Hadobutrol | Gadovist syringes 1 mmol / ml 5 ml, 5 pcs.

Packing

5 ampoules

Pharmacological action

Paramagnetic contrast agent for magnetic resonance imaging (MRI).

The increase in contrast is due to the active component gadobutrol, which is a neutral complex of gadolinium (III) with a macrocyclic ligand - dihydroxy-hydroxymethylpropyl tetraazacyclododecane-triacetic acid (butrol).

When using T2 * -weighted pulse sequences, the induction of local inhomogeneity of the magnetic field under the influence of the strong magnetic moment of gadolinium at its high concentration (bolus administration) leads to a change in the signal from the tissues (contrasting effect).

Gadobutrol even in low concentrations causes a significant shortening of the relaxation time. The ability to change the relaxation times T1 and T2, determined by the effect on the time of spin-lattice and spin-spin relaxation of protons in plasma at pH = 7 and a temperature of 40 РC, is quantitatively approximately 5.6 l / mmol s and 6.5 l / mmol with respectively. Ability to influence time pRelaxation only to a small extent depends on the magnetic field strength.

Gadovist’s introduction allows obtaining more accurate diagnostic information compared to the data obtained with conventional MRI in areas with high permeability of the BBB or its absence, causing impaired perfusion or increased extracellular space, for example, in cases of primary tumors, inflammatory and demyelinating diseases .

Gadovist® does not activate the complement system, and therefore the likelihood of developing anaphylactoid reactions is extremely low.

No binding of gadobutrol with any proteins or their inhibition of enzyme activity was detected.

The results of clinical trials indicate the absence of a negative effect of Gadovist on overall well-being, as well as on liver function, kidney and cardiovascular system.

The pharmacokinetics of gadobutrol is similar to the pharmacokinetics of other highly hydrophilic biologically inert substances excreted by the kidneys (for example, mannitol or inulin).

Pharmacokinetics in humans are proportional to the dose of gadobutrol administered.

Distribution

Intravenous gadobutrol is rapidly distributed in the extracellular space and excreted unchanged by the kidneys through glomerular filtration.

Does not bind to plasma proteins.

Excretion

Emergency excretion of the drug is so small that it may not be taken into account.

If the dose of gadobutrol does not exceed 0.4 mmol / kg body weight, the elimination phase begins after the initial distribution phase and its plasma level decreases from T1 / 2 1.81 h (1.33-2.13 h), which corresponds to the rate of excretion by the kidneys. At a dose of gadobutrol of 0.1 mmol / kg body weight 2 minutes after injection, its plasma level was 0.59 mmol / L, and 60 minutes after injection it was 0.3 mmol / L. Within 2 hours, more than 50% of the administered dose is excreted in the urine, and over 90% within 12 hours. If the administered dose of gadobutrol is 0.1 mmol / kg body weight, then 100.3 ± 2.6% of this dose is excreted from the body in 72 hours. Does the renal clearance of gadobutrol in healthy individuals range from 1.1 to 1.7 ml / min kg thus, it is comparable with the clearance of inulin, which indicates the predominant excretion of gadobutrol by glomerular filtration. Less than 0.1% of the substance administered is excreted in the feces.

No metabolites found in plasma and urine.

Pharmacokinetics in special clinical cases of

T1 / 2 gadobutrol in patients with impaired renal function increases in proportion to the degree of decrease in glomerular filtration. In patients with mild or moderate renal impairment, gadobutrol is completely excreted in the urine within 72 hours. In patients with severe renal impairment, 80% of the administered dose is excreted in the urine within 120 hours.

Indications

The drug is intended solely for diagnostic purposes.

Gadovist® is shown to adults, adolescents and children over the age of 7 years:

- increasing contrast when conducting magnetic resonance imaging (MRI) of the head and spine (cranial and spinal MRI)

- increasing contrast when conducting MRI of the whole body, including liver and kidney

- increased contrast during magnetic resonance angiography.

For spinal MRI,

is a differential diagnosis between intra- and extramedullary tumors

is the identification of the boundaries of solid tumors in the spinal canal and the prevalence of the intramedullary tumor is determined.

Gadovista solution (1 mmol / ml) has special advantages when there are indications for the use of magnetic resonance contrast agents in high doses, for example, in cases when the identification or exclusion of additional lesions may affect the treatment or medical tactics, as well as the detection of minor injuries and to visualize lesions that are difficult to contrast with conventional means.

Gadovista solution (1 mmol / ml) is also indicated for perfusion studies (for the diagnosis of stroke, recognition of focal cerebral ischemia and assessment of tumor blood supply).

Pregnancy and lactation

There are no data on the use of gadobutrol during pregnancy. GadovistВ® is not recommended for use during pregnancy, unless absolutely necessary.

In experimental animal studies, no Gadovist embryotoxic or teratogenic effects were detected in diagnostic doses. In the study of gadobutrol in repeated doses, only the introduction of pregnant animals in toxic doses (exceeding the diagnostic dose by 8-17 times) caused a delay in the development of embryos and their mortality, but did not lead to teratogenicity.

To date, the possibility of penetration of gadobutrol into human milk has not been studied. In experimental studies, it was found that gadobutrol in minimal amounts (less than 0.01% of the administered dose) is excreted in breast milk. Therefore, after the administration of Gadovist, breastfeeding should be interrupted for at least 24 hours.

Special instructions

In patients with known hypersensitivity to gadobutrol or other components of the drug, a particularly careful assessment of the risk and benefit of using Gadovist is required.

The use of Gadovist (as well as other contrast agents for iv administration) may be accompanied by manifestations of hypersensitivity - anaphylactoid reactions and other manifestations of idiosyncrasy, characterized by reactions from the cardiovascular, respiratory system or skin reactions that turn into serious conditions, including shock. Most of these reactions develop within 0.5-1 hours after drug administration.

The risk of developing hypersensitivity reactions is higher in cases of a previous reaction to a contrast medium, bronchial asthma, and a history of allergic diseases.

After a diagnostic procedure with Gadovist (as well as after the use of other contrast agents), monitoring of the patient's condition is recommended.

In a study using Gadovist (as well as other contrast agents for iv administration), it is necessary to have drugs and equipment for resuscitation.

Patients receiving beta-blockers, may be resistant to drugs with beta-adrenostimulating effects used to treat hypersensitivity reactions.

Before prescribing Gadovist, all patients should be examined for renal function.

The risk / benefit ratio of the drug should be especially carefully evaluated in patients with severe renal impairment, since in such cases the excretion of the contrast medium is slowed down. In severe cases, gadobutrol should be removed from the body using hemodialysis. In relation to patients who are already receiving hemodialysis at the time of Gadovist administration, consideration should be given to the expediency of initiating hemodialysis immediately after administration of Gadovist in order to accelerate the elimination of the contrast medium. After three courses of dialysis, approximately 98% of gadobutrol is excreted from the body.

Cases of development of nephrogenic systemic fibrosis have been reported in connection with the administration of gadolinium-containing contrast agents to patients with severe acute or chronic renal failure (glomerular filtration rate <30 ml / min / 1.73 m2) to patients with acute renal failure of any severity caused by hepatic-renal syndrome, or in the period before and after liver transplantation. Despite the fact that, due to the macrocyclic structure, gadobutrol has a very high stability of the complex, there is the possibility of developing nephrogenic systemic fibrosis with the use of Gadovist. Therefore, in such patients, Gadovist® should be used only after a careful assessment of the benefit / risk ratio.

In patients with severe cardiovascular disease, Gadovist® should be used only after a thorough assessment of the risk / benefit ratio, as information regarding this category of patients is limited.

The results of preclinical safety studies (studying systemic toxicity, genotoxicity and contact sensitivity potential) showed that gadobutrol does not pose any danger to humans.

Influence on the ability to drive vehicles and control mechanisms

No effect of the drug on the ability to drive vehicles and other activities requiring a high concentration of attention and speed of psychomotor reactions was observed.

Dosage and administration

The required dose is administered iv in the form of a bolus. MRI with increased contrast can be started immediately (shortly after injection, depending on the applied pulse sequence and study design). Optimal contrasting is usually observed approximately 15 minutes after the administration of Gadovist (this time depends on the characteristics of the damage and the nature of the tissue). Usually, increased contrast persists for up to 45 minutes after administration of Gadovist. When conducting an MRI, the general safety rules should be followed.

Side effects like nausea and vomiting can be observed with all MR contrast media. Therefore, to minimize the risk of vomiting and possible aspiration, the patient should refrain from eating for 2 hours before the study.

With the on / in the introduction of a contrast agent, the patient (if possible) should be in a supine position. After the introduction of Gadovist, the patient should remain under medical supervision for at least 30 minutes, since, as experience with the use of contrast agents has shown, most undesirable side effects are observed during this period.

For studies with increased contrast, T1-weighted pulse sequences are most suitable for scanning. For perfusion studies of the brain, it is recommended to use T2 * -weighted impulse sequences.

Terms of use of the drug

GadovistВ® should be collected into a regular syringe only immediately before the study. The rubber stopper of the vial should not be punctured more than 1 time. GadovistВ® in a syringe should be removed from the packaging and prepared for injection immediately before administration. The syringe tip cover should be removed immediately before insertion. Unused in one study, part of the drug must be destroyed. GadovistВ® should not be mixed with other drugs, since compatibility data are not available.

Adults

When choosing a dosage regimen for adults, the following guidelines should be followed.

The dose of the drug depends on the indications. A single intravenous administration of Gadovist 1 mmol / ml in a dose of 0.1 ml / kg body weight is usually sufficient. The maximum dose of Gadovist is 0.3 ml / kg body weight.

MRI of the head and spine (cranial and spinal tomography)

As a rule, iv administration of Gadovist at a dose of 0.1 ml / kg body weight (which is equivalent to 0.1 mmol / kg body weight) is sufficient. If there are still suspicions of the presence of lesions, or if more accurate information is needed on the number, size and prevalence of lesions for the development of medical tactics and treatment, then the diagnostic effectiveness of the study can be increased by additional administration of a Gadovist solution in a dose of 0.1-0.2 ml / kg body weight per within 30 minutes after the previous injection.

To exclude metastases or relapse of the tumor, a Gadovist solution is administered at a dose of 0. 3 ml / kg of body weight, which often helps to increase the diagnostic effectiveness of the study. This applies to lesions with a weak severity of the blood vessel network, with a small extracellular space or a combination of these factors, as well as the use of relatively less intense T1-weighted pulse sequences during scanning.

For perfusion studies of the brain, it is recommended to use T2 * -weighted impulse sequences in combination with MRI of the brain and spinal cord to detect volume lesions or local ischemia in the absence of assumptions about volume lesions.

For this study, it is recommended to use an injector Gadovista solution is administered at a dose of 0.3 ml / kg body weight at a speed of 3-5 ml / sec.

whole body MRI

I / O administration of Gadovist (1 mmol / ml) at a dose of 0.1 ml / kg body weight (equivalent to 0.1 mmol / kg body weight) is usually sufficient.

Magnetic resonance angiography

Single field of view: Gadovist's dose is 0.1-0.15 mmol / kg body weight. For patients with a body weight of less than 75 kg, the drug is administered in a volume of 7.5 ml, for patients with a body weight of 75 kg or more - 10 ml.

Two or more fields of view: Gadovist's dose is 0.2-0.3 mmol / kg body weight. For patients with a body weight of less than 75 kg, the drug is administered in a volume of 15 ml, for patients with a body weight of 75 kg and more - 20 ml.

Children

For children over 7 years of age and adolescents, the recommended dose of Gadovist is 0.1 mmol / kg body weight (equivalent to 0.1 ml / kg body weight) for all indications.

Side effects of

In clinical trials, the following side effects were observed associated with the use of the drug GadovistΠ(n = 2900). In most cases, side effects were characterized by mild or moderate intensity.

From the side of the central nervous system and peripheral nervous system: sometimes (? 1/1000, <1/100) - headache, dizziness, dysgeusia, paresthesia rarely (<1/1000) - parosmia.

From the digestive system: sometimes (? 1/1000, <1/100) - nausea is rare (<1/1000) - vomiting.

From the cardiovascular system: sometimes (? 1/1000, <1/100) - vasodilation rarely (<1/1000) - arterial hypotension.

From the respiratory system: rarely (<1/1000) - shortness of breath.

Allergic reactions: rarely (<1/1000) - urticaria, rash, anaphylactoid reactions. Perhaps the development of delayed allergic reactions (after several hours or days).

Local reactions: sometimes (? 1/1000, <1/100) - pain at the injection site, reaction at the injection site. Due to venipuncture or the administration of a contrast agent at the injection site, a short, slight or moderate sensation of cold, heat or pain is possible. Accidental introduction of Gadovista into the perovascular tissue can cause pain lasting up to several minutes.

Side effects observed in post-marketing studies

From the side of the central nervous system: rarely (<1/1000) - loss of consciousness, convulsions.

From the cardiovascular system: rarely (<1/1000) - cardiac arrest, tachycardia, collapse, hot flashes.

From the respiratory system: rarely (<1/1000) - respiratory arrest, bronchospasm, cyanosis, oropharyngeal edema, cough, nasal congestion.

From the side of the organ of vision: rarely (<1/1000) - conjunctivitis, edema of the eyelids.

Allergic reactions: rarely (<1/1000) - laryngeal edema, anaphylactic shock.

Dermatological reactions: rarely (<1/1000) - hyperhidrosis, pruritus, erythema.

Other: feeling of heat, general malaise.

Drug Interactions

No drug interactions with other drugs have been identified.

Gadovist® should not be mixed with other drugs, since compatibility data are not available.

Overdose of

To date, there have been no cases of intoxication associated with an overdose of Gadovist in its clinical use. Based on the results of studies of acute toxicity, the risk of acute intoxication in connection with the use of Gadovista is extremely unlikely.

Treatment: In case of accidental overdose, Gadovist® can be excreted by extracorporeal dialysis. In case of overdose, monitoring of the functions of the cardiovascular system (including ECG) and monitoring of renal function are recommended as a precaution.

In clinical trials, the maximum tested dose of Gadovist solution (1.0 mmol / ml) of 1.5 ml / kg body weight was well tolerated.

Storage conditions

After opening the bottle under aseptic conditions, Gadovist® remains stable for 8 hours at room temperature.

Expiration

The product should be stored out of the reach of children at a temperature not exceeding 30 РC. Expiration - 3 years.

Deystvuyuschee substances

Hadobutrol

Bayer Pharma AG, Germany