Primovist - instructions for use, doses, side effects, contraindications

Active substanceHadoxetic acidHadoxetic acid

Similar drugsTo uncover

solution in / in

Dosage form: & nbspSolution for intravenous administration.

Composition:

In 1 ml of solution contains:

Active substance: disodium salt of gadoxetic acid (Gd-EOB-DTPA) 181.430 mg, which corresponds to a concentration of 0.25 mmol / ml.

Excipients: kaloxetic acid trisodium salt, trometamol, hydrochloric acid sodium, hydroxide, water for injection.

Description:Transparent from a colorless to light yellow solution, free from mechanical inclusions.

Pharmacotherapeutic group:Contrast agent for MRI

ATX: & nbsp

V.08.C.A Paramagnetic contrast media

Pharmacodynamics:Primavere is a paramagnetic contrast agent based on gadolinium and is used for T1-weighted magnetic resonance imaging (MRV) of the liver. On dynamic and deferred images Primavere improves the detection of focal liver lesions (including their number, size, segmental distribution and visualization) and allows to obtain additional data on the characterization and classification of focal liver lesions, thereby increasing the reliability of the diagnosis.

The effect of increasing the contrast is due to a stable gadolinium complex - Gd-EOB-DTPA. The paramagnetic efficiency or relaxation ability, determined from the effect on the spin-lattice relaxation time of protons in plasma, is about 8.7 l / mmol / s at pH 7, temperature 39 ° C and magnetic field strength 0.47 T. It is only in negligible depends on the strength of the magnetic field. When scanning using T1-weighted pulse sequences, the shortening of the spin-lattice relaxation time of excited atomic nuclei caused by gadolinium ions leads to an increase in the signal intensity and, thus, to an increase in the contrast of the image of some tissues.

EOB-DTPA forms a stable complex with a paramagnetic gadolinium ion with extremely high thermodynamic stability (logKGdl = -23.46). Cd-EOB-DTPA is a hydrophilic compound with high water solubility. The presence of the ethoxybenzyl group gives the complex lipophilic properties.

Physicochemical characteristics of the ready-to-use drug solution Primavere are listed below:

Osmolality at 37 ° C (mOsm / kg water)	688
Viscosity at 37 ° C (mPa ∙ s)	1,19
Density 37 ° C (g / ml)	1,0881
pH	7,0

Pharmacokinetics:

Distribution

After intravenous administration, the active substance diffuses rapidly into the intercellular space. Seven days after intravenous injection of Gd-EOB-DTPA in the body, rats and dogs are determined to be well below 1% of the dose received, with the highest concentration of the substance found in the kidneys and liver. The active substance does not pass through the intact blood-brain barrier and only diffuses slightly through the placental barrier.

Excretion

The half-life of Gd-EOB-DTPA from human serum is 1.0 ± 0.1 hours and is not significantly dependent on the doses received. Period T1/2 in the terminal phase is equal to 1.65 ± 0.23 hours or less. The observed pharmacokinetics is linear up to a dose of 0.4 ml / kg (100 μmol / kg) of body weight.

Gd-EOB-DTPA is completely eliminated from the body in equal proportions through the kidneys and hepatobiliary system.

Patient characteristics

In severe violations of kidney and liver functions, the nature of excretion changes accordingly. In patients with severe impairment of liver function, the half-life of serum increases slightly,whereas in patients with severe renal failure (requiring hemodialysis), the half-life period increases noticeably.

Indications:

Primavere is intended solely for diagnostic purposes.

Contrast enhancement during T1-weighted magnetic resonance imaging of the liver to improve the detection of focal liver lesions (including their number, size, segmental distribution and visualization) and to obtain additional data on the characterization and classification of focal pathology of the liver.

Contraindications:- Hypersensitivity to the active substance or any of the auxiliary components of the drug,
- Primovist® is not recommended for use in children younger than 18 years due to insufficient data on efficacy and safety.

Carefully:- Hypersensitivity to similar contrast agents based on gadolinium (CSOG) in the anamnesis. The use of the drug in patients with a history of hypersensitivity reactions to contrast agents, the presence in the history of allergic diseases, including bronchial asthma, is possible only after a thorough assessment of the benefit / risk ratio. Most of these reactions are noted within half an hour after the administration of the drug.However, less so, as with the use of other contrast agents in this class, in rare cases, the development of delayed reactions (from several hours to days) is possible.
The use of the drug should be limited to the introduction of a standard dose.
- Cardiovascular pathology
Data on the administration of Primovist® to patients with severe cardiovascular diseases are limited, so care must be taken in these cases.
It is necessary to carefully evaluate the benefit / risk ratio in patients at risk of arrhythmias, in particular, patients with an extended QT interval and when using drugs that extend the QT interval.
- Severe kidney disease
In patients with severe renal dysfunction, contrast media removal is slowed, so in such cases it is necessary to carefully evaluate the benefit / risk ratio. Repeated administration should not be performed for 7 days in patients with acute or chronic severe impairment of renal function. There have been reports of the association of nephrogenic systemic fibrosis (NSF) using some contrast agents containing gadolinium,in patients with acute or chronic severe impairment of function of the night (GFR <30 ml / min / 1.73 m2) and acute renal failure of any severity due to hepatorenal syndrome or during pre and post liver transplantation. Therefore, the use of Primovist® in such patients can only be done after a thorough assessment of the benefit / risk ratio (see the "Side effect" section).

Pregnancy and lactation:Pregnancy
Clinical data are not available for the use of disodium salt of disodium salt in pregnant women. Studies in animals using clinically significant doses did not reveal reproductive toxicity after repeated application.
The potential risk to humans is unknown. There is no experience of using Primovist® in people during pregnancy. Primovist® should not be used for examination of pregnant women, unless it is very necessary to perform MRI with contrast enhancement and the intended benefit to the mother from using it exceeds the potential risk to the fetus.
Breastfeeding period
It is not known whether disadameric acid is released into the breast milk of a human.
Preclinical studies have shown that small amounts of disodium salt of disodium salt (less than 0.5% of the intravenously administered dose) are excreted into breast milk, while its absorption through the gastrointestinal tract is negligible (approximately 0.4% of the oral dose is excreted by the kidneys).
Breastfeeding should be discontinued for 24 hours after the administration of Primovist®.

Dosing and Administration:Primovist® is intended for intravenous administration.
The dose is administered in undiluted form by intravenous bolus injection. After injection of the contrast agent, the intravenous cannula / catheter should be washed with 0.9% sodium chloride solution.
After the bolus injection of Primovist®, dynamic visualization in the arterial, portogenous and equilibrium phases allows to obtain an unequal temporal pattern of contrasting of different types of liver lesions. This information makes it possible to classify the detected formations (benign / malignant) and describe their specific characteristics.This test method further improves the visualization of hypervascular lesions of the liver.
The delayed (hepatospecific) phase begins approximately 10 minutes after the injection (in confirmatory studies most of the data were obtained 20 minutes after the injection), with a visualization period of at least 120 minutes. In patients who require hemodialysis, as well as in patients with a high concentration of bilirubin (> 3 mg / dl), the visualization period is reduced to 60 minutes (see "Interaction with other drugs and other interactions").
The detection of lesions is improved by contrasting the liver parenchyma during the hepatospecific phase, allowing to determine the number of lesions, their segmental location, visualization and boundaries. The difference in liver damage by the nature of the contrast / washout dynamics of the contrast medium allows us to obtain additional information.
Hepatic excretion of the Primovist ® drug provides contrasting of the bile excretory system. It is necessary to observe the generally accepted precautions when conducting magnetic resonance imaging.If a patient has a pacemaker and a ferromagnetic implantable device, magnetic resonance imaging is not recommended.
Within two hours before the examination, the patient should refrain from eating to reduce the risk of aspiration, since all contrast agents can cause such side effects as nausea and vomiting. If possible, the patient should be in a horizontal position during the injection of the contrast agent.
Also see the "Rules for the Use / Handling of Medicinal Forms".
Doses:
Adults:
0.1 ml / kg of Primovist® (corresponding to 25 μmol / kg body weight).
Some groups of patients:
- Patients of advanced age (over 65 years)
No dose adjustment is required. Taking into account the data of clinical trials and the experience of using the drug in clinical practice, the differences in efficacy and safety in young and elderly (over 65 years) patients have not been revealed.
- Patients with hepatic impairment
No dose adjustment is required. Taking into account the data of clinical trials and the experience of using the drug in clinical practice, differences in efficacy and safety in patients with normal and impaired liver function were not detected.
- Patients with impaired renal function
In clinical trials, there was no difference in the efficacy and safety of the drug in patients with normal and impaired renal function. In patients with impaired renal function, the removal of disodium salt of disodium salt has been slowed down, however, in order to obtain a high-quality image, the dose adjustment should be followed by ns (see section "Special instructions").

Side effects:

The general safety profile of Primovist® is based on data on the use of 1,900 patients in clinical trials and on post-marketing and drug results.
Most often (≥0.5%) there were such undesirable reactions as nausea, headache, hot flashes, high blood pressure and dizziness. The most serious adverse reaction in patients treated with Primovist® is anaphylactic shock.
In rare cases, delayed reactions were observed in the type of allergic (from several hours to several days after drug administration).
Most adverse events were of mild to moderate intensity.
The adverse reactions that were observed after the use of Primovist® were classified by organ systems (MedDRA classification) and are presented in the table below.Undesirable reactions, identified during clinical trials, are distributed according to the frequency of occurrence. Frequency distribution is carried out as follows: often - from ≥ 1/100 to <1/10, infrequently - from ≥ 1/1000 to <1/100, rarely - from ≥ 1/10 000 to <1/1000. Undesirable reactions identified only at the stage of postmarketing observations, for which it is impossible to assess the frequency, are categorized as "frequency unknown".
Within each group allocated by frequency, undesirable phenomena are presented in order of decreasing severity.
Table 1: Undesirable reactions identified with Priminst® in clinical trials or postmarketing control data

Class of organ systems	Frequency of adverse reactions
Class of organ systems	Often	Infrequently	Rarely	Frequency unknown
Immune system disorders				Hypersensitivity / anaphylactoid reaction (eg shock, blood pressure decrease, laryngeal and pharyngeal edema, urticaria, facial edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, coughing, pallor)
Disturbances from the nervous system	Headache	Dizziness Disturbance of taste sensations, Paresthesia Perversion of sense of smell	Tremor Akathisia	Anxiety
Heart Disease			Blockade of the bundle branch legs Heart palpitations	Tachycardia
Vascular disorders		Increased blood pressure "Hot flushes" of heat
Disturbances from the respiratory system, chest and mediastinal organs		Respiratory disorders (shortness of breath *, respiratory distress syndrome)
Disorders from the gastrointestinal tract	Nausea	Vomiting Dry mouth	Unpleasant sensations in the mouth Increased salivation
Disturbances from the skin and subcutaneous tissues		Rash Itching **	Maculopapular rash Increased sweating
Disturbances from musculoskeletal and connective tissue		Backache
General disorders and disorders at the injection site		Chest pain Reactions at the injection site *** Feeling of heat Chills Feeling tired Bad feeling	Feeling of discomfort Malaise

* There have been reports of life-threatening and / or lethal cases. These messages were received in the postmarketing period.
** Itching (general itching, itching in the eyes).
*** Reactions (of various kinds) at the injection site: extravasation at the injection site, burning at the injection site, a feeling of cold at the injection site, irritation at the injection site, pain at the injection site.
Description of some adverse reactions
There are reports of cases of development of nephrogenic systemic fibrosis (PFS) in the application of certain gadolinium containing contrast media (see also the section "Special instructions").
After the administration of Primovist®, less than 1%
patients there was a slight increase in the concentration of iron and bilirubin in the plasma. However, these values did not exceed the original values by more than 2-3 times and returned to the initial values within 1-4 days without developing any symptoms.
On the part of laboratory indicators, when administering Primovist®, it is possible to develop such side effects as: increased activity of "liver" transaminases, decreased hemoglobin, leukocyturia, hyperglycemia, hyponatremia, leukocytosis, giocalismia, etc.

Overdose:Single administration of disodium salt of disodium salt in a dose of up to 0.4 ml / kg (100 μmol / kg) is well tolerated. Among a limited number of patients, a dose of 2 ml / kg (500 μmol / kg) of body weight was tested during clinical trials. These patients had an increased incidence of side effects, but no additional adverse reactions were found.
In clinical use, no cases of overdose have been reported.Thus, signs and symptoms of an overdose of gadoxetic acid disodium salt are not described.
There is no specific antidote and the treatment is symptomatic.
Patients with impaired renal and / or liver function
In case of unintentional overdose in patients with severe renal and / or liver dysfunction, Primovist® can be removed from the body by hemodialysis (see the sections on "Specific guidance" and "Pharmacokinetic properties").

Interaction:- Interaction with transport protein inhibitors of organic anions
Studies in animals have shown that compounds belonging to the class of anionic drugs, for example, rifampicin, block the capture of gadoxetic acid by liver cells, thereby reducing the effectiveness of contrasting the liver. In this case, the expected benefits of Primovist® may not be fully apparent. According to studies in animals, no other interactions with drugs have been identified.
In a study in healthy volunteers, it was shown that the simultaneous use of erythromycin with an inhibitor of the transport protein of organic anions did not affect the efficacy and pharmacokinetics of gadoxetic acid.There were no other clinical studies on interactions with other drugs.
- Influence of elevated bilirubin or ferritin
An increase in the concentration (> 3 mg / dl) of bilirubin or ferritin may decrease the effectiveness of the contrast of the liver with Primovist®. When Primovist® is used in these patients, the procedure for magnetic resonance imaging should be completed no later than 60 minutes after the administration of the drug.
- Impact on results of diagnostic tests
When determining the content of iron in the blood serum by complexometric methods (for example, by complexation with ferrocin) within 24 hours after the examination with Primovist®, it is possible to obtain falsely high or false values due to the presence in the solution of the contrast agent of the free complexing agent trisodium salt kaloketova acid.
- Incompatibilities
In the absence of studies on incompatibility, this medication should not be mixed with other drugs.

Special instructions:Hypersensitivity
As with other drugs in this class, the administration of Primovist® may be associated with the development of hypersensitivity reactions / allergic reactions or other manifestations of idiosyncrasy characterized by cardiovascular, respiratory or skin manifestations. Severe reactions are possible, including anaphylactic shock.
The risk of developing hypersensitivity reactions increases with:
- previously had reactions to the introduction of contrast media,
- bronchial asthma,
- Allergic diseases.
Most of these reactions occur within 30 minutes after drug administration. Therefore, follow-up care is recommended after the study.
To treat hypersensitivity reactions,
appropriate medicines and readiness for emergency resuscitation.
In rare cases, there may be delayed reactions (from several hours to several days) (see "Side effect").
Patients with the development of such reactions against the background of taking beta-blockers may be resistant to treatment with this group of drugs.
- Cardiovascular pathology
Data on the administration of Primovist® to patients with severe cardiovascular diseases are limited, so care must be taken in these cases.
It is necessary to carefully evaluate the benefit / risk ratio in patients at risk of arrhythmias, in particular, patients with an extended QT interval and when using drugs that extend the QT interval.
- Dysfunction of the kidneys
In patients with normal renal function of gadoxetic acid, the disodium salt is excreted by the kidneys and through the gastrointestinal tract in equal proportions.
Prior to the introduction of Primovist®, all patients should be examined for possible impairment of kidney function by collecting anamnesis and / or conducting laboratory tests.
In patients with severe renal dysfunction, contrast media removal is slowed, so in such cases it is necessary to carefully evaluate the benefit / risk ratio. Repeated administration should not be performed for 7 days in patients with acute or chronic severe impairment of renal function. Hadoxetic acid disodium salt can be removed from the body by hemodialysis.Approximately 30% of the administered dose is withdrawn from the body after a single three-hour hemodialysis session started 1 hour after the injection. In patients with renal insufficiency of gadoxetic acid, disodium salt was almost completely eliminated by hemodialysis and by excretion with bile for 6 days, and in most patients - for 3 days. In patients already on hemodialysis during the use of Primovist ®, after the administration of the drug, it is necessary to quickly begin the procedure of hemodialysis to improve the removal of contrast media from the body.
There have been reports of the association of nephrogenic systemic fibrosis using some gadolinium-containing contrast media in patients with acute or chronic severe renal impairment (GFR <30 mL / min / 1.73 m2) and acute renal failure of any severity due to hepatorenal syndrome or during the period before and after liver transplantation.
Although the introduction of the diagnostic dose of Primovist® is systemic, gadolinium exposure is low and there are two ways of excretion (by the kidneys and through the gastrointestinal tract), the possibility of the formation of an NSF after administration of the drug is not ruled out.Therefore, the use of Primovist® in such patients can only be done after a thorough assessment of the benefit / risk ratio (see the "Side effect" section).
- Reactions at the site of administration
It is necessary to strictly avoid intramuscular injection of the drug, as it may be the cause of the development of intolerance reactions at the site of administration, including focal necrosis.
- Preclinical safety data
The results of preclinical studies on the administration of repeated doses indicate the absence of any hazard to humans with respect to toxicity, genotoxicity and sensitization by contact exposure.
Reproductive Toxicity
With repeated intravenous administration of Primovist ® in doses exceeding the single dose administered in humans 25.9 times (calculated per body surface area) or 80 times (based on body weight), embryotoxic effects were found in animal studies.
Local reactions and sensitization by contact exposure
The results of experimental studies indicate a good local tolerance of the drug Primovist ® after intravascular (intravenous and intraarterial) and paravenous administration.
However, with intramuscular injection, local reactions of intolerance were observed, including hemorrhage, edema at the site of injection, and focal necrosis of muscle fibers, and therefore, intramuscular administration of the drug should be avoided (see above).
Rules of use / handling of medicinal forms
Visual inspection
The drug should be thoroughly inspected before use.
Primovist® should not be used in cases of marked discoloration, mechanical inclusions and packaging defects.
Bottles
This drug is a ready-to-use solution intended for single use only.
A set of preparation in a syringe is carried out immediately before the introduction. Rubber stopper vial should be punctured once, repeated sampling of the drug from the bottle is unacceptable.
Pre-filled syringes
The pre-filled syringe should be removed from the package and prepared for injection immediately before the examination. The cap from the filled syringe should be removed immediately before the administration of the drug.
The rest of the unused contrast medium should be destroyed.

Effect on the ability to drive transp. cf. and fur:Unknown.

Form release / dosage:Solution for intravenous administration 0.25 mmol / ml.

Packaging:Vials of colorless glass type 1 (Hebrew Pharmaceutical or USP) in volume of 6 ml and 10 ml with a filling of 5; 7,5 and 10 ml, sealed with a rubber stopper and rolled with an aluminum cap with a colored plastic disc.

Pre-filled syringes made of colorless glass type 1 (Hev.Pharm or USP) with a volume of 10 ml with a filling of 5; 7.5 and 10 ml with a plunger and a top cover made of chlorobutyl elastomer type 1 (Hearth.Pharm.) Black.

1, 5 or 10 bottles together with instructions for use in a cardboard pack.

1, 5 or 10 syringes in blisters together with instructions for use in a cardboard pack.

Storage conditions:At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

Shelf life 5 years. Do not use after expiry date.

Shelf life after the first opening of the container:

Primovist is chemically and physically stable. From the point of view of microbiology, this drug should be used immediately after the discovery.

Terms of leave from pharmacies:On prescription

Registration number:LSR-003252/07

Date of registration:17.10.2007

The owner of the registration certificate:Bayer Pharma AGBayer Pharma AG Germany

Manufacturer: & nbsp

BAYER PHARMA, AG Germany

Information update date: & nbsp2015-12-06

Illustrated instructions

Instructions

Primovist® (Primovist® )