Composition, form of production and packaging
A solution for intravenous administration of 1 mmol / ml is transparent, free from foreign inclusions.
1 ml
gadobutrol 604.72 mg,
which is equivalent to 1 mmol
osmolarity at 37 В° C - 1117 mOsm / l solution osmolality at 37 В° C - 1603 mOsm / kg H 2 O viscosity at 37 В° C - 4.96 mPa.s
Excipients: sodium calcobutrol - 513 Ојg, trometamol - 1.211 mg, hydrochloric acid 0.1M - up to pH7.2 В± 0.2, water d / u - up to 1 ml.
5 ml - syringes of colorless glass (1) - blisters (5) - packs cardboard.
7.5 ml - colorless glass syringes (1) - blisters (5) - cardboard packs.
15 ml - bottles of colorless glass (5) - packs of cardboard.
30 ml - bottles of colorless glass (1) - packs cardboard.
15 ml - plastic cartridges with a capacity of 65 ml (5) - packs cardboard.
30 ml - plastic cartridges with a capacity of 65 ml (5) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Paramagnetic contrast preparation for magnetic resonance imaging (MRI).
The increase in contrast is due to the active component gadobutrolom, which is a neutral complex of gadolinium (III) with a macrocyclic ligand - dihydroxy-hydroxymethylpropyltetraazacyclododecane-triacetic acid (butrol).
When T2 * -weighted pulse sequences are used, the induction of the local inhomogeneity of the magnetic field under the influence of the strong magnetic moment of gadolinium at its high concentration (bolus injection) leads to a change in the signal from the tissues (the contrasting effect).
Gadobutrol even in low concentrations causes a significant shortening of the relaxation time. The ability to vary the relaxation time T1 and T2, determined from the effect of the spin-lattice and spin-spin relaxation of protons in the plasma at pH 7 and temperature 40 В° C, amounts to about 5.6 l / mmol / s and 6.5 l / mmol / s respectively. The ability to influence the relaxation time depends only to a small extent on the strength of the magnetic field.
The introduction of Gadovist makes it possible to obtain more accurate diagnostic information in comparison with the data obtained with conventional MRV in areas with a high BBB permeability or lack thereof, causing a violation of perfusion or an increase in the volume of extracellular space, for example, in cases of primary tumors, inflammatory and demyelinating diseases.
Gadovist В® does not activate the complement system, and therefore the probability of anaphylactoid reactions is extremely low.
No binding of gadobutrol with any proteins or inhibition of enzyme activity was observed.
The results of clinical trials indicate that Gadovist has no negative effect on overall health, as well as on liver, kidney and cardiovascular functions.
PHARMACOKINETICS
The pharmacokinetics of gadobutrol are similar to the pharmacokinetics of other highly hydrophilic biologically inert substances released by the kidneys (eg, mannitol or inulin).
The pharmacokinetics in humans are proportional to the administered dose of gadobutrol.
Distribution
Entered in / in gadobutrol quickly distributed in the extracellular space and in an unchanged form is excreted by the kidneys through glomerular filtration.
Does not bind to plasma proteins.
Excretion
The extrarenal excretion of the drug is so insignificant that it can be ignored.
If the dose of gadobutrol does not exceed 0.4 mmol / kg of body weight, after the initial phase of the distribution, the elimination phase begins and its plasma level decreases from T 1/2 1.81 h (1.33-2.13 h), which corresponds to the rate of excretion by the kidneys. At a dose of 0.1 mmol / kg of body weight gadobutrol, 2 minutes after injection, its plasma level was 0.59 mmol / L, and 60 minutes after injection 0.3 mmol / L. Within 2 hours with urine, more than 50% of the administered dose is discharged, and within 12 hours - more than 90%. If the administered dose of gadobutrol is 0.1 mmol / kg of body weight, then 100.3 В± 2.6% of this dose is excreted from the body in 72 hours. The kidney clearance of gadobutrol in healthy individuals is 1.1 to 1.7 ml / min-kg; Thus, it is comparable with the clearance of inulin, which indicates the preferential removal of gadobutrol by glomerular filtration. Less than 0.1% of the administered substance is excreted from the body with feces.
Metabolites in plasma and urine are not detected.
Pharmacokinetics in special clinical cases
T 1/2 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 dysfunction, gadobutrol is completely excreted in the urine for 72 hours. In patients with severe renal dysfunction, 80% of the administered dose is excreted in the urine for 120 hours.
INDICATIONS
The drug is intended exclusively for diagnostic purposes.
Gadovist В® is shown to adults, adolescents and children aged 7 years to increase the contrast when performing magnetic resonance imaging (MRI) of the whole body, including:
- increased contrast in the conduct of cranial and spinal MRV;
- Increase in contrast when carrying out MRV of the head and neck;
- Increase of contrast in carrying out MRV of the thorax;
- Increase of contrast during breast MPB;
- Increased contrast when carrying out an MPR of the abdominal cavity (including pancreas, liver and spleen);
- Increase in contrast when carrying out the MRV of the pelvic region (including the prostate gland, bladder and uterus);
- Increase in contrast when carrying out RTM of retroperitoneal space (including kidneys);
- Increased contrast when carrying out the MRI of the musculoskeletal system and limbs;
- increased contrast in magnetic resonance angiography (MRA);
- increased contrast in heart MRB (including for evaluation of myocardial perfusion under conditions of pharmacological stress and diagnosis of tissue viability "delayed contrasting").
Among the special indications for spinal MRV are: the differential diagnosis between intra- and extramedullary tumors, the detection of the boundaries of solid tumors in the spinal canal and the definition of the prevalence of the intramedullary tumor.
The Gadovist solution (1 mmol / ml) has special advantages in the presence of indications for the use of high-dose magnetic resonance drugs, for example, in cases where detection or exclusion of additional lesions may affect the treatment or practice, damage or for visualization of lesions difficult to contrast with conventional means.
The Gadovist solution (1 mmol / ml) can also be used for perfusion studies: in the diagnosis of stroke, recognition of focal cerebral ischemia or evaluation of blood supply to the tumor.
DOSING MODE
general information
The required dose is given IV in the form of a bolus. Magnetic resonance imaging with increased contrast can be started immediately (soon after the injection, depending on the pulse sequence used and the protocol of the study).
Optimal contrast enhancement is observed during the arterial phase during MRA with contrast enhancement and for a period of time measured in minutes after administration of Gadovist В® in other studies (time depends on the type of injury / tissue).
When conducting magnetic resonance imaging, general safety rules must be observed.
For studies with contrast, T1-weighted pulse sequences are most appropriate.
Terms of use
Before administration, you should carefully inspect the bottle, syringe or cartridge. If the color changes significantly, if visible particles are detected or if the integrity of the packaging is violated, the drug should not be used.
Gadovist В® should only be taken into the syringe immediately before administration. The rubber stopper of the bottle should not be pierced more than 1 time.
The drug Gadovist В® in a syringe should be removed from the package and prepared for injection immediately before administration. The lid of the syringe tip should be removed immediately before administration.
The drug Gadovist В® in cartridges should be administered by a specialist in accordance with the instructions supplied with the equipment for the use of cartridges. The drug should be administered under sterile conditions.
Part of the drug unused during one study should be destroyed.
Do not mix Gadovist В® with other drugs, as there is no compatibility data.
Dosing regimen
When choosing the dosing regimen for adults , the following rules should be followed.
The dose depends on the indications. One-time intravenous administration of the drug Gadovist В® 1 mmol / ml at a dose of 0.1 ml per 1 kg of body weight is usually sufficient. The maximum dose of Gadovist В® is 0.3 mmol per 1 kg of body weight (equivalent to 0.3 ml per 1 kg of body weight).
MPW of the whole body (except MRA)
As a rule, intravenous administration of Gadovist В® (1 mmol / ml) in a dose of 0.1 ml per 1 kg of body weight (equivalent to 0.1 mmol per 1 kg of body weight) is sufficient.
In addition to cranial and spinal MRB
As a rule, intravenous administration of Gadovist В® (1 mmol / ml) in a dose of 0.1 ml per 1 kg of body weight (equivalent to 0.1 mmol per 1 kg of body weight) is sufficient.
If there are still suspicions about the presence of lesions or if more precise information is needed on the number, size and prevalence of lesions, the diagnostic efficiency of the study can be increased by additionally adding a solution of Gadovist В® (0.1 mmol / ml) at 0.1 or even 0.2 ml per 1 kg body weight within 30 minutes after the previous injection.
To exclude metastases or relapse of the tumor, a solution of Gadovist В® (0.1 mmol / ml) in a dose of 0.3 ml per 1 kg of body weight is administered, which often contributes to improving the diagnostic efficiency of the study. This refers to lesions with a weakly expressed network of blood vessels, with a small extracellular space or a combination of these factors, and also to the use of scanning relatively less intense T1-weighted pulse sequences.
For perfusion studies of the brain it is recommended to use an injector and a solution of the drug Gadovist В® (1 mmol / ml), which is administered at a dose of 0.3 ml per 1 kg of body weight at a rate of 3-5 ml / s.
Magnetic resonance angiography
One scan area: 7.5 ml - for body weight less than 75 kg; 10 ml - for body weight 75 kg and more (corresponds to 0.1-0.15 mmol per 1 kg of body weight)
Two or more scanning areas: 15 ml - for body weight less than 75 kg; 20 ml - for body weight 75 kg and more (corresponds to 0.2-0.3 mmol per 1 kg of body weight)
Use in children
For children over 7 years and adolescents, the recommended dose of Gadovist В® is 0.1 mmol per 1 kg of body weight (equivalent to 0.1 ml per 1 kg of body weight) for all indications.
The drug Gadovist В® is not recommended for use in children under 2 years due to lack of data on efficacy and safety.
SIDE EFFECT
The overall safety profile of Gadovist В® is based on clinical trials in more than 5,700 patients, as well as post-marketing surveillance data.
The most frequent adverse reactions (? 0.5%) that were observed in patients receiving Gadovist В® include: headache, nausea and dizziness.
The most serious adverse reactions in patients receiving Gadovist В® are cardiac arrest, severe anaphylactic / anaphylactoid reactions.
Delayed allergic reactions (a few hours or days) were rare.
In most cases, the side effects were characterized by a mild or moderate degree of severity. Adverse reactions that were observed with the administration of the drug Gadovist В® are presented below. The data are based on the classification of organ systems by MedDRA (Medical Dictionary for Regulatory Activities). The most appropriate medical terms (MedDRA version 14.1) are listed.
Undesirable reactions are classified according to the frequency of manifestation. The frequency grouping was 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). Adverse reactions detected during post-marketing observations or reactions for which the frequency can not be counted are listed in this table in the column "frequency unknown".
Undesirable reactions reported during clinical trials and postmarketing studies in patients receiving Gadovist В®
From the side of the immune system: infrequently - hypersensitivity / anaphylactic and anaphylactoid reactions (anaphylactic shock 1,2 , cardiovascular failure 1,2 , respiratory arrest 1,2 , bronchospasm, cyanosis 1 , laryngeal edema 1,2 , lower body temperature 2 , increased blood pressure 1 , chest pain, facial edema 1 , angioedema 1 , edema of the eyelids 1 , "hot flashes", intense sweating 1 , cough 1 , sneezing 1 , fever 1 , pallor.
From the nervous system: often - headache; infrequently - dizziness, dysgeusia, paresthesia; rarely - loss of consciousness (fainting), cramps, parosmia.
From the side of the cardiovascular system: rarely - tachycardia, palpitation; frequency unknown - cardiac arrest 2 .
From the respiratory system : infrequently - shortness of breath 2 .
From the digestive system: often - nausea; infrequently - vomiting; rarely dry mouth.
From the skin and subcutaneous structures: infrequently - erythema, itching (including generalized form), rash (including maculopapular rash with itching); frequency unknown - nephrogenic systemic fibrosis.
General pathology and changes in the injection site: infrequent - reactions at the injection site 3 , sensations of fever; rarely - malaise, chills.
1 - Hypersensitivity / anaphylactic reactions that were detected only in post-marketing studies (frequency unknown).
2 - Cases associated with a life threat and / or fatal.
3 - Reactions at the site of administration (of various types) include the following: hemorrhage at the site of injection, burning at the injection site, a feeling of cold at the injection site, a feeling of heat at the injection site, erythema and rash at the injection site, pain at the injection site, hematoma in place introduction.
CONTRAINDICATIONS
When used according to the indications in the recommended doses, there are no absolute contraindications for the use of Gadovist.
With caution should apply the drug with increased sensitivity to one of the components of the drug, with severe violations of kidney function, severe cardiovascular disease, with a low threshold of convulsive readiness.
PREGNANCY AND LACTATION
Data on the use of gadobutrol during pregnancy are absent. Gadovist В® is not recommended for use in pregnancy, except in cases of extreme necessity.
In experimental studies on animals, there was no embryotoxic or teratogenic effect of Gadovist in diagnostic doses. In the study of gadobutrol in repeated doses, only administration to pregnant animals in toxic doses (exceeding the diagnostic dose by 8-17 times) caused a delay in the development of embryos and their lethality, but did not lead to teratogenicity.
Until now, the possibility of penetration of gadobutrol into human breast milk has not been studied. In experimental studies , it has been established that gadobutrol in minimal amounts (less than 0.01% of the administered dose) is excreted in breast milk. Therefore, after Gadovist administration, breastfeeding should be interrupted for at least 24 hours.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution appoint Gadovist patients with severe impairment of kidney function, because in this situation, the excretion of contrast medium is slowed down. In especially severe cases, Gadovist should be removed from the body with hemodialysis. After 3 courses of dialysis, about 98% of the contrast agent is excreted from the body.
In case of renal insufficiency, the dose of Gadovist solution should not exceed 0.1 ml / kg of body weight.
APPLICATION FOR CHILDREN
For children older than 7 years 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.
The drug Gadovist В® is not recommended for use in children under 2 years due to lack of data on efficacy and safety.
SPECIAL INSTRUCTIONS
Hypersensitivity
In patients with known hypersensitivity to gadobutrol or other components of the drug, a particularly careful assessment of the risk-benefit ratio of Gadovist В® isrequired.
As with other contrast agents for intravenous administration, the use of the drug Gadovist В® may be accompanied by hypersensitivity, anaphylactoid reactions and other manifestations of idiosyncrasy characterized by reactions from the cardiovascular, respiratory system or skin reactions that turn into severe conditions, including shock .
The risk of developing hypersensitivity reactions is higher in the following cases:
- previous reaction to contrast agent;
- bronchial asthma;
- allergic diseases in the anamnesis.
Most of these reactions develop within 0.5-1 h after administration.
In patients with a predisposition to developing allergic reactions, the decision to use Gadovist В® should be taken only after a thorough assessment of the risk / benefit ratio.
Rarely observed delayed allergic reactions (within a few hours - the day after administration).
After carrying out a diagnostic procedure to Preparation Gadovist В® (as well as after the application of other contrast agents) recommended monitoring of the patient.
On examination it is necessary to have drugs and equipment for resuscitation.
Patients receiving beta-blockers, in the development of hypersensitivity reactions may be resistant to the action of beta agonists used to treat such reactions.
Severe renal impairment
is still impaired renal function were observed.
Before administration Gadovist formulation В®all patients should be checked for renal dysfunction by history data collection and / or laboratory tests.
It should be carefully weighed against the risk / benefit of the drug in patients with severely impaired renal function, because in such cases the elimination of the contrast medium is retarded. After three dialysis courses of the body is derived gadobutrola about 98%. For patients on hemodialysis, should consider the appropriateness of immediate initiation of hemodialysis after administration of the drug Gadovist В® to accelerate the elimination of the contrast agent.
Reported cases of nephrogenic systemic fibrosis (NSF) in connection with the introduction of the gadolinium-containing contrast agents, including Gadovist formulationВ® , patients with the following diseases / conditions:
- acute or chronic renal failure (GFR <30 mL / min / 1.73 m 2 ) or
- acute renal failure of any severity caused by hepatorenal syndrome or during the period before and after liver transplantation.
Despite the fact that the Gadovist formulation В® has a very high stability of the complex, due to their macrocyclic structure, there is the possibility of using ASN Gadovist formulation В® . Therefore, such patients use Gadovist formulation В® should only after careful evaluation benefit / risk ratio.
convulsive status
Particular care is required when assigning Gadovist formulation В® , as well as other contrast agents containing gadolinium chelate, patients with a low threshold seizure.
OVERDOSE
A single injection of Gadovist formulation В® (1 mmol / ml) at a dose of 1.5 ml per 1 kg body weight or higher was well tolerated.
Hitherto no symptoms of intoxication associated with overdose Gadovist formulation В® during its clinical application. Based on acute toxicity studies the risk of acute intoxication due to the use of the drug Gadovist В® is highly unlikely.
If unintentional overdose as a precaution it is recommended monitoring functions of the cardiovascular system (including ECG) and monitoring of renal function. Gadovist formulation В® can be removed from the body by hemodialysis.
DRUG INTERACTION
Drug interactions with other drugs is not revealed.
Do not mix Gadovist В® with other drugs because of the compatibility data are not available.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
Shelf life - 3 years.
After the vial was opened under aseptic conditions Gadovist formulation В® remains stable for at least 8 to 24 hours at a temperature of from 20 В° to 25 В° C.
