients receiving Primovist is anaphylactoid shock.

Delayed allergoid reactions (hours later up to several days) have been rarely observed.

Most of the undesirable effects were transient and of mild to moderate intensity.

·          Tabulated list of adverse reactions

The adverse drug reactions observed with Primovist are represented in the table below. They are classified according to System Organ Class (MedDRA version 12.1). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions from clinical trials are classified according to their frequencies. Frequency groupings are defined according to the following convention: common: ³ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ³ 1/10,000 to < 1/1,000. The adverse drug reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under ‘not known’.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Adverse drug reactions reported in clinical trials or during post-marketing surveillance in patients treated with Primovist

* Life-threatening and/or fatal cases have been reported. These reports originated from post-marketing experience.

**Pruritus (generalized pruritus, eye pruritus)

***Injection site reactions (various kinds) comprise the following terms: Injection site extravasation, injection site burning, injection site coldness, injection site irritation, injection site pain

·          Description of selected adverse reactions

Laboratory changes such as elevated serum iron, elevated bilirubin, increases in liver transaminases, decrease of hemoglobin, elevation of amylase, leucocyturia, hyperglycemia, elevated urine albumin, hyponatremia, elevated inorganic phosphate, decrease of serum protein, leucocytosis, hypokalemia, elevated LDH were reported in clinical trials. ECGs were regularly monitored during clinical studies and transient QT prolongation was observed in some patients without any associated adverse clinical events.

Cases of nephrogenic systemic fibrosis (NSF) have been reported with other gadolinium-containing contrast agents (see section 4.4).”

Section 4.9: Overdose

“No cases of overdose have been reported and no symptoms could be characterised.

Single doses of Primovist as high as 0.4 ml/kg (0.1mmol/kg) body weight were tolerated well.

In a limited number of patients, a dose of 2.0 ml/kg (500 micromol 0.5 mmol /kg) body weight was tested in clinical trials, more frequent occurrences of adverse events but no new undesirable effects were found in these patients.

In the event of excessive inadvertent overdose, the patient should be carefully observed including cardiac monitoring. In this case induction of QT prolongations is possible (see section 5.3).

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

Section 5.1: Pharmacodynamic properties has been updated as follows:

Section 5.2: Pharmacokinetic properties has been updated as follows:

Section 5.3: Preclinical safety data:

“Preclinical data reveal no special hazard for humans based on conventional studies of acute and subchronic toxicity and, genotoxicity and contact-sensitising potential.

·         Cardiac safety

In telemetered conscious dogs a small and transient QT prolongation was observed at the highest dose tested of 0.5 mmol/kg, which represents 20 times the human dose. At high concentrations, Gd-EOB-DTPA blocked the HERG channel and prolonged the action potential duration in isolated guinea pig papillary muscles. This indicates a possibility that Primovist might induce QT prolongation when overdosed.

No findings have been observed in safety pharmacology studies in other organ systems.

·         Reproduction toxicology and lactation

In a rabbit embryotoxicity study, an increased number of postimplantational losses and increased abortion rate were observed after repeated administration of 2.0 mmol/kg of Gd-EOB-DTPA, representing 25.9 times (based on body surface area) or approx. 80 times (based on body weight) the recommended human dose.

In lactating rats, less than 0.5% of the intravenously administered dose (0.1 mmol/kg) of radioactively labelled gadoxetate was excreted into the breast milk. Absorption after oral administration was very low in rats with 0.4%.

·         Local tolerance

Local intolerance reactions were only observed after intramuscular administration of Gd-EOB-DTPA.

·         Carcinogenicity

No carcinogenicity studies were performed.”

Section 6.1: List of excipients has been updated as follows:

Section 6.6: Special precautions for disposal and other handling:

·         Inspection

This medicinal product is a clear, colorless to pale yellow solution. It should be visually inspected before use.

Primovist should not be used in case of severe discoloration, the occurrence of particulate matter or a defective container.

·         Handling

The prefilled syringe must be taken from the pack and prepared for the injection immediately before the examination.

The tip cap should be removed from the prefilled syringe immediately before use.

·         Disposal

Any solution not used in one examination is to unused product should be discarded disposed of in accordance with local requirements.

The peel-off tracking label on the prefilled 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.

The  Date of revision of the text (section 10) has been updated to “October 2011”

Section 1: Qualitative and quantitative composition:

“1 Each ml solution for injection contains 0.25 mmol gadoxetate 181.43 mg gadoxetic acid, disodium (Gd‑EOB‑DTPA disodium), equivalent to 0.25 mmol Gd-EOB-DTPA disodium 181.43 mg gadoxetate disodium.

1 prefilled syringe with 5.0 ml contains 907 mg gadoxetic acid gadoxetate, disodium,

1 prefilled syringe with 7.5 ml contains 1361 mg gadoxetic acid gadoxetate, disodium,

1 prefilled syringe with 10.0 ml contains 1814 mg gadoxetic acid gadoxetate, disodium.

Contains 11.7 mg sodium/ ml.

For a full list of excipients, see section 6.1.”

{Deleted text; Inserted text}

Section 4.2: Posology and method of administration has been updated as follows:

Section 4.4: Special warnings and precautions for use:

“The usual safety precautions for MRI must be observed, e.g. exclusion of cardiac pacemakers and ferromagnetic implants.

Diagnostic procedures that involve the use of contrast agents should be carried out under the direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed.

The patient should refrain from eating for two hours prior to examination to reduce the risk of aspiration, as nausea and vomiting are known possible adverse reactions.

Whenever possible, the contrast agent should be administered with the patient lying down. After the injection, the patient should be kept under observation for at least 30 minutes, since experience with contrast media shows that the majority of undesirable effects occur within this time.

This medicinal product contains 11.7 mg sodium per ml, and the dosage is 0.1 ml/kg body weight. To be taken into consideration by patients on a controlled sodium diet.

·         Impaired renal function

Prior to administration of Primovist, 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< 30ml/min/1.73 m²). 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 Primovist, it should therefore be avoided in patients with severe renal impairment and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI.

Haemodialysis shortly after Primovist administration may be useful at removing Primovist 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.

·         Elderly

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

·         Patients with cardiovascular disease

Caution should be exercised when Primovist is administered to patients with severe cardiovascular problems because only limited data are available so far.

Gd-EOB-DTPA Primovist should not be used in patients with uncorrected hypokalemia.

Gd-EOB-DTPA Primovist should be used with special care in patients

- with known congenital long QT syndrome or a family history of congenital long QT syndrome

- with known previous arrhythmias when on drugs that prolong cardiac repolarisation

- who are currently taking a drug that is known to prolong cardiac repolarisation e.g. a class III antiarrhythmic, (e.g. amiodarone, sotalol).

Primovist may cause transient QT-prolongation in individual patients (see section 5.3).

·         Hypersensitivity

Allergy-like reactions, including shock, are known to be rare events after administration of gadolinium-based MRI contrast media. Most of these reactions occur within half an hour after administration of contrast media. However, as with other contrast media of this class, delayed reactions may occur after hours to days in rare cases.

Medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures are necessary.

The risk of hypersensitivity reactions is higher in case of:

- previous reaction to contrast media

- history of bronchial asthma

- history of allergic disorders.

In patients with an allergic disposition (especially with a history of the above mentioned conditions) the decision to use Primovist must be made after particularly careful evaluation of the risk-benefit ratio.

Hypersensitivity reactions can be more intense in patients on beta-blockers, particularly in the presence of bronchial asthma. It should be considered that patients on beta-blockers may be refractory to standard treatment of hypersensitivity reactions with beta-agonists.

If hypersensitivity reactions occur, injection of the contrast medium must be discontinued immediately.

·         Local intolerance

Intramuscular administration may cause local intolerance reactions including focal necrosis and should must therefore be strictly avoided (see section5.3).

• Excipients

This medicinal product contains 11.7 mg sodium per ml, and the dosage is 0.1 ml/kg body weight. To be taken into consideration by patients on a controlled sodium diet.”

Section 4.5: Interaction with other medicinal products and other forms of interaction

“As transport of gadoxetate to the liver may be mediated by OATP transporters it cannot be excluded that potent OATP inhibitors could cause drug interactions reducing the hepatic contrast effect. However, no clinical data have been presented to support that theory. No interaction studies have been performed in man. But in general, anionic drugs primarily excreted into the bile (such as rifampicin) may compete with the hepatic contrast enhancement and the biliary excretion of Primovist. Animal studies demonstrated that compounds belonging to the class of rifamycins block the hepatic uptake of Primovist thus reducing the hepatic contrast effect. In this case the expected benefit of an injection of Primovist might be limited. No further interactions with other medicinal products are known. An interaction study in healthy subjects demonstrated that the co-administration of erythromycin did not influence efficacy and pharmacokinetics of Primovist. No further clinical interaction studies with other medicinal products have been performed.

·         Interference from elevated bilirubin or ferritin levels in patients

Elevated levels of bilirubin or ferritin can reduce the hepatic contrast effect of Primovist (see section 5.1).

·         Interference with diagnostic tests

Serum iron determination using complexometric methods (e.g. Ferrocine complexation method) may result in false values for up to 24 hours after the examination with Primovist because of the free complexing agent contained in the contrast medium solution.”

Section 4.6: Pregnancy and lactation

·         Pregnancy

There are no data from the use of gadoxetic acid gadoxetate in pregnant women.. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3). Primovist should not be used during pregnancy unless the clinical condition of the woman requires use of gadoxetic acid gadoxetate.

·         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 Primovist, should be at the discretion of the doctor and lactating mother.

Section 4.8: Undesirable effects has been updated as follows:

BEFORE:

“During the clinical development phase the overall incidence of adverse reactions which were classified as related was below 5 %. Most of the undesirable effects were transient and of mild to moderate intensity.

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs)

No individual adverse reaction reached a frequency greater than 1/100. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

*Pruritus (generalized pruritus, eye pruritus)

**Injection site reactions (various kinds) comprise the following terms: Injection site extravasation, injection site burning, injection site coldness, injection site irritation, injection site pain

*** Since the reactions were not observed during clinical trials with more than 1,700 patients, best estimate is that they occur rarely (<1/1,000)

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions

Laboratory changes as elevated serum iron, elevated bilirubin, increases in liver transaminases, decrease of hemoglobin, elevation of amylase, leucocyturia, hyperglycemia, elevated urine albumin, hyponatremia, elevated inorganic phosphate, decrease of serum protein, leucocytosis, hypokalemia, elevated LDH were reported in clinical trials. ECGs were regularly monitored during clinical studies and transient QT prolongation was observed in some patients without any associated adverse clinical events.

In very rare cases anaphylactoid reactions leading to shock may occur.

Cases of nephrogenic systemic fibrosis (NSF) have been reported with other gadolinium-containing contrast agents (see section 4.4).”

AFTER:

·      “Summary of the safety profile

The overall safety profile of Primovist is based on data from more than 1,900 patients in clinical trials, and from post-marketing surveillance.

The most frequently observed adverse drug reactions (³ 0.5 %) in patients receiving Primovist are nausea, headache, feeling hot, blood pressure increased, back pain and dizziness.

The most serious adverse drug reaction in patients receiving Primovist is anaphylactoid shock.

Delayed allergoid reactions (hours later up to several days) have been rarely observed.

Most of the undesirable effects were transient and of mild to moderate intensity.

·          Tabulated list of adverse reactions

The adverse drug reactions observed with Primovist are represented in the table below. They are classified according to System Organ Class (MedDRA version 12.1). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions from clinical trials are classified according to their frequencies. Frequency groupings are defined according to the following convention: common: ³ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ³ 1/10,000 to < 1/1,000. The adverse drug reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under ‘not known’.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Adverse drug reactions reported in clinical trials or during post-marketing surveillance in patients treated with Primovist

* Life-threatening and/or fatal cases have been reported. These reports originated from post-marketing experience.

**Pruritus (generalized pruritus, eye pruritus)

***Injection site reactions (various kinds) comprise the following terms: Injection site extravasation, injection site burning, injection site coldness, injection site irritation, injection site pain

·          Description of selected adverse reactions

Laboratory changes such as elevated serum iron, elevated bilirubin, increases in liver transaminases, decrease of hemoglobin, elevation of amylase, leucocyturia, hyperglycemia, elevated urine albumin, hyponatremia, elevated inorganic phosphate, decrease of serum protein, leucocytosis, hypokalemia, elevated LDH were reported in clinical trials. ECGs were regularly monitored during clinical studies and transient QT prolongation was observed in some patients without any associated adverse clinical events.

Cases of nephrogenic systemic fibrosis (NSF) have been reported with other gadolinium-containing contrast agents (see section 4.4).”

Section 4.9: Overdose

“No cases of overdose have been reported and no symptoms could be characterised.

Single doses of Primovist as high as 0.4 ml/kg (0.1mmol/kg) body weight were tolerated well.

In a limited number of patients, a dose of 2.0 ml/kg (500 micromol 0.5 mmol /kg) body weight was tested in clinical trials, more frequent occurrences of adverse events but no new undesirable effects were found in these patients.

In the event of excessive inadvertent overdose, the patient should be carefully observed including cardiac monitoring. In this case induction of QT prolongations is possible (see section 5.3).

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

Section 5.1: Pharmacodynamic properties has been updated as follows:

Section 5.2: Pharmacokinetic properties has been updated as follows:

Section 5.3: Preclinical safety data:

“Preclinical data reveal no special hazard for humans based on conventional studies of acute and subchronic toxicity and, genotoxicity and contact-sensitising potential.

·         Cardiac safety

In telemetered conscious dogs a small and transient QT prolongation was observed at the highest dose tested of 0.5 mmol/kg, which represents 20 times the human dose. At high concentrations, Gd-EOB-DTPA blocked the HERG channel and prolonged the action potential duration in isolated guinea pig papillary muscles. This indicates a possibility that Primovist might induce QT prolongation when overdosed.

No findings have been observed in safety pharmacology studies in other organ systems.

·         Reproduction toxicology and lactation

In a rabbit embryotoxicity study, an increased number of postimplantational losses and increased abortion rate were observed after repeated administration of 2.0 mmol/kg of Gd-EOB-DTPA, representing 25.9 times (based on body surface area) or approx. 80 times (based on body weight) the recommended human dose.

In lactating rats, less than 0.5% of the intravenously administered dose (0.1 mmol/kg) of radioactively labelled gadoxetate was excreted into the breast milk. Absorption after oral administration was very low in rats with 0.4%.

·         Local tolerance

Local intolerance reactions were only observed after intramuscular administration of Gd-EOB-DTPA.

·         Carcinogenicity

No carcinogenicity studies were performed.”

Section 6.1: List of excipients has been updated as follows:

Section 6.6: Special precautions for disposal and other handling:

·         Inspection

This medicinal product is a clear, colorless to pale yellow solution. It should be visually inspected before use.

Primovist should not be used in case of severe discoloration, the occurrence of particulate matter or a defective container.

·         Handling

The prefilled syringe must be taken from the pack and prepared for the injection immediately before the examination.

The tip cap should be removed from the prefilled syringe immediately before use.

·         Disposal

Any solution not used in one examination is to unused product should be discarded disposed of in accordance with local requirements.

The peel-off tracking label on the prefilled 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.

The  Date of revision of the text (section 10) has been updated to “October 2011”

4.4 Special warnings and precautions for use

1.      The following text was inserted;

• “Impaired renal function

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< 30ml/min /1.73 m2) or

- acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.

As there is a possibility that NSF may occur with Primovist, it should therefore only be used in these patients after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI).

All patients should be screened, in particular patients over the age of 65, for renal dysfunction by obtaining a history and/or laboratory tests.

Haemodialysis shortly after Primovist administration in patients currently receiving haemodialysis may be useful at removing Primovist 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.”

2.      The  following heading was inserted;

• “Patients with cardiovascular disease”

3.      The following text was removed;

“Adequate measures for resuscitation should be made readily available prior to administration of contrast agents” and “The risk of hypersensitivity reactions is higher in case of:

-         Previous reaction to contrast media

-         History of bronchial asthma

-         History of allergic disorders.”

Was added.

4.7 Effects on ability to drive and use machines

“Not relevant.” Was inserted instead of “On the basis of the pharmacodynamic profile, Primovist is expected to exert no or negligible influence on the ability to drive or use machines.”

4.8 Undesirable effects

The following text was deleted along with the table “The table below reports adverse reactions by body system. No individual adverse reaction reached a frequency greater than 1/100.” The following text and table were inserted in place of the above;

“Frequency of adverse reactions from clinical trial data:

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs)

No individual adverse reaction reached a frequency greater than 1/100. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.