GADOVIST

Active material: Gadobutrol
When ATH: V08CA09
CCF: Contrast diagnostic drug for magnetic resonance imaging
ICD-10 codes (testimony): Z03
When CSF: 30.01.02
Manufacturer: BAYER SCHERING PHARMA AG (Germany)

Pharmaceutical form, composition and packaging

The solution for the on / in the 1 mg / ml clear, free of foreign inclusions.

Excipients: sodium kalkobutrol, trometamol, 0.1M hydrochloric acid, water d / and.

15 ml – bottles (1) – packs cardboard.
7.5 ml – Glass syringes (1) – Containers (1) – packs cardboard.
7.5 ml – Glass syringes (1) – Containers (5) – packs cardboard.

Pharmacological action

The paramagnetic contrast agent for magnetic resonance imaging (LRA).

Contrast enhancement is due to the active ingredient gadobutrol, which is a neutral gadolinium complex (III) with macrocyclic ligands - дигидрокси-гидроксиметилпропилтетраазациклододекан-триуксусной acid (butrolom).

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

Gadobutrol even in low concentrations causes a significant shortening of the relaxation time. The ability to modify the relaxation time T1 and T2, determined by the influence on the spin-lattice and spin-spin relaxation time of protons in plasma at pH 7 and 40 ° C, It is quantitatively about 5.6 l / mmol × s and 6.5 l / mmol, respectively ×. Ability to influence the relaxation time only to a small extent dependent on the strength of the magnetic field.

Introduction Gadovist^® It provides a more accurate diagnostic information compared with the data, obtained in conventional MRI, in areas with high permeability of the BBB, or lack of it, lead to the violation of perfusion or an increase in the extracellular space, in such cases, the primary tumor, inflammatory and demyelinating diseases.

Gadovist^® not activate the complement system, and so the likelihood of anaphylactoid reactions is very low.

Not detected binding gadobutrola any proteins or inhibit their enzyme activity.

Clinical trials show no adverse effect Gadovist^® on the overall well-being, and liver function, kidney and cardiovascular system.

Pharmacokinetics

The pharmacokinetics of gadobutrol is similar to the pharmacokinetics of other biologically inert substances vysokogidrofilnyh, excreted by the kidneys (eg, mannitola or inulin).

Indicators proportional pharmacokinetics in humans administered dose gadobutrola.

Distribution

Introduced in / gadobutrol is rapidly distributed in the extracellular space and in unchanged form excreted by the kidneys by glomerular filtration.

It binds to plasma proteins.

Deduction

Extrarenal excretion of the drug is so small, that can not be ignored.

If the dose does not exceed gadobutrola 0.4 mmol / kg body weight, after an initial phase of a phase distribution and elimination of the plasma level decreases with T_1/2 1.81 no (1.33-2.13 no), which corresponds to the rate of excretion by the kidneys. At a dose of gadobutrol 0.1 mmol / kg body weight via 2 min after its injection level in the plasma was 0.59 mmol / l, and through 60 min after injection - 0.3 mmol / l. During 2 h urine output more 50% of the administered dose, and for 12 h - more 90%. If the dose administered is gadobutrola 0.1 mmol / kg body weight, the 100.3 ± 2.6% of the dose is excreted from the body 72 no. Renal clearance of gadobutrol in healthy individuals is between 1.1 to 1.7 ml / min × kg; thus, it is comparable with inulin clearance, which indicates the preferential breeding gadobutrola by glomerular filtration. Less 0.1% administered substance excreted in the feces.

Metabolites in the plasma and urine was not detected.

Pharmacokinetics in special clinical situations

T_1/2 gadobutrola in patients with impaired renal function increases in proportion to the degree of reduction of glomerular filtration. In patients with mild or moderate renal impairment gadobutrol completely excreted in the urine within 72 no. In patients with severely impaired renal function 80% of the administered dose is excreted in the urine within 120 no.

Testimony

- Contrast enhancement during MRI of the head and spine (kranialьnoй and spinalьnoй LRA);

- Contrast enhancement during MRI of the whole body, incl. liver and kidneys;

- Increase contrast in magnetic resonance angiography.

For spinal MRI

- Differential diagnosis between intra- and extramedullary tumors;

- Identification of the boundaries of solid tumors in the spinal canal and to determine the prevalence of intramedullary tumor.

Gadovist^® It has special advantages in the presence of the indications for the use of MRI contrast agents in high doses, eg, in cases, when the identification or exclusion of additional lesions may affect the treatment, or medical tactics, as well as the detection of small lesions and for visualization of lesions, kontrastiruemyh difficult by conventional means.

Gadovist^® Also shown for perfusion studies (in the diagnosis of stroke, recognition of focal cerebral ischemia and evaluation of tumor blood supply).

Dosage regimen

The desired dose is administered in / bolus. MRI with high contrast can be started immediately (shortly after the injection, depending on the applied pulse sequence and study design). Optimal opacification is generally observed for about 15 minutes after the administration of Gadovist^® (this time depends on the characteristics and nature of tissue damage). Typically, high contrast persists until 45 minutes after the administration of Gadovist^®. During the MRI should comply with the general safety rules.

Using all the MRI contrast media can be observed side effects, nausea and vomiting. Therefore, to minimize the risk of vomiting and possible aspiration, the patient should refrain from eating for 2 h before the test.

The on / in a patient of a contrast agent (possibly) It must be in the supine position. After the introduction of Gadovist^® the patient must remain under medical supervision for at least 30 m, since, as the experience of the use of contrast agents, Most adverse events observed during this period.

For studies with high contrast most suitable scanning T1-weighted pulse sequence. For perfusion studies of brain recommend using T2 * -weighted pulse sequences.

Stringing Gadovist^® a conventional syringe should only immediately prior to the study. Do not use in a study of the drug must be destroyed.

When selecting the dosing regimen for Adult should be guided by the following rules.

The dose depends on the indication. A single in / introduction Gadovist^® 1 mmol / ml dose 0.1 ml / kg body weight will usually suffice. The maximum dose of Gadovist^® is 0.3 ml / kg body weight.

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

Usually, it is sufficient in / introduction Gadovist^® dose 0.1 ml / kg body weight (equivalent 0.1 mmol / kg body weight). If the suspicions remain about the presence of lesions, or if you need more accurate information on the number of, size and extent of lesions to develop tactics and medical treatment, diagnostic efficiency studies can be increased by introducing additional solution Gadovist^® dose 0.1-0.2 ml / kg body weight for 30 minutes after the previous injection.

In order to exclude metastases or tumor recurrence, imposed solution Gadovist^® dose 0.3 ml / kg body weight, which often contributes to the diagnostic efficacy studies. This applies to lesions with a weak network of blood vessels, Low extracellular space, or a combination of these factors, and the use of scanning relatively less intense T1-weighted pulse sequences.

To brain perfusion studies recommended for T2 * -weighted pulse sequences, in combination with MRI brain and spinal cord lesions to identify bulk or a local ischemia in the absence of assumptions about the bulk lesions.

To carry out this study, it is recommended to use the injector; solution Gadovist^® administered at a dose of 0.3 ml 1 kg of body weight with a rate 3-5 ml / sec.

MRI of the whole body

Usually, it is sufficient in / introduction Gadovist^® (1 mg / ml) dose 0.1 ml / kg body weight (equivalent 0.1 mmol / kg body weight).

Magnetic resonance angiography

A single field of view: dose Gadovista^® is 0.1-0.15 mmol / kg body weight. Patients weighing less than 75 kg preparation is administered in a volume 7.5 ml, patients with a body weight 75 kg or more – 10 ml.

Two or more field of view: dose Gadovista^® is 0.2-0.3 mmol / kg body weight. Patients weighing less than 75 kg preparation is administered in a volume 15 ml, patients with a body weight 75 kg or more – 20 ml.

Side effect

In clinical studies The following side effects observed, associated with the use of the drug Gadovist^® (n=2900). In most cases, side effects are characterized by weak or moderate intensity.

From the central and peripheral nervous system: sometimes (≥1/1000, <1/100) – headache, dizziness, disgevziya, paraesthesia; rarely (<1/1000) – parosmija.

From the digestive system: sometimes (≥1/1000, <1/100) – nausea; rarely (<1/1000) – vomiting.

Cardio-vascular system: sometimes (≥1/1000, <1/100) – vasorelaxation; rarely (<1/1000) – hypotension.

The respiratory system: rarely (<1/1000) – breathlessness.

Allergic reactions: rarely (<1/1000) – hives, rash, anaphylactoid reactions. Perhaps the development of delayed allergic reactions (after a few hours or days).

Local reactions: sometimes (≥1/1000, <1/100) – pain at the injection site, reaction at the injection site. Because of venipuncture and administration of contrast agents at the injection site may transient slight or moderate sensation of cold, heat or pain. Accidental introduction of Gadovist^® in the perivascular tissue can cause pain lasting up to several minutes,.

Side effects, observed in post-marketing studies

CNS: rarely (<1/1000) – loss of consciousness, convulsions.

Cardio-vascular system: rarely (<1/1000) – cardiac arrest, tachycardia, collapse, tides.

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

On the part of the organ of vision: rarely (<1/1000) – conjunctivitis, swelling of the eyelids.

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

Dermatological reactions: rarely (<1/1000) – hyperhidrosis, itch, эritema.

Other: feeling the heat, general malaise.

Contraindications

In the application of the testimony at the recommended doses absolute contraindications to the use of Gadovist^® not available.

FROM caution use in patients with hypersensitivity to one of the components of the drug, with severe renal impairment, severe cardiovascular diseases, under reduced seizure threshold.

Sufficient clinical experience with Gadovist^® in patients younger than 18 years of absence.

Pregnancy and lactation

Data on the use of gadobutrol in pregnancy. Gadovist^® not recommended for use during pregnancy except in cases of emergency.

IN experimental studies in animals revealed no embryotoxic or teratogenic effects of Gadovist^® in diagnostic doses. In the study of repeated doses in gadobutrola, Only the introduction of pregnant animals to toxic doses (exceeding diagnostic dose 8-17 time) caused a delay embryo development and lethality, but it did not lead to teratogenicity.

To date, no study the possibility of penetration gadobutrola into breast milk in humans. IN experimental studies found, that gadobutrol in minimal quantities (less 0.01% of the administered dose) excreted in breast milk. Therefore, after the introduction Gadovist^® breastfeeding be interrupted by at least 24 no.

Cautions

In patients with known hypersensitivity to gadobutrol or any other components of the drug is required particularly careful evaluation of the risks and benefits of application Gadovist^®.

Application Gadovist^® (as well as other contrast agents / in the) It can be accompanied by symptoms of hypersensitivity – anaphylactoid reactions or other manifestations of idiosyncrasy, of the response on the part of the cardiovascular, respiratory or skin reactions, turning into serious conditions, including shock. Most of these reactions occur within 0.5-1 hours after injection.

The risk of hypersensitivity reactions is higher in case of previous reaction to contrast media, bronchial asthma and allergic diseases.

After the diagnostic procedure with Gadovist^® (as well as after the application of other contrast agents), recommended monitoring of the patient.

In the study with Gadovist^® (as well as other contrast agents / in the) You need to have drugs and equipment for resuscitation.

Patients, receiving beta blockers, may be resistant to drugs, having the effect of beta-adrenostimuliruyuschee, used for the treatment of hypersensitivity reactions.

Before the appointment of Gadovist^® all patients must renal function.

Should carefully evaluate the risk / benefit ratio of the drug in patients with severely impaired renal function, because in such cases the elimination of the contrast medium is retarded. In severe cases, gadobutrol should be removed from the body by hemodialysis. For patients, at the time of the introduction of Gadovist^® already receiving hemodialysis, should consider the immediate initiation of hemodialysis after the administration of Gadovist^® to accelerate the elimination of the contrast agent. After three courses of dialysis from the body is derived approximately 98% gadobutrola.

It reported cases of nephrogenic systemic fibrosis in connection with the introduction of gadolinium contrast agents in patients with acute or chronic severe renal insufficiency (glomerular filtration rate < 30 ml / min /1.73 m²); Patients with acute renal failure of any severity, induced hepatic renal syndrome, or before and after liver transplantation. Despite, that thanks to the macrocyclic structure gadobutrol has a very high stability of the complex, There is the possibility of developing nephrogenic systemic fibrosis when using Gadovist^®. Therefore, in such patients to use Gadovist^® It should be only after a thorough evaluation of benefit / risk ratio.

In patients with severe cardiovascular disease Gadovist^® It should only be used after careful assessment of risk / benefit ratio, tk. information, relating to this category of patients, limited.

Preclinical safety studies (study of systemic toxicity, genotoxicity and the potential of the contact sensitivity) shown, that gadobutrol does not pose any danger to humans.

Effects on ability to drive vehicles and management mechanisms

There was no effect of the drug on the ability to drive vehicles and other activities, require high concentration and speed of psychomotor reactions.

Overdose

So far, there were no cases of intoxication, related overdose Gadovist^® during its clinical application. Based on the results of acute toxicity studies the risk of acute intoxication due to the use of Gadovist^® highly unlikely.

Treatment: Accidental overdose Gadovist^® It can be removed from the body via extracorporeal dialysis. In case of overdose, as a precaution we recommend monitoring the cardiovascular system (including an electrocardiogram) and monitoring of renal function.

In clinical trials, the maximum tested dose solution Gadovist^® (1.0 mg / ml), component 1.5 ml / kg body weight, well tolerated.

Drug Interactions

Drug interactions with other drugs have been identified.

Not to be confused Gadovist^® with other drugs, since there are no compatibility data.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at or above 30 ° C. Shelf life - 3 year.

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