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

  • Name:

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

  • Company:
    info
  • Active Ingredients:

    Gadoxetic acid, disodium

  • Legal Category:

    Product subject to restricted prescription (C)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 09/02/18

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Summary of Product Characteristics last updated on medicines.ie: 12/2/2018
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Bayer Limited

Bayer Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 12 February 2018 PIL

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Section 4.1: Added: Primovist should be used only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI) and when delayed phase imaging is required.

Section 4.2: Added: The lowest dose that provides sufficient enhancement for diagnostic purposes should be used. The dose should be calculated based on the patient's body weight, and should not exceed the recommended dose per kilogram of bodyweight detailed in this section.

Section 4.3: Added: Accumulation in the body: After administration of gadoxetate disodium gadolinium can be retained in the brain and in other tissues of the body (bones, liver, kidneys, skin) and can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Clinical consequences are unknown. The possible diagnostic advantages of using gadoxetate disodium in patients who will require who will require repeated scans should be weighted against the potential for deposition of gadolinium in the brain and other tissues.

Section 5.2: Added: Gadoxetate disodium is a linear GdCA. Studies have shown that after exposure to GdCAs gadolinium is retained in the body. This includes retention in the brain and in other tissues and organs. With the linear GdCAs this can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Signal intensity increase and non-clinical data show that gadolinium is released from linear GdCAs.

Date of Revision: November 2017

Updated on 12 February 2018 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Section 4.1: Added: Primovist should be used only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI) and when delayed phase imaging is required.

Section 4.2: Added: The lowest dose that provides sufficient enhancement for diagnostic purposes should be used. The dose should be calculated based on the patient's body weight, and should not exceed the recommended dose per kilogram of bodyweight detailed in this section.

Section 4.3: Added: Accumulation in the body: After administration of gadoxetate disodium gadolinium can be retained in the brain and in other tissues of the body (bones, liver, kidneys, skin) and can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Clinical consequences are unknown. The possible diagnostic advantages of using gadoxetate disodium in patients who will require who will require repeated scans should be weighted against the potential for deposition of gadolinium in the brain and other tissues.

Section 5.2: Added: Gadoxetate disodium is a linear GdCA. Studies have shown that after exposure to GdCAs gadolinium is retained in the body. This includes retention in the brain and in other tissues and organs. With the linear GdCAs this can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Signal intensity increase and non-clinical data show that gadolinium is released from linear GdCAs.

Date of Revision: November 2017

Updated on 12 February 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to restricted prescription (C)

Updated on 9 February 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 13 May 2016 SmPC

Reasons for updating

  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

In section 5.2 Pharmacokinetic properties:

The compound does not pass the intact blood-brain barrier and diffuses through the placental barrier only to
a small extent. -was removed.

In section 10. DATE OF REVISION OF THE TEXT:
December 2015 May 2016 -was removed and added respectively.

Updated on 13 May 2016 PIL

Reasons for updating

  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

In section 5.2 Pharmacokinetic properties:

The compound does not pass the intact blood-brain barrier and diffuses through the placental barrier only to
a small extent. -was removed.

In section 10. DATE OF REVISION OF THE TEXT:
December 2015 May 2016 -was removed and added respectively.

Updated on 9 December 2015 PIL

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 6.5 - Nature and contents of container

Free text change information supplied by the pharmaceutical company

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.

Updated on 9 December 2015 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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.

Updated on 14 August 2015 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

[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’

Updated on 14 August 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

[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’

Updated on 30 July 2014 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

{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 “26th 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.

Updated on 30 July 2014 PIL

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

{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 “26th 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.

Updated on 22 November 2011 PIL

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.1 - List of excipients
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company


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:

 

BEFORE

AFTER

“Primovist is a ready-to-use aqueous solution to be administered undiluted as an intravenous bolus injection at a flow rate of about 2 ml/sec. After the injection of the contrast medium the intravenous cannula should be flushed using sterile 9 mg/ml (0.9 %) saline solution.

The recommended dose of Primovist is:

Adults:

0.1 ml/kg body weight Primovist.
For detailed imaging information refer to section 5.1.

Repeated use:

No clinical information is available about repeated use of Primovist.

 

Special Populations

 

Impaired renal function

 

Use of Primovist should be avoided in patients with severe renal impairment (GFR < 30 ml/min/1.73m2) and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4).  If use of Primovist cannot be avoided, the dose should not exceed 0.025 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Primovist injections should not be repeated unless the interval between injections is at least 7 days.

 

Patients with hepatic impairment:

No dosage adjustment is necessary.

 

Paediatric population

 

The safety and efficacy of Primovist has not been established in patients under 18 years old. Therefore, use of Primovist in this patient group cannot be recommended.

 

Elderly population (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

Primovist is a ready-to-use aqueous solution to be administered undiluted as an intravenous bolus injection at a flow rate of about 2 ml/sec. After the injection of the contrast medium the intravenous cannula/ line should be flushed using sterile 9 mg/ml (0.9 %) saline solution.

For detailed imaging information refer to section 5.1.

For additional instructions see section 6.6.

 

Posology

The recommended dose of Primovist is:

Adults:

0.1 ml per kg body weight Primovist.

 

Repeated use:

No clinical information is available about repeated use of Primovist.

 

Additional information on special populations

 

·         Impaired renal function

Use of Primovist should be avoided in patients with severe renal impairment (GFR < 30 ml/min/1.73m2) and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4).  If use of Primovist cannot be avoided, the dose should not exceed 0.025 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Primovist injections should not be repeated unless the interval between injections is at least 7 days.

 

·         Patients with hepatic impairment

No dosage adjustment is necessary.

 

·         Paediatric population

The safety and efficacy of Primovist has not been established in patients under 18 years old. Therefore, use of Primovist in this patient group cannot be recommended.

 

·         Elderly population (aged 65 years and above)

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

 

 

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.

  

 

 

 

Adverse reactions

 

 

From clinical trial data

From postmarketing spontaneous reporting

System Organ Class (MedDra)

 

Uncommon

(≥1/1000 to <1/100)

Rare

(≥1/10 000 to <1/1000)

Frequency not known (cannot be estimated from available data)***

Nervous system disorders

headache

dizziness

dysgeusia

paresthesia

parosmia

vertigo

akathisia

tremor

 

restlessness

 

 

 

Cardiac disorders

 

bundle branch block

palpitation

tachycardia

 

Vascular disorders

blood pressure increased

flushing

 

 

 

Respiratory, thoracic and mediastinal disorders

respiratory disorders

(dyspnea, respiratory distress)

 

 

 

Gastrointestinal disorders

vomiting

nausea

dry mouth

oral discomfort

salivary hypersecretion

 

 

 

 

 

Skin and subcutaneous tissue disorders

rash

pruritus*

 

maculopapular rash

hyperhidrosis

 

 

Musculoskeletal and connective tissue

disorders

 

 

back pain

 

General disorders and administration site conditions

chest pain

injection site reactions

(various kinds)**

feeling hot

 

chills

discomfort

fatigue

malaise

feeling abnormal

 

 

 

 

 

 

 

Immune system disorders

 

 

hypersensitivity/

anaphylactoid reaction (e.g. shock, hypotension, pharyngolaryngeal oedema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypo(a) esthesia, sneezing, cough, pallor)

*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

 

System Organ Class (MedDra)

 

Common

Uncommon

 

Rare

 

Not known

Immune system disorders

 

 

 

Hypersensitivity /

anaphylactoid reaction (e.g. shock*, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough, pallor)

Nervous system disorders

Headache

Vertigo

Dizziness

Dysgeusia

Paresthesia

Parosmia

Tremor

Akathisia

 

Restlessness

 

 

 

Cardiac disorders

 

 

Bundle branch block

Palpitation

Tachycardia

 

Vascular disorders

 

Blood pressure increased

Flushing

 

 

 

Respiratory, thoracic and mediastinal disorders

 

Respiratory disorders

(Dyspnea*, Respiratory distress)

 

 

 

Gastrointestinal disorders

Nausea

Vomiting

Dry mouth

Oral discomfort

Salivary hypersecretion

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

Rash

Pruritus**

 

Maculopapular rash

Hyperhidrosis

 

 

Musculoskeletal and connective tissue

disorders

 

Back pain

 

 

General disorders and administration site conditions

 

Chest pain

Injection site reactions

(various kinds)***

Feeling hot

Chills

Fatigue

Feeling abnormal

 

Discomfort

Malaise

 

 

 

 

 

 

 

* 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:

 

BEFORE

AFTER

“Pharmacotherapeutic group: paramagnetic contrast media, ATC code: V08 C A10

 

Primovist is a paramagnetic contrast agent for magnetic resonance imaging. The contrast-enhancing effect is mediated by the stable gadolinium complex, Gd-EOB-DTPA. The paramagnetic efficacy, the relaxivity (determined from the influence on the spin-lattice relaxation time of protons in plasma) is about 8.7 l/mmol/sec at pH 7, 39 °C at 0.47 T and displays only slight dependency on the strength of the magnetic field. In T1-weighted scanning the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase in signal intensity and, hence, to an increase in the image contrast of certain tissues.

EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with extremely high thermodynamic stability (log KGdl = –23.46). Gd-EOB-DTPA is a highly water-soluble, hydrophilic compound with a lipophilic moiety due to the ethoxybenzyl group.

 

Lesions with no or minimal hepatocyte function (cysts, metastases, the majority of hepatocellular carcinoma) will not accumulate Primovist. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a correct diagnosis.

 

Imaging

After bolus injection of Primovist, dynamic imaging during arterial, portovenous and equilibrium phases utilizes the different temporal enhancement pattern of different liver lesions as basis for the radiological lesion characterization.

The enhancement of liver parenchyma during the hepatocyte phase assists in the identification of the number, segmental distribution, visualization, and delineation of liver lesions, thus improving lesion detection. The differential enhancement/washout pattern of liver lesions contributes to the information from the dynamic phase.

The delayed (hepatocyte) phase can be investigated at 20 minutes post injection with an imaging window lasting at least 120 minutes. The diagnostic and technical efficacy results of the clinical studies show a minimal improvement at 20 minutes post injection over those at 10 minutes post injection.

The imaging window is reduced to 60 minutes in patients requiring hemodialysis and in patients with elevated bilirubin values (> 3 mg/dl).

 

Hepatic excretion of Primovist results in enhancement of biliary structures.

The physico-chemical characteristics of the ready-to-use solution of Primovist are as follows:

 

Osmolality at 37 oC (mOsm/kg H2O)

688

Viscosity at 37 oC (mPa . s)

1.19

Density at 37 oC (g/ml)

1.0881

pH

7.4

“Pharmacotherapeutic group: paramagnetic contrast media, ATC code: V08 C A10

 

·         Mechanism of action

Primovist is a paramagnetic contrast agent for magnetic resonance imaging.

 

The contrast-enhancing effect is mediated by gadoxetate (Gd EOB DTPA), an ionic complex consisting of gadolinium (III) and the ligand ethoxybenzyl-diethylenetriamine-pentaacetic acid (EOB-DTPA).

When T1-weighted scanning sequences are used in proton magnetic resonance imaging, the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues.

 

·          Pharmacodynamic effects

Gadoxetate disodium leads to a distinct shortening of the relaxation times even at low concentrations. At pH 7, a magnetic field strength of 0.47 T and 40°C the relaxivity (r1) ‑ determined from the influence on the spin‑lattice relaxation time (T1) of protons in plasma ‑ is about 8.18 l/mmol/sec and the relaxivity (r2) ‑ determined from the influence on the spin-spin relaxation time (T2) ‑ is about 8.56 l/mmol/sec. At 1.5 T and 37°C the respective relaxivities in plasma are r1 = 6.9 l/mmol/sec and r2 = 8.7 l/mmol/sec. The relaxivity displays a slight inverse dependency on the strength of the magnetic field.

 

EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with extremely high thermodynamic stability (log KGdl = 23.46). Gd-EOB-DTPA is a highly water-soluble, hydrophilic compound with a partition coefficient between n‑butanol and buffer at pH 7.6 of about 0.011. Due to its lipophilic ethoxybenzyl moiety gadoxetate disodium exhibits a biphasic mode of action: first, distribution in the extracellular space after bolus injection and subsequently selective uptake by hepatocytes. The relaxivity r1 in liver tissue is 16.6 l/mmol/sec (at 0.47T) resulting in increased signal intensity of liver tissue. Subsequently gadoxetate disodium is excreted into the bile.

Lesions with no or minimal hepatocyte function (cysts, metastases, the majority of hepatocellular carcinoma) will not accumulate Primovist. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a correct diagnosis.

The substance does not display any significant inhibitory interaction with enzymes at clinically relevant concentrations.

 

·         Imaging

After bolus injection of Primovist, dynamic imaging during arterial, portovenous and equilibrium phases utilizes the different temporal enhancement pattern of different liver lesions as basis for the radiological lesion characterization.

The enhancement of liver parenchyma during the hepatocyte phase assists in the identification of the number, segmental distribution, visualization, and delineation of liver lesions, thus improving lesion detection. The differential enhancement/washout pattern of liver lesions contributes to the information from the dynamic phase.

The delayed (hepatocyte) phase can be investigated at 20 minutes post injection with an imaging window lasting at least 120 minutes. The diagnostic and technical efficacy results of the clinical studies show a minimal improvement at 20 minutes post injection over those at 10 minutes post injection.

The imaging window is reduced to 60 minutes in patients requiring hemodialysis and in patients with elevated bilirubin values (> 3 mg/dl).

Hepatic excretion of Primovist results in enhancement of biliary structures.

 

The physico-chemical characteristics of the ready-to-use solution of Primovist are as follows:

 

Osmolality at 37 °C (mOsm/kg H2O)

688

Viscosity at 37 °C (mPa·s)

1.19

Density at 37 °C (g/ ml)

1.0881

pH

7.4

 

Section 5.2: Pharmacokinetic properties has been updated as follows:

 

BERORE

AFTER

 

·         Distribution

After intravenous administration the concentration time profile of Gd-EOB-DTPA was characterised by a bi-exponential decline.

 

Gd-EOB-DTPA distributes in the extracellular space (distribution volume at steady state about 0.21 l/kg).

 

The substance elicits only minor protein binding (less than 10%).

 

The compound does not pass the intact blood-brain barrier and diffuses through the placental barrier only to a small extent.

 

·         Elimination

Gd-EOB-DTPA is equally eliminated via the renal and hepatobiliary routes. The half–life of Gd-EOB-DTPA was approximately 1.0 hour. The pharmacokinetics was dose-linear up to the dose of 0.4 ml/kg (100 micromol/kg).

A total serum clearance (Cltot) of about 250 ml/min was recorded, whereas the renal clearance (Clr) corresponds to about 120 ml/min.

·         Characteristics in patients

In patients with mild and moderate hepatic impairment , a slight to moderate increase in plasma concentration, half-life and urinary excretion, as well as decrease in hepatobiliary excretion have been observed in comparison to subjects with normal liver function. However, no clinically relevant differences in hepatic signal enhancement were observed. In patients with severe hepatic impairment, especially in patients with abnormally high ( > 3 mg/dl) serum bilirubin levels, plasma concentration and half-life is increased with pronounced decrease in hepatobiliary excretion and reduced hepatic signal enhancement.

 

In patients with end-stage renal failure the half-life is markedly prolonged and the AUC increased 6-fold. Hemodialysis increased the clearance of Gd-EOB-DTPA (see section 4.2). In an average dialysis session of about 3-hour duration, about 30% of the Gd-EOB-DTPA dose was removed by hemodialysis.

 

 

·    Distribution

After intravenous administration the concentration time profile of Gd-EOB-DTPA was characterised by a bi-exponential decline.

Gd-EOB-DTPA distributes in the extracellular space (distribution volume at steady state about 0.21 l/kg).

The substance elicits only minor protein binding (less than 10%).

The compound does not pass the intact blood-brain barrier and diffuses through the placental barrier only to a small extent.

 

·     Metabolism

Gadoxetate disodium is not metabolized.

 

·    Elimination

Gd-EOB-DTPA is equally eliminated via the renal and hepatobiliary routes. The half–life of Gd-EOB-DTPA was approximately 1.0 hour.The pharmacokinetics was dose-linear up to the dose of  0.4 ml/kg (100 micromol/kg).

A total serum clearance (Cltot) of about 250 ml/min was recorded, whereas the renal clearance (Clr) corresponds to about 120 ml/min.

 

·    Characteristics in in special patient population

 

Elderly population (aged 65 years and above)

In accordance with the physiological changes in renal function with age, the plasma clearance of gadoxetate disodium was reduced from 210 ml/min in non-elderly subjects to 163 ml/min in elderly subjects aged 65 years and above. Terminal half-life and systemic exposure were higher in the elderly (2.3 h and 197 µmol*h/l, compared to 1.6 h and 153 µmol*h/l, respectively). The renal excretion was complete after 24 h in all subjects with no difference between elderly and non-elderly healthy subjects.

 

Renal and/or hepatic impairment

In patients with mild and moderate hepatic impairment, a slight to moderate increase in plasma concentration, half-life and urinary excretion, as well as decrease in hepatobiliary excretion have been observed in comparison to subjects with normal liver function. However, no clinically relevant differences in hepatic signal enhancement were observed. In patients with severe hepatic impairment, especially in patients with abnormally high ( > 3 mg/dl) serum bilirubin levels, the AUC was increased to 259 µmol*h/l compared to 160 µmol*h/l in the control group. The elimination half-life was increased to 2.6 h compared to 1.8 h in the control group. The hepatobiliary excretion substantially decreased to 5.7% of the administered dose and  the hepatic signal enhancement is reduced in these patients.

 

In patients with end-stage renal failure the AUC increased 6-fold to about 903 µmol*h/l and the terminal half-life was prolonged to about 20 h. Hemodialysis increased the clearance of gadoxetate disodium (see section 4.4). In an average dialysis session of about 3-hour duration, about 30% of the gadoxetate disodium dose was removed by hemodialysis starting 1 hour post injection. In addition to clearance by hemodialysis, a significant fraction of the administered gadoxetate dose is biliary excreted in these patients as shown by a mean recovery of about 50% in feces within 4 days (range 24.6 to 74.0%, n=6 patients).

 

 

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:

BEFORE

AFTER

caloxetic acid, trisodium

trometamol

hydrochloric acid (for pH adjustment)

sodium hydroxide (for pH adjustment)

water for injections

Caloxetate trisodium

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Trometamol

Water for injections

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”

 

 

 

Updated on 22 November 2011 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.1 - List of excipients
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company


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:

 

BEFORE

AFTER

“Primovist is a ready-to-use aqueous solution to be administered undiluted as an intravenous bolus injection at a flow rate of about 2 ml/sec. After the injection of the contrast medium the intravenous cannula should be flushed using sterile 9 mg/ml (0.9 %) saline solution.

The recommended dose of Primovist is:

Adults:

0.1 ml/kg body weight Primovist.
For detailed imaging information refer to section 5.1.

Repeated use:

No clinical information is available about repeated use of Primovist.

 

Special Populations

 

Impaired renal function

 

Use of Primovist should be avoided in patients with severe renal impairment (GFR < 30 ml/min/1.73m2) and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4).  If use of Primovist cannot be avoided, the dose should not exceed 0.025 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Primovist injections should not be repeated unless the interval between injections is at least 7 days.

 

Patients with hepatic impairment:

No dosage adjustment is necessary.

 

Paediatric population

 

The safety and efficacy of Primovist has not been established in patients under 18 years old. Therefore, use of Primovist in this patient group cannot be recommended.

 

Elderly population (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

Primovist is a ready-to-use aqueous solution to be administered undiluted as an intravenous bolus injection at a flow rate of about 2 ml/sec. After the injection of the contrast medium the intravenous cannula/ line should be flushed using sterile 9 mg/ml (0.9 %) saline solution.

For detailed imaging information refer to section 5.1.

For additional instructions see section 6.6.

 

Posology

The recommended dose of Primovist is:

Adults:

0.1 ml per kg body weight Primovist.

 

Repeated use:

No clinical information is available about repeated use of Primovist.

 

Additional information on special populations

 

·         Impaired renal function

Use of Primovist should be avoided in patients with severe renal impairment (GFR < 30 ml/min/1.73m2) and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4).  If use of Primovist cannot be avoided, the dose should not exceed 0.025 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Primovist injections should not be repeated unless the interval between injections is at least 7 days.

 

·         Patients with hepatic impairment

No dosage adjustment is necessary.

 

·         Paediatric population

The safety and efficacy of Primovist has not been established in patients under 18 years old. Therefore, use of Primovist in this patient group cannot be recommended.

 

·         Elderly population (aged 65 years and above)

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

 

 

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.

  

 

 

 

Adverse reactions

 

 

From clinical trial data

From postmarketing spontaneous reporting

System Organ Class (MedDra)

 

Uncommon

(≥1/1000 to <1/100)

Rare

(≥1/10 000 to <1/1000)

Frequency not known (cannot be estimated from available data)***

Nervous system disorders

headache

dizziness

dysgeusia

paresthesia

parosmia

vertigo

akathisia

tremor

 

restlessness

 

 

 

Cardiac disorders

 

bundle branch block

palpitation

tachycardia

 

Vascular disorders

blood pressure increased

flushing

 

 

 

Respiratory, thoracic and mediastinal disorders

respiratory disorders

(dyspnea, respiratory distress)

 

 

 

Gastrointestinal disorders

vomiting

nausea

dry mouth

oral discomfort

salivary hypersecretion

 

 

 

 

 

Skin and subcutaneous tissue disorders

rash

pruritus*

 

maculopapular rash

hyperhidrosis

 

 

Musculoskeletal and connective tissue

disorders

 

 

back pain

 

General disorders and administration site conditions

chest pain

injection site reactions

(various kinds)**

feeling hot

 

chills

discomfort

fatigue

malaise

feeling abnormal

 

 

 

 

 

 

 

Immune system disorders

 

 

hypersensitivity/

anaphylactoid reaction (e.g. shock, hypotension, pharyngolaryngeal oedema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypo(a) esthesia, sneezing, cough, pallor)

*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

 

System Organ Class (MedDra)

 

Common

Uncommon

 

Rare

 

Not known

Immune system disorders

 

 

 

Hypersensitivity /

anaphylactoid reaction (e.g. shock*, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough, pallor)

Nervous system disorders

Headache

Vertigo

Dizziness

Dysgeusia

Paresthesia

Parosmia

Tremor

Akathisia

 

Restlessness

 

 

 

Cardiac disorders

 

 

Bundle branch block

Palpitation

Tachycardia

 

Vascular disorders

 

Blood pressure increased

Flushing

 

 

 

Respiratory, thoracic and mediastinal disorders

 

Respiratory disorders

(Dyspnea*, Respiratory distress)

 

 

 

Gastrointestinal disorders

Nausea

Vomiting

Dry mouth

Oral discomfort

Salivary hypersecretion

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

Rash

Pruritus**

 

Maculopapular rash

Hyperhidrosis

 

 

Musculoskeletal and connective tissue

disorders

 

Back pain

 

 

General disorders and administration site conditions

 

Chest pain

Injection site reactions

(various kinds)***

Feeling hot

Chills

Fatigue

Feeling abnormal

 

Discomfort

Malaise

 

 

 

 

 

 

 

* 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:

 

BEFORE

AFTER

“Pharmacotherapeutic group: paramagnetic contrast media, ATC code: V08 C A10

 

Primovist is a paramagnetic contrast agent for magnetic resonance imaging. The contrast-enhancing effect is mediated by the stable gadolinium complex, Gd-EOB-DTPA. The paramagnetic efficacy, the relaxivity (determined from the influence on the spin-lattice relaxation time of protons in plasma) is about 8.7 l/mmol/sec at pH 7, 39 °C at 0.47 T and displays only slight dependency on the strength of the magnetic field. In T1-weighted scanning the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase in signal intensity and, hence, to an increase in the image contrast of certain tissues.

EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with extremely high thermodynamic stability (log KGdl = –23.46). Gd-EOB-DTPA is a highly water-soluble, hydrophilic compound with a lipophilic moiety due to the ethoxybenzyl group.

 

Lesions with no or minimal hepatocyte function (cysts, metastases, the majority of hepatocellular carcinoma) will not accumulate Primovist. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a correct diagnosis.

 

Imaging

After bolus injection of Primovist, dynamic imaging during arterial, portovenous and equilibrium phases utilizes the different temporal enhancement pattern of different liver lesions as basis for the radiological lesion characterization.

The enhancement of liver parenchyma during the hepatocyte phase assists in the identification of the number, segmental distribution, visualization, and delineation of liver lesions, thus improving lesion detection. The differential enhancement/washout pattern of liver lesions contributes to the information from the dynamic phase.

The delayed (hepatocyte) phase can be investigated at 20 minutes post injection with an imaging window lasting at least 120 minutes. The diagnostic and technical efficacy results of the clinical studies show a minimal improvement at 20 minutes post injection over those at 10 minutes post injection.

The imaging window is reduced to 60 minutes in patients requiring hemodialysis and in patients with elevated bilirubin values (> 3 mg/dl).

 

Hepatic excretion of Primovist results in enhancement of biliary structures.

The physico-chemical characteristics of the ready-to-use solution of Primovist are as follows:

 

Osmolality at 37 oC (mOsm/kg H2O)

688

Viscosity at 37 oC (mPa . s)

1.19

Density at 37 oC (g/ml)

1.0881

pH

7.4

“Pharmacotherapeutic group: paramagnetic contrast media, ATC code: V08 C A10

 

·         Mechanism of action

Primovist is a paramagnetic contrast agent for magnetic resonance imaging.

 

The contrast-enhancing effect is mediated by gadoxetate (Gd EOB DTPA), an ionic complex consisting of gadolinium (III) and the ligand ethoxybenzyl-diethylenetriamine-pentaacetic acid (EOB-DTPA).

When T1-weighted scanning sequences are used in proton magnetic resonance imaging, the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues.

 

·          Pharmacodynamic effects

Gadoxetate disodium leads to a distinct shortening of the relaxation times even at low concentrations. At pH 7, a magnetic field strength of 0.47 T and 40°C the relaxivity (r1) ‑ determined from the influence on the spin‑lattice relaxation time (T1) of protons in plasma ‑ is about 8.18 l/mmol/sec and the relaxivity (r2) ‑ determined from the influence on the spin-spin relaxation time (T2) ‑ is about 8.56 l/mmol/sec. At 1.5 T and 37°C the respective relaxivities in plasma are r1 = 6.9 l/mmol/sec and r2 = 8.7 l/mmol/sec. The relaxivity displays a slight inverse dependency on the strength of the magnetic field.

 

EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with extremely high thermodynamic stability (log KGdl = 23.46). Gd-EOB-DTPA is a highly water-soluble, hydrophilic compound with a partition coefficient between n‑butanol and buffer at pH 7.6 of about 0.011. Due to its lipophilic ethoxybenzyl moiety gadoxetate disodium exhibits a biphasic mode of action: first, distribution in the extracellular space after bolus injection and subsequently selective uptake by hepatocytes. The relaxivity r1 in liver tissue is 16.6 l/mmol/sec (at 0.47T) resulting in increased signal intensity of liver tissue. Subsequently gadoxetate disodium is excreted into the bile.

Lesions with no or minimal hepatocyte function (cysts, metastases, the majority of hepatocellular carcinoma) will not accumulate Primovist. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a correct diagnosis.

The substance does not display any significant inhibitory interaction with enzymes at clinically relevant concentrations.

 

·         Imaging

After bolus injection of Primovist, dynamic imaging during arterial, portovenous and equilibrium phases utilizes the different temporal enhancement pattern of different liver lesions as basis for the radiological lesion characterization.

The enhancement of liver parenchyma during the hepatocyte phase assists in the identification of the number, segmental distribution, visualization, and delineation of liver lesions, thus improving lesion detection. The differential enhancement/washout pattern of liver lesions contributes to the information from the dynamic phase.

The delayed (hepatocyte) phase can be investigated at 20 minutes post injection with an imaging window lasting at least 120 minutes. The diagnostic and technical efficacy results of the clinical studies show a minimal improvement at 20 minutes post injection over those at 10 minutes post injection.

The imaging window is reduced to 60 minutes in patients requiring hemodialysis and in patients with elevated bilirubin values (> 3 mg/dl).

Hepatic excretion of Primovist results in enhancement of biliary structures.

 

The physico-chemical characteristics of the ready-to-use solution of Primovist are as follows:

 

Osmolality at 37 °C (mOsm/kg H2O)

688

Viscosity at 37 °C (mPa·s)

1.19

Density at 37 °C (g/ ml)

1.0881

pH

7.4

 

Section 5.2: Pharmacokinetic properties has been updated as follows:

 

BERORE

AFTER

 

·         Distribution

After intravenous administration the concentration time profile of Gd-EOB-DTPA was characterised by a bi-exponential decline.

 

Gd-EOB-DTPA distributes in the extracellular space (distribution volume at steady state about 0.21 l/kg).

 

The substance elicits only minor protein binding (less than 10%).

 

The compound does not pass the intact blood-brain barrier and diffuses through the placental barrier only to a small extent.

 

·         Elimination

Gd-EOB-DTPA is equally eliminated via the renal and hepatobiliary routes. The half–life of Gd-EOB-DTPA was approximately 1.0 hour. The pharmacokinetics was dose-linear up to the dose of 0.4 ml/kg (100 micromol/kg).

A total serum clearance (Cltot) of about 250 ml/min was recorded, whereas the renal clearance (Clr) corresponds to about 120 ml/min.

·         Characteristics in patients

In patients with mild and moderate hepatic impairment , a slight to moderate increase in plasma concentration, half-life and urinary excretion, as well as decrease in hepatobiliary excretion have been observed in comparison to subjects with normal liver function. However, no clinically relevant differences in hepatic signal enhancement were observed. In patients with severe hepatic impairment, especially in patients with abnormally high ( > 3 mg/dl) serum bilirubin levels, plasma concentration and half-life is increased with pronounced decrease in hepatobiliary excretion and reduced hepatic signal enhancement.

 

In patients with end-stage renal failure the half-life is markedly prolonged and the AUC increased 6-fold. Hemodialysis increased the clearance of Gd-EOB-DTPA (see section 4.2). In an average dialysis session of about 3-hour duration, about 30% of the Gd-EOB-DTPA dose was removed by hemodialysis.

 

 

·    Distribution

After intravenous administration the concentration time profile of Gd-EOB-DTPA was characterised by a bi-exponential decline.

Gd-EOB-DTPA distributes in the extracellular space (distribution volume at steady state about 0.21 l/kg).

The substance elicits only minor protein binding (less than 10%).

The compound does not pass the intact blood-brain barrier and diffuses through the placental barrier only to a small extent.

 

·     Metabolism

Gadoxetate disodium is not metabolized.

 

·    Elimination

Gd-EOB-DTPA is equally eliminated via the renal and hepatobiliary routes. The half–life of Gd-EOB-DTPA was approximately 1.0 hour.The pharmacokinetics was dose-linear up to the dose of  0.4 ml/kg (100 micromol/kg).

A total serum clearance (Cltot) of about 250 ml/min was recorded, whereas the renal clearance (Clr) corresponds to about 120 ml/min.

 

·    Characteristics in in special patient population

 

Elderly population (aged 65 years and above)

In accordance with the physiological changes in renal function with age, the plasma clearance of gadoxetate disodium was reduced from 210 ml/min in non-elderly subjects to 163 ml/min in elderly subjects aged 65 years and above. Terminal half-life and systemic exposure were higher in the elderly (2.3 h and 197 µmol*h/l, compared to 1.6 h and 153 µmol*h/l, respectively). The renal excretion was complete after 24 h in all subjects with no difference between elderly and non-elderly healthy subjects.

 

Renal and/or hepatic impairment

In patients with mild and moderate hepatic impairment, a slight to moderate increase in plasma concentration, half-life and urinary excretion, as well as decrease in hepatobiliary excretion have been observed in comparison to subjects with normal liver function. However, no clinically relevant differences in hepatic signal enhancement were observed. In patients with severe hepatic impairment, especially in patients with abnormally high ( > 3 mg/dl) serum bilirubin levels, the AUC was increased to 259 µmol*h/l compared to 160 µmol*h/l in the control group. The elimination half-life was increased to 2.6 h compared to 1.8 h in the control group. The hepatobiliary excretion substantially decreased to 5.7% of the administered dose and  the hepatic signal enhancement is reduced in these patients.

 

In patients with end-stage renal failure the AUC increased 6-fold to about 903 µmol*h/l and the terminal half-life was prolonged to about 20 h. Hemodialysis increased the clearance of gadoxetate disodium (see section 4.4). In an average dialysis session of about 3-hour duration, about 30% of the gadoxetate disodium dose was removed by hemodialysis starting 1 hour post injection. In addition to clearance by hemodialysis, a significant fraction of the administered gadoxetate dose is biliary excreted in these patients as shown by a mean recovery of about 50% in feces within 4 days (range 24.6 to 74.0%, n=6 patients).

 

 

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