Gadoxetic acid, disodium.
Each ml contains 0.25 mmol gadoxetate disodium (equivalent to 181.43 mg gadoxetate disodium).
Excipients/Inactive Ingredients: Caloxetate trisodium, Hydrochloric acid (for pH adjustment), Sodium hydroxide (for pH adjustment), Trometamol, Water for injection.
Pharmacology: Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based on conventional studies of systemic toxicity, genotoxicity, contact-sensitizing potential.
Reproduction toxicology: Repeated intravenous dosing of Gadoxetic acid, disodium (Primovist) in studies on embryofetal development caused embryotoxicity (increased post implantational loss) in rabbits at 25.9 times (based on body surface area) or 80 times (based on body weight) the human single dose.
Local tolerance: Experimental local tolerance studies with Gadoxetic acid, disodium (Primovist) indicated good local tolerability after intravascular (intravenous and intraarterial) and paravenous administration.
However, intramuscular administration caused local intolerance reactions and must therefore be strictly avoided in humans (see Precautions).
This medicinal product is for diagnostic use only.
Gadoxetic acid, disodium (Primovist) is a gadolinium-based contrast agent for T1-weighted magnetic resonance imaging of the liver.
In dynamic and delayed imaging, Gadoxetic acid, disodium (Primovist) improves the detection of liver lesions (e.g. number, size, segmental distribution and visualization) and provides additional information regarding classification and characterization of focal liver lesions, thereby increasing diagnostic confidence.
Adults: 0.1 ml per kg body weight Gadoxetic acid, disodium (Primovist) (equivalent to 25 μmol per kg body weight).
Additional information on special populations: Pediatric population: Gadoxetic acid, disodium (Primovist) is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.
Elderly population (aged 65 years and above): No dosage adjustment is necessary. In clinical studies, no overall differences in safety or efficacy were observed between elderly (aged 65 years and above) and younger patients, and other reported clinical experience has not identified differences between the elderly and younger patients.
Patients with hepatic impairment: No dosage adjustment is necessary. In clinical studies, no overall differences in safety or efficacy were observed between patients with and without hepatic impairment, and other reported clinical experience has not identified differences in patients with hepatic impairment and healthy subjects.
Patients with renal impairment: In clinical studies, no overall differences in safety and efficacy were observed between patients with renal impairment and patients with normal kidney function. The elimination of gadoxetate disodium is prolonged in renally impaired patients. To ensure diagnostically useful images, no dosage adjustment is recommended (see Precautions).
Method of administration: This medicinal product is for intravenous administration.
The dose is administered undiluted as a bolus injection.
After the injection of the contrast medium the intravenous cannula/line should be flushed using physiological saline solution.
After bolus injection of Gadoxetic acid, disodium (Primovist), dynamic imaging during arterial, portovenous, and equilibrium phases utilizes the different temporal enhancement pattern of different liver lesion types to obtain information about their classification (benign/malignant) and the specific characterization. It further improves visualization of hypervascular liver lesions.
The delayed (hepatocyte) phase starts at about 10 minutes post injection (in confirmatory studies most of the data were obtained at 20 minutes post injection) with an imaging window lasting at least 120 minutes. The imaging window is reduced to 60 minutes in patients requiring hemodialysis and in patients with elevated bilirubin values (>3 mg/dl) (see Instructions for use /handling under Cautions for Usage).
Single doses of gadoxetate disodium as high as 0.4 ml/kg (100 μmol/kg) body weight were tolerated well. There have been no cases of overdose observed or reported in clinical use. Therefore, the signs and symptoms of overdosage have not been characterized.
Patients with renal and/or hepatic impairment: In case of inadvertent overdosage in patients with severely impaired renal and/or hepatic function, Gadoxetic acid, disodium (Primovist) can be removed from the body by hemodialysis (see Precautions).
Hypersensitivity: Particularly careful risk-benefit assessment is required in patients with known hypersensitivity to Gadoxetic acid, disodium (Primovist).
As with other intravenous contrast agents, Gadoxetic acid, disodium (Primovist) can be associated with anaphylactoid/hypersensitivity or other idiosynchratic 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 Gadoxetic acid, disodium (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, post-procedure observation of the patient is recommended. Medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures are necessary.
Delayed reactions after hours up to several days have been rarely observed (see Adverse Reactions).
Cardiovascular disease: Caution should be exercised when Gadoxetic acid, disodium (Primovist) is administered to patients with severe cardiovascular problems because only limited data are available so far.
Impaired renal function: In healthy subjects, gadoxetate disodium is equally eliminated via renal and hepatobiliary routes.
Prior to administration of Gadoxetic acid, disodium (Primovist), it is recommended, that all patients are screened for renal dysfunction by obtaining a history and/or laboratory tests.
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 re-administration in patients with renal impairment should be ensured.
Gadoxetate disodium can be removed from the body by hemodialysis. 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 end-stage renal failure patients, gadoxetate disodium 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 hemodialysis at the time of Gadoxetic acid, disodium (Primovist) administration, prompt initiation of hemodialysis following the administration of Gadoxetic acid, disodium (Primovist) should be considered, in order to enhance the contrast agent's elimination.
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 (GFR <30 ml/min/1.73m2) and acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.
Although the systemic body exposure with gadolinium is low based on the diagnostic dosage of Gadoxetic acid, disodium (Primovist) as well as its dual elimination pathways (renal and hepatobiliary), there is a possibility that NSF may occur with Gadoxetic acid, disodium (Primovist). Therefore, Gadoxetic acid, disodium (Primovist) should only be used in these patients after careful risk/benefit assessment (see Adverse Reactions).
Local intolerance: Intramuscular administration must be strictly avoided, because it may cause local intolerance reactions including focal necrosis (see Pharmacology: Toxicology: Preclinical safety data under Actions.)
Effects on ability to drive or use machines: Not known.
Pregnancy: For gadoxetate disodium no clinical study data on exposed pregnancies are available.
Animal studies at clinically relevant doses have not shown reproductive toxicity after repeated administration (see Pharmacology: Toxicology: Preclinical safety data under Actions).
The potential risk for humans is unknown.
Gadoxetic acid, disodium (Primovist) should only be used during pregnancy if the clinical condition of the woman requires the use of gadoxetate disodium.
Lactation: It is unknown whether gadoxetate disodium is excreted in human milk.
There is evidence from non-clinical data that gadoxetate is excreted into breast milk in very small amounts (less than 0.5% of the dose intravenously administered) and the absorption via the gastrointestinal tract is poor (about 0.4% of the dose orally administered were excreted in the urine).
At clinical doses, no effects on the infant are anticipated and Gadoxetic acid, disodium (Primovist) can be used during breastfeeding.
Summary of the safety profile:
The overall safety profile of Gadoxetic acid, disodium (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 (≥0.5%) in patients receiving Gadoxetic acid, disodium (Primovist) are nausea, headache, feeling hot, blood pressure increased and dizziness.
The most serious adverse drug reaction in patients receiving Gadoxetic acid, disodium (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 Gadoxetic acid, disodium (Primovist) are represented in the table as follows. They are classified according to System Organ Class. 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. 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. (See table.)
Click on icon to see table/diagram/image
Description of selected adverse reactions:
Cases of nephrogenic systemic fibrosis (NSF) have been reported with some contrast agents containing gadolinium (see also Precautions).
Slightly elevated serum iron and serum bilirubin values have been observed in less than 1% of patients after administration of Gadoxetic acid, disodium (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.
Interference with OATP inhibitors: Animal studies demonstrated that compounds belonging to the class of anionic medicinal products, e.g. rifampicin, block the hepatic uptake of Gadoxetic acid, disodium (Primovist) thus reducing the hepatic contrast effect. In this case, the expected benefit of an injection of Gadoxetic acid, disodium (Primovist) might be limited. No other interactions with medicinal products are known from animal studies.
An interaction study in healthy subjects demonstrated that the co-administration of the OATP inhibitor erythromycin did not influence efficacy and pharmacokinetics of Gadoxetic acid, disodium (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 (>3 mg/dl) or ferritin can reduce the hepatic contrast effect of Gadoxetic acid, disodium (Primovist). If Gadoxetic acid, disodium (Primovist) is used in these patients, complete the magnetic resonance imaging no later than 60 minutes after Gadoxetic acid, disodium (Primovist) administration.
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 Gadoxetic acid, disodium (Primovist) because of the free complexing agent caloxetate trisodium contained in the contrast medium solution.
Instructions for use/handling: Visual Inspection: This medicinal product should be visually inspected before use.
Gadoxetic acid, disodium (Primovist) should not be used in case of severe discoloration, the occurrence of particulate matter or a defective container.
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 solution not used in one examination must be discarded.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Store at temperatures not exceeding 30°C.
V08CA10 - gadoxetic acid ; Belongs to the class of paramagnetic contrast media. Used as a magnetic resonance contrast medium.
Soln for IV inj (pre-filled syringe) 0.25 mmol/mL x 10 mL.