Consumer medicine information

Primovist

Gadoxetic acid

BRAND INFORMATION

Brand name

Primovist Solution for injection

Active ingredient

Gadoxetic acid

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Primovist.

WHAT IS IN THIS LEAFLET

This leaflet answers some of the common questions about Primovist. It does not contain all available information. It does not take the place of talking to your doctor.

All diagnostic agents have risks and benefits. Your doctor has weighed the risks of you using Primovist against the benefits they expect it will have for you.

If you have any concerns about using this diagnostic agent, ask your doctor or radiologist.

Keep this leaflet.

You may need to read it again.

WHAT PRIMOVIST IS USED FOR

Primovist is used to help detect and diagnose changes that may be found in the liver. Abnormal signs within the liver can be better evaluated. Primovist can also help the doctor determine the nature of any abnormalities, thereby increasing the confidence one can have in the diagnosis. The diagnosis can be made quicker, earlier, and with greater accuracy than without using Primovist.

Primovist is used together with an imaging technique called magnetic resonance imaging (MRI). MRI is a form of medical diagnostic imaging that distinguishes between normal and abnormal tissues without using x-rays.

Primovist is a magnetic liquid that alters the way in which tissues appear, showing abnormalities that may not be visible using MRI alone.

Primovist is available only at MRI units for use in conjunction with MRI.

Primovist is for diagnostic use only.

Ask your doctor/radiologist if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

BEFORE YOU ARE GIVEN PRIMOVIST

When you must not be given it

You must not be given Primovist if you have an allergy to:

  • disodium gadoxetate, the active ingredient in Primovist
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

You must not be given Primovist after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

The doctor will check this for you.

If you are not sure whether you should be given this diagnostic agent, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any medicines, foods, preservatives or dyes.

In some cases you may need special care with Primovist and your doctor will need to consider whether to give you Primovist.

Your doctor might check your kidney function before giving Primovist.

Recent information shows that gadolinium (as in Primovist) may build up in the brain after multiple uses and the effect on the brain is unknown right now. Your doctor will:

  • carefully consider whether to use repeated doses
  • use the lowest dose

Tell your doctor if you have, or have had, any medical conditions especially the following:

  • severe heart problems
  • kidney problems
  • any allergies
  • bronchial asthma.

Tell your doctor if you are pregnant, or think you may be pregnant, or if you are breastfeeding.

Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you have a heart pacemaker or any material implanted in your body.

Tell your doctor if are on a low sodium diet.

The use of PRIMOVIST in patients younger than 18 years is not recommended because no clinical experience is available.

If you have not told your doctor about any of the above, tell him/her before you are given Primovist.

Taking other medicines

Tell your doctor or radiologist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Primovist may interfere with each other. These include:

  • medicines to treat high blood pressure
  • medicines that affect the rhythm of the heart
  • medicines to treat infections (such as rifampicin)

These medicines may be affected by Primovist or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Your doctor/radiologist has more information on medicines to be careful with or avoid while receiving Primovist.

HOW PRIMOVIST IS GIVEN

How much is given

The dose of Primovist varies depending on your weight. The doctor will decide how much Primovist is needed for your examination.

How it is given

You will be asked to lie down on the MRI scanning bed and then you will be given Primovist by injection into a vein. The usual injection site is the back of your hand or just in front of your elbow.

When it is given

Scanning may start immediately after the Primovist injection. After the injection you will be observed for at least 30 minutes.

How to prepare the PRIMOVIST syringe for injection

Glass syringe only:

Peel the cover from the syringe tray and take the syringe and plunger rod out of the package.

Screw the plunger into the syringe tightly

Break the first part of the protective grey cap

Remove the protective grey cap from the tip of the syringe

Remove the black stopper from the second part of the grey cap

Remove the air in the syringe

Plastic syringe only:

Hand injection:

  1. Open the package
  1. Take the syringe and plunger rod out of the package
  1. Screw the plunger rod into the syringe
  1. Unscrew the cap from the syringe
  1. Remove the air in the syringe

Injection with a power injector:

  1. Open the package
  1. Take the syringe out of the package
  1. Unscrew the cap from the syringe
  1. Connect the tip of the syringe onto the tubing system and follow the device manufacturer’s instructions

If you take are given too much (overdose)

As Primovist is administered by a doctor, overdose is unlikely. If it does happen, the doctor will treat any symptoms that follow.

If you currently have a problem with your kidneys or liver, the doctor may decide to remove Primovist from the body by means of a blood-cleansing procedure (dialysis).

If in doubt it is recommended to telephone the Poisons Information Centre (Australia: 13 11 26 or New Zealand: 0800 POISON or 0800 764 766) for advice if you think that you or anyone else may have been given too much Primovist. Do this even if there are no signs of discomfort or poisoning.

AFTER YOU ARE GIVEN PRIMOVIST

Things you must do

Follow carefully the directions given to you by your doctor and other medical staff.

You may also be advised to take fluids before and after the procedure to help protect your kidneys.

Things to be careful of

Tell you doctor if you are going to have any laboratory tests.

Be careful when driving or operating machinery until you know how Primovist affects you.

SIDE EFFECTS

Tell your doctor or radiologist as soon as possible if you do not feel well whilst receiving or after being given Primovist.

All diagnostic agents can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • headache
  • nausea
  • feeling hot
  • dizziness

The above list includes the more common side effects of Primovist. They are usually mild and short-lived. If they persist or get worse, tell your doctor.

Tell your doctor immediately if you notice any of the following:

  • swelling of the face, eyelids, lips, tongue or other parts of the body
  • watering, sore or inflamed eyes
  • sneezing, runny nose, coughing or throat irritation
  • itching or hives
  • difficulty breathing, gasping
  • decrease sense of touch or sensation
  • pale skin

Some of these side effects could be the first signs of an allergic reaction. You may need urgent medical attention or hospitalisation.

Allergic reactions occur more frequently in patients with an allergic disposition.

Severe reactions requiring emergency treatment can occur, causing low blood pressure, increase in heart rate, difficulty breathing, and swelling of the face, lips or tongue leading to severe breathing difficulties and shock may occur.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people. Rarely, delayed reactions can occur.

STORING PRIMOVIST

Storage

The MRI unit will store Primovist under the conditions advised by the manufacturer. Shelf life and storage conditions are printed on the pack.

PRODUCT DESCRIPTION

What it looks like

Primovist is supplied in glass vials or glass pre-filled syringes or plastic pre-filled syringes.

Ingredients

Active ingredients:

  • Primovist – contains 181.43 mg (250 μmol) of disodium gadoxetate

Inactive ingredients:

  • trisodium caloxetate
  • trometamol
  • hydrochloric acid
  • sodium hydroxide
  • water for injections

Australian Registration Number

Primovist 5mL vial -
AUST R 102088

Primovist 5mL pre filled syringe -
AUST R 102089

Primovist 7.5mL vial -
AUST R 104374

Primovist 7.5mL pre filled syringe -
AUST R 104380

Primovist 10mL vial -
AUST R 104379

Primovist 10mL pre filled syringe -
AUST R 104381

Supplier

Made in Germany for:

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Bayer New Zealand Limited
3 Argus Place, Hillcrest,
North Shore
Auckland 0627

Date of Preparation

October 2017

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website (www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered Trademark of Bayer AG, Germany

© Bayer Australia Ltd

All rights reserved.

BRAND INFORMATION

Brand name

Primovist Solution for injection

Active ingredient

Gadoxetic acid

Schedule

Unscheduled

 

1 Name of Medicine

Disodium gadoxetate.

6.7 Physicochemical Properties

Chemical structure.

Primovist 0.25 mmol/mL, solution for injection is an injectable contrast media agent for use in Magnetic Resonance Imaging (MRI) and contains disodium gadoxetate (Gd-EOB-DTPA). The chemical name for disodium gadoxetate is (4S)-4-(4-ethoxybenzyl)-3,6,9-triazaundecanedioic acid, gadolinium-complex, disodium salt and has the following chemical structure:
Molecular weight: 725.7.

CAS number.

135326-22-6.
Chemical formula: C23H28N3O11.Gd.2Na.

Physicochemical properties.

The physicochemical properties of Primovist are listed below:
Osmolality at 37°C (mOsm/kg H2O): 688.
Density at 37°C (g/mL): 1.0881.
Viscosity at 37°C (mPa.s): 1.19.
pH: 6.8-8.0.

2 Qualitative and Quantitative Composition

Each 1 mL of the magnetic resonance imaging (MRI) contrast agent Primovist contains 0.25 mmol disodium gadoxetate (equivalent to 181.43 mg disodium gadoxetate as the active ingredient).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Primovist is a paramagnetic contrast agent for magnetic resonance imaging. The contrast enhancing effect is mediated by gadoxetate, an ionic complex consisting of gadolinium (III) and the ethoxybenzyl diethylenetriamine pentaacetic acid which contains the lipophilic ethoxybenzyl moiety (Gd-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.

Disodium gadoxetate leads to a distinct shortening of the relaxation times even at low concentrations. At 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 8.7 L/(mmol.sec) and the relaxivity (r2) determined from the influence on the spin spin relaxation time (T2) is about 13 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.
Ethoxybenzyl-diethylenetriaminepenta-acetate forms a stable complex with the paramagnetic gadolinium ion with extremely high thermodynamic in vitro stability (thermodynamic stability constant: log KGdL = 23.46). Disodium gadoxetate is a highly water soluble, hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.011.

Clinical trials.

There were four pivotal phase III studies conducted with Primovist, consisting of 2 twin studies (same protocol used in Europe and USA). The first pair of studies determined the diagnostic efficacy and safety of a single dose of Primovist 0.1 mL/kg (25 micromol/kg) bodyweight with regard to liver lesion detection in adult patients with known or suspected liver lesions who were scheduled for surgery (study number 96129; report number A00518 and study number 97160; report number A03779). The second pair of studies investigated the ability of Primovist 0.1 mL/kg (25 micromol/kg) bodyweight to provide additional information for characterisation of liver lesions in adult patients with known or suspected focal liver lesions (study number 12387; report number A05742 and study number 14763; report number A01908). There were 816 patients enrolled in the pivotal phase III studies with 621 and 673 patients included in the preferred efficacy analysis and ITT (intent to treat) efficacy analysis, respectively, and 797 patients valid for the safety analysis. All clinical phase III studies were designed as intraindividual, controlled, multicentre studies with unenhanced precontrast scans and biphasic enhanced spiral CT as the clinical standard for intraindividual comparison. The images from the 4 pivotal studies were assessed by independent experienced radiologists in a blinded evaluation (blinded reading) in addition to the clinical evaluation. The results of the 4 pivotal studies were based on a predefined standard of reference (standard of truth).
The results of the phase III clinical studies are presented in Tables 2, 3 and 4.
Statistically significant increase in sensitivity in lesion detection was seen for 3/6 readers in the preferred population and 4/6 readers in the intent to treat (ITT) population for combined pre- and post-contrast MRI compared to precontrast MRI. When post-contrast images were evaluated alone, a statistically significant increase in sensitivity compared to precontrast MRI was shown by 4/6 readers for the preferred (PP) and ITT population. In comparison to biphasic spiral CT, there was a comparable performance of the combined pre- and post-contrast MRI and post-contrast MRI for 4/6 readers. The number of false positive lesions was higher for 5/6 readers in biphasic enhanced spiral CT compared to combined pre- and post-contrast MRI and for 4/6 readers compared to post-contrast MRI.

5.2 Pharmacokinetic Properties

Absorption and distribution.

After intravenous administration, the plasma concentration time profile of disodium gadoxetate is characterised by a bi-exponential decline. The total distribution volume of disodium gadoxetate at steady state is about 0.21 L/kg (extracellular space). The plasma protein binding is less than 10%.
The compound diffuses through the placental barrier only to a small extent as demonstrated in rats.
Current evidence suggests that gadolinium accumulates in the brain after repeated administrations of gadolinium-based contrast agents (GBCAs) although the exact mechanism of gadolinium passage into the brain has not been established.

Metabolism.

Disodium gadoxetate is not metabolised.

Excretion.

Disodium gadoxetate is equally eliminated via the renal and hepatobiliary routes.
The mean terminal elimination half-life of disodium gadoxetate (dose 0.01 to 0.1 mmol/kg) observed in healthy subjects was about 1 hour. A total serum clearance (CL) of about 250 mL/min was recorded, whereas renal clearance (CLr) corresponds to about 120 mL/min, a value similar to the glomerular filtration rate in healthy subjects.

Linearity/nonlinearity.

Disodium gadoxetate shows linear pharmacokinetics, i.e. pharmacokinetic parameters change dose proportionally (e.g. Cmax, AUC) or are dose independent (e.g. Vss, t1/2), up to a dose of 100 micromol/kg body weight (0.4 mL/kg).

Characteristics in special patient populations.

A phase III study with 25 micromol per kg body weight Primovist compared subjects with various levels of impaired hepatic function, impaired renal function, coexistent hepatic and renal impairment, and healthy subjects of different age groups, including elderly.

Patients with renal impairment.

Although the systemic body exposure with gadolinium is low based on the diagnostic dosage of Primovist as well as its dual elimination pathways (renal and hepatobiliary), there is a possibility that NSF may occur with Primovist. Therefore, gadolinium containing contrast agents should only be used in these patients after careful consideration.
In patients with moderate renal impairment, an increase in AUC to 237 micromol.h/L and of terminal half-life to 2.2 h was observed. In patients with end-stage renal failure, the AUC was increased to about 903 micromol.h/L and the terminal half-life prolonged to about 20 h in patients. About 55% of the administered dose was recovered in faeces within the observation period of 6 days, the majority within 3 days.
Disodium gadoxetate can be removed from the body by haemodialysis. About 30% of the administered dose were recovered in the dialysate in a 3 hour dialysis starting 1 hour post injection. In the study with endstage renal failure patients, disodium gadoxetate was almost completely eliminated via dialysis and biliary excretion within 6 days. Plasma concentrations of disodium gadoxetate were measurable up to 72 hours postdose in these patients (see Section 4.4 Special Warnings and Precautions for Use).

Patients with hepatic impairment.

In patients with mild or moderate hepatic impairment, a slight to moderate increase in plasma AUC, half-life and urinary excretion, as well as a decrease in hepatobiliary excretion were observed in comparison to healthy subjects.
In patients with severe hepatic impairment, especially in patients with abnormally high serum bilirubin levels (> 3 mg/dL, > 51.3 mmol/L) the AUC was increased to 259 micromol.h/L compared to 160 micromol.h/L in the control group. The elimination half-life was increased to 2.6 hours compared to 1.8 h in the control group. The hepatobiliary excretion substantially decreased to 5.7% of the administered dose in these patients.

5.3 Preclinical Safety Data

Genotoxicity.

Gadoxetic acid was not mutagenic in bacteria (Salmonella typhimurium and Escherichia coli) or a mammalian cell line (Chinese hamster V79), did not induce chromosomal aberrations in human lymphocytes in vitro, did not induce unscheduled DNA synthesis in rat hepatocytes in vitro or in vivo and did not induce micronuclei in bone marrow erythrocytes in mice.

Carcinogenicity.

Long-term animal studies to evaluate the carcinogenic potential of gadoxetic acid have not been performed.

4 Clinical Particulars

4.1 Therapeutic Indications

This medicinal product is for diagnostic use only.
Primovist is indicated for use in adults for the enhancement of magnetic resonance imaging (MRI) of focal liver lesions.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Warning nephrogenic systemic fibrosis.

Gadolinium based contrast agents increase the risk of nephrogenic systemic fibrosis (NSF) in patients with:
acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73 m2), or
acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period.
See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.

Impaired renal function.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with the use of some contrast agents containing gadolinium in patients with acute or chronic severe renal impairment (a glomerular filtration rate < 30 mL/min/1.73 m2) and patients with acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period. NSF is a debilitating and sometimes fatal disease affecting the skin, muscle, and internal organs.
Disodium gadoxetate can be removed from the body by haemodialysis. About 30% of the administered dose is eliminated from the body by a single dialysis session of 3 hours starting 1 hour post injection. In endstage renal failure patients, disodium gadoxetate was almost completely eliminated via dialysis and biliary excretion within the observation period of 6 days, the majority within 3 days.
For patients already receiving haemodialysis at the time of Primovist administration, prompt initiation of haemodialysis following the administration of Primovist should be considered, in order to enhance the contrast agent's elimination (see Section 5.2 Pharmacokinetic Properties).

NSF risk minimisation.

In patients with severely impaired renal function, the benefits must be weighed carefully against the risks, since contrast medium elimination is delayed in such cases. A sufficient period of time for elimination of the contrast agent from the body prior to any readministration in patients with renal impairment should be ensured.
Prior to administration of Primovist, it is recommended, that all patients are screened for renal dysfunction by obtaining a history and/or laboratory tests.

Impaired hepatic function.

Elevated levels of bilirubin (> 3 mg/dL or 51.3 micromol/L) or ferritin can reduce the hepatic contrast effect of Primovist. If Primovist is used in these patients, complete the magnetic resonance imaging no later than 60 minutes after Primovist administration.

Hypersensitivity.

Particularly careful risk/benefit assessment is required in patients with known hypersensitivity to Primovist. As with other intravenous contrast agents, Primovist can be associated with anaphylactoid/hypersensitivity or other idiosyncratic reactions characterized by cardiovascular, respiratory and cutaneous manifestations and ranging to severe reactions including shock.
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 the decision to use Primovist must be made after particularly careful evaluation of the risk/benefit ratio.
Most of these reactions occur within half an hour of administration. Therefore postprocedure observation of the patient is recommended. Due to the possibility of severe hypersensitivity reactions after intravenous contrast administration, medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures is necessary.
Delayed reactions after hours up to several days have been rarely observed (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients who experience such reactions while taking beta blockers may be resistant to treatment effects of beta agonists.

Local intolerance.

Intramuscular administration must be strictly avoided, because it may cause local intolerance reactions including focal necrosis.

Excipients.

This medicinal product contains 4 mmol sodium (82 mg) per dose (based on the amount given to a 70 kg person). To be taken into consideration by patients on a controlled sodium diet.

Cardiovascular disease.

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

QT prolongation.

In some in vitro and preclinical studies, there was evidence that administration of Primovist at doses significantly higher than recommended can lead to QTc prolongation. ECGs were regularly monitored during clinical studies and transient QT prolongation was observed in some patients without any associated adverse clinical events. Two of 468 patients (0.4%) in 2 phase III studies had an increase in QTc of > 60 msec from baseline to time points up to 20 to 28 hours after injection; no control group was studied. (QTc was calculated with the Fridericia formula. The baseline value was calculated as the mean QTc from two ECGs recorded before Primovist was given.) Given these observations, appropriate caution should be exercised when using Primovist, particularly in patients with known risk factors for arrhythmias associated with QT prolongation (e.g. underlying QT prolongation or use of other drugs that may prolong the QT interval).

Accumulation of gadolinium in the brain.

The current evidence suggests that gadolinium accumulates in the brain after multiple administrations of GBCAs. Increased signal intensity on non-contrast Tl weighted images of the brain has been observed after multiple administrations of GBCAs in patients with normal renal function. Gadolinium has been detected in brain tissue after multiple exposures to GBCAs, particularly in the dentate nucleus and globus pallidus. The evidence suggests that gadolinium accumulation is higher after repeat administration of linear than after repeat administration of macrocyclic agents.
The clinical significance of gadolinium accumulation in the brain is presently unknown. In order to minimise potential risks associated with gadolinium accumulation in the brain, it is recommended to use the lowest effective dose and perform a careful benefit risk assessment before administering repeated doses.

Use in renal impairment.

When administering a gadolinium-containing contrast agent (GBCA), do not exceed the dose recommended in the product labelling. Allow sufficient time for elimination of the GBCA prior to any re-administration.

Use in the elderly.

A phase III study with 25 micromol per kg body weight Primovist compared subjects with various levels of impaired hepatic function, impaired renal function, coexistent hepatic and renal impairment, and healthy subjects of different age groups, including elderly (see Section 5.2 Pharmacokinetic Properties, Characteristics in special patient populations).

Paediatric use.

Primovist is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.

Effects on laboratory tests.

Elevation of serum iron values and serum bilirubin laboratory values were reported in less than 1% of patients after administration of Primovist. The values did not exceed more than 2 to 3 times the baseline values and returned to baseline within 1 to 4 days (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interference with OATP (organic anion transporting peptide) inhibitors.

Animal studies demonstrated that compounds belonging to the class of anionic medicinal products such as rifampicin, 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 other interactions with medicinal products are known from animal studies.
An interaction study in healthy subjects demonstrated that the coadministration of the OATP inhibitor erythromycin did not influence efficacy and pharmacokinetics of Primovist. No further clinical interaction studies with other medicinal products have been performed.

Interference with diagnostic tests.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A reproduction and fertility study in rats receiving gadoxetic acid at IV doses up to 1 mmol/kg/day (7.3 x clinical dose, adjusted for body surface area) during gametogenesis, mating and early gestation showed no effects on male or female fertility.
(Category B3)
For disodium gadoxetate no clinical study data on exposed pregnancies are available. Animal studies at clinically relevant doses have not shown reproductive toxicity after repeated administration. The potential risk for humans is unknown. After IV administration of radiolabelled gadoxetic acid to pregnant rats on gestation day 15, small amounts of radioactivity were detected in the fetuses.
Embryofetal development studies were conducted with gadoxetic acid in rats and rabbits. In rats, IV administration of up to 5 mmol/kg/day (36.4 x the clinical dose, adjusted for body surface area) during organogenesis resulted in maternotoxicity (clinical signs, decreased bodyweight gain), but there were no effects on embryofetal development (F1 and F2 generations). In rabbits, IV administration of up to 2 mmol/kg/day (26.7 x the clinical dose, adjusted for body surface area) during organogenesis resulted in increases in the abortion rate and postimplantation loss at the high dose, but embryofetal development was otherwise unaffected.
In a rat peri-postnatal study, IV administration of up to 3.6 mmol/kg/day of gadoxetic acid from gestation day 15 to postpartum day 21 resulted in maternotoxicity at the high dose, but the F1 and F2 generations were unaffected.
Primovist should be used in pregnancy only if necessary, after a clear benefit to risk analysis. Primovist should only be used during pregnancy if the clinical condition of the woman requires the use of disodium gadoxetate.
It is unknown whether disodium gadoxetate is excreted in human milk.
There is evidence from nonclinical data that disodium gadoxetate is excreted into breast milk in very small amounts. In lactating rats, less than 0.5% of an intravenously administered dose of disodium gadoxetate was excreted into the breast milk during lactation. Absorption after oral administration was very low (about 0.4% of dose) in rats. It is recommended that breastfeeding be interrupted for 24 hours after administration of Primovist.
At clinical doses, no effects on the infant are anticipated and Primovist can be used during breastfeeding.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The overall safety profile of Primovist is based on data from more than 1,900 patients in clinical trials.
The most frequently observed adverse drug reactions (≥ 0.5%) in patients receiving Primovist are nausea, headache, feeling hot, blood pressure increased 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 of mild to moderate intensity.

Tabulated list of adverse reactions.

The adverse drug reactions observed with Primovist are represented in Table 1. 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: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to > 1/100; rare: ≥ 1/10,000 to < 1/1,000.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Description of selected adverse reactions.

Cases of nephrogenic systemic fibrosis (NSF) have been reported with contrast agents containing gadolinium (see Section 4.4 Special Warnings and Precautions for Use).
Elevated serum iron and serum bilirubin values have been observed in less than 1% of patients after administration of Primovist. However, the values did not exceed more than 2-3 times the baseline values and returned to their initial values without any symptoms within 1 to 4 days.

Additional adverse reactions from postmarketing spontaneous reporting.

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.

Restlessness.

Cardiac disorders.

Tachycardia.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea*.
* Life threatening and/or fatal cases have been reported. These reports originated from postmarketing experience.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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:
In Australia: http://www.tga.gov.au/reporting-problems.
In New Zealand: https://nzphvc.otago.ac.nz/reporting/.

4.2 Dose and Method of Administration

General information.

The usual safety rules for magnetic resonance imaging must be observed, e.g. exclusion of cardiac pacemakers and ferromagnetic implants.
Primovist is for use as a single dose in one patient only. Discard any remaining content.

Dosage.

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 through a large bore needle or indwelling catheter (18-20 gauge is recommended). After the injection of the contrast medium the intravenous cannula should be flushed using physiological saline solution.
The recommended dose of Primovist is:

Adults.

0.1 mL/kg bodyweight Primovist (equivalent to 25 micromol/kg bodyweight).

Imaging.

After bolus injection of Primovist, dynamic imaging during arterial, portovenous and equilibrium phases utilises the different temporal enhancement pattern of different liver lesion types to obtain information about their classification (benign/malignant) and the specific characterisation. It further improves visualization of hypervascular liver lesions.
The delayed (hepatocyte) phase starts at about 10 minutes postinjection (in confirmatory studies most of the data were obtained at 20 minutes postinjection) with an imaging window lasting at least 120 minutes. The imaging window is reduced to 60 minutes in patients requiring haemodialysis and in patients with elevated bilirubin values (> 3 mg/dL).
The enhancement of liver parenchyma during the hepatocyte phase assists in the identification of the number, segmental distribution, visualisation and delineation of liver lesions, thus improving lesion detection. The different enhancement/washout patterns of liver lesions contribute to the information from the dynamic phase.
Hepatic excretion of Primovist results in enhancement of biliary structures.

Paediatric population.

Primovist is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.

Instructions for use/handling.

Visual inspection.

This medicinal product should be visually inspected before use.
Primovist is supplied ready to use as a clear, colorless to pale yellow solution.
Primovist should not be used in case of severe discoloration, the occurrence of particulate matter or a defective container.

Vials.

This medicinal product is a ready to use solution for single use only. Vials containing contrast media are not intended for the withdrawal of multiple doses. The rubber stopper should never be pierced more than once. The medicinal product should only be drawn into the syringe immediately before use.
Any contrast medium not used in one examination must be discarded.

Prefilled syringes.

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.
Any contrast medium not used in one examination is to be discarded.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

Based on the results of acute toxicity studies in animals, there is no risk of acute intoxication when using Primovist.
Single doses of disodium gadoxetate as high as 0.4 mL/kg (100 micromol/kg) bodyweight were tolerated well. In a limited number of patients, a dose of 2.0 mL/kg (500 micromol/kg) bodyweight was tested in clinical trials. More frequent occurrences of adverse events but no new undesirable effects were found in these patients.
In view of the low volume and the extremely low gastrointestinal absorption rate of Primovist, and based on acute toxicity data, intoxication due to inadvertent oral ingestion of the contrast medium is extremely improbable. There have been no cases of overdose observed or reported in clinical use. Therefore, the signs and symptoms of overdosage have not been characterised.

Treatment.

In the event of excessive inadvertent overdosage in patients with severely impaired renal and/or hepatic function, Primovist can be removed by haemodialysis (see Section 4.4 Special Warnings and Precautions for Use).
For information on the management of overdose, contact:
Australia: The Poison Information Centre on 131126 (Australia).
New Zealand: The National Poisons Centre on 0800 POISON (0800 764766).

7 Medicine Schedule (Poisons Standard)

Unscheduled.

6 Pharmaceutical Particulars

6.1 List of Excipients

Primovist also contains trisodium caloxetate trometamol, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment) and water for injections. Each mL contains 0.511 mmol (equivalent to 11.755 mg) of sodium (see Section 4.4 Special Warnings and Precautions for Use).
Primovist contains no antimicrobial preservative.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

1, 5 and 10 x 5 mL (in 6 mL glass vial).
1, 5 and 10 x 7.5 mL (in 10 mL glass vial).
1, 5 and 10 x 10 mL (in 10 mL glass vial).
1, 5 and 10 x 5 mL (in 10 mL glass or plastic prefilled syringe).
1, 5 and 10 x 7.5 mL (in 10 mL glass prefilled syringe).
1, 5 and 10 x 10 mL (in 10 mL glass or plastic prefilled syringe).
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

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

Summary Table of Changes