Гадовист®

General characteristics. Structure:

Active agent:
604,72 mg (1,0 mmol) of a gadobutrol.
Excipients: калкобутрол sodium of 0,513 mg, трометамол 1,211 mg, Acidum hydrochloricum 0,1 M to pH 7,2 ± 0,2, water for injections to 1 ml.
Description. Transparent liquid, free from particles.

Physical and chemical properties
Gadobutrol is very well dissolved in water and has extremely high hydrophily (the coefficient of its distribution between N butanol and the buffer at pH 7,6 is equal to about 0,006). The macrocyclic ligand forms a strong complex with a paramagnetic ion of gadolinium, the characterized exclusively high stability both in vivo, and in vitro.
Physical and chemical properties of solution of Gadovist (1 mmol/ml) are included below.

Osmolarity at 37 °C (¼Äß¼/l solution) 1117
Osmolality at 37 °C (¼Äß¼/kg waters) 1603
Viscosity at 37 °C (мПас) 4,96.

Pharmacological properties:

Pharmacodynamics. The Gadovist is a paramagnetic contrast means for the magnetic and resonant tomography (MRT). Strengthening of contrast is caused by its active component gadobutroly which represents a neutral (not ionic) complex of gadolinium (III) with a macrocyclic ligand — дигидрокси-гидроксиметилпропил-тетраазациклододекан-триуксусной acid (butroly).
When using T2* - the weighed pulse sequences induction of local inhomogeneity of magnetic field under the influence of the strong magnetic moment of gadolinium at its high concentration (bolyusny introduction) leads to change of a signal from fabrics (contrast strengthening).
Gadobutrol even in low concentration causes considerable shortening of time of a relaxation. Quantitatively ability to change time of a relaxation of T1 and T2, determined by influence on time of backs-reshetochnoy and the spin-spin relaxation of protons in plasma at pH 7 and 40 °C, makes about 5,6 l/mmol" with and 6,5 l/mmol" with respectively. Ability to influence relaxation time only in small degree depends on tension of magnetic field.
Gadovist's introduction allows to obtain more exact diagnostic information in comparison with data of usual MRT in areas with the broken permeability of a blood-brain barrier, for example, in cases of primary or secondary tumors, inflammatory and demyelinating diseases.
The Gadovist does not activate system of a complement and therefore the probability of induction by this substance of anaphylactoid reactions is extremely low.
Binding of a gadobutrol any proteins or inhibition to them activity of enzymes is not revealed.
Results of clinical trials testify to lack of negative influence of Gadovist on overall health, and also on function of a liver, kidneys and serdechnoksosudisty system.

Pharmacokinetics. The behavior of a gadobutrol in an organism is similar to behavior of other highly hydrophilic biologically inert substances emitted by kidneys (for example, Mannitolum or inulin).
Entered intravenously гадобутрол quickly it is distributed in extracellular space and in not changed form it is removed by kidneys by glomerular filtering. Extrarenal elimination is so insignificant that can not be considered.
Pharmacokinetics indicators at the person are proportional to the entered dose of a gadobutrol. If the dose of a gadobutrol does not exceed 0,4 mmol on 1 kg of body weight, after an initial phase of distribution there come the phase of elimination and its concentration in plasma decreases with an elimination half-life 1,81 hours (1,33 — 2,13 hours) that corresponds to removal speed kidneys. At a dose of a gadobutrol of 0,1 mmol/kg of body weight in 2 minutes after an injection its level in plasma made 0,59 mmol/l, and in 60 minutes after an injection — 0,3 mmol/l. Within two hours with urine more than 50% of the entered dose, and within 12 hours — more than 90% are removed. If the entered dose of a gadobutrol is equal to 0,1 mmol/kg of body weight, then 100,3 ± 2,6% of this dose are brought out of an organism in 72 hours. The renal clearance of a gadobutrol at healthy faces makes from 1,1 to 1,7 ml / мин.кг; thus, it is comparable with clearance of inulin that demonstrates preferential removal of a gadobutrol by glomerular filtering. Less than 0,1% of the entered substance are removed from an organism with a stake. It was not succeeded to find any metabolites in plasma and urine.
The elimination half-life of a gadobutrol at patients with an impaired renal function increases in proportion to extent of decrease in glomerular filtering.
At patients with an easy or moderate renal failure Gadobutrol is completely brought with urine within 72 hours. At patients with heavy disturbance of renal function of, at least, 80% of the entered dose it is removed with urine within 120 hours. MRT TsNS, a liver, kidneys with contrasting or the magnetic and resonant angiography (MRA) with contrasting, with introduction of one dose of a gadobutrol were carried out at 140 children (from 2 to 17 years) during clinical trials of a phase. These researches showed that the pharmacokinetics of a gadobutrol at children of 2 years and is more senior is similar to pharmacokinetics at adults. Pharmacokinetic indicators, such as the general clearance of creatinine, the area under curve (AUC) and volume (V) increase in proportion to body weight. Gender and age additional impact on pharmacokinetics is not exerted. 98,7% (average value) of the entered dose of a gadobutrol are removed by kidneys within 6 hours that confirms bystry removal of a gadobutrol at children.

Indications to use:

This medicine is intended only for the diagnostic purposes. The Gadovist is shown to adults, teenagers and children aged from 2 years for increase in contrast when carrying out a magnetic and resonant tomography of all body, including:
- strengthening of contrast when carrying out cranial and spinal MRT.
- strengthening of contrast when carrying out MRT of area of the head and neck.
- strengthening of contrast when carrying out MRT of area of a thorax
- strengthening of contrast when carrying out MRT of mammary glands
- strengthening of contrast when carrying out MRT of an abdominal cavity (including a pancreas, a liver and a spleen).
- strengthening of contrast when carrying out MRT of area of a small pelvis (including prostates, a bladder and a uterus).
- strengthening of contrast when carrying out MRT of retroperitoneal space (including kidneys)
- strengthening of contrast when carrying out MRT of a musculoskeletal system and extremities.
- strengthening of contrast when carrying out the magnetic and resonant angiography (MRA).
- strengthening of contrast when carrying out MRT of heart (including for assessment of myocardial perfusion in the conditions of a pharmacological stress and diagnosis of viability of "the delayed contrasting" fabric).
Are among special indications to spinal MRT: carrying out the differential diagnosis between intra-and extramedullary tumors, identification of borders of solid tumors in the spinal channel and definition of prevalence of an intramedullary tumor.
Gadovist's solution (1 mmol/ml) has particular advantages in the presence of indications to use of magnetic and resonant means in high doses, for example in cases when identification or an exception of the additional centers of defeat can influence the carried-out treatment or medical tactics, and also at identification of small damages or for visualization of the defeats which are difficult contrasted by usual means.
Gadovist's solution (1 mmol/ml) can also be applied to perfused researches: at diagnosis of a stroke, recognition of focal ischemia of a brain or assessment of blood supply of a tumor.

Route of administration and doses:

The necessary dose is entered intravenously in the form of a bolus. Carrying out a magnetic and resonant tomography with contrasting can be begun at once (soon after an injection depending on the applied pulse sequence and the protocol of a research). Optimum contrast strengthening is observed during an arterial phase when carrying out MRA with contrasting and during the span measured for minutes, after Gadovist's introduction when carrying out other researches (time depends on damage/fabric type).
The general safety rules inherent in a magnetic and resonant tomography have to be followed (see. "Special instructions").
With contrasting are most suitable for researches when scanning T1 - the weighed pulse sequences. Recommend to apply T2* to perfused researches of a brain - the weighed pulse sequences. Rules of use of drug
Before introduction it is necessary to examine attentively a bottle, the syringe or a cartridge. At considerable discoloration, detection of visible particles or disturbance of integrity of packaging drug cannot be used.
It is necessary to gather Gadovist in the syringe only just before introduction. The rubber bung of a bottle should not be punctured more than 1 time.
Gadovist in the syringe it is necessary to take from packaging and to prepare for an injection just before introduction. The cover of a tip of the syringe should be deleted just before introduction.
The Gadovist in cartridges has to be entered by the specialist according to the instructions attached to the equipment for use of cartridges. Administration of drug has to be carried out in sterile conditions.
Part of drug, unused during one research, should be destroyed.
  It is not necessary  to mix  Gadovist  with  other  drugs  as  data  about
compatibility is absent.

Dosing mode

Choosing the dosing mode for adults, it is necessary to be guided by the following rules.
The dose depends on indications. Single intravenous administration of Gadovist of 1 mmol/ml in a dose of 0,1 ml/kg of body weight usually happens sufficient. The maximum dose of Gadovist makes 0,3 ml/kg of body weight.

• MRT of all body (except MRA).
As a rule, intravenous administration of Gadovist (1 mmol/ml) in a dose of 0,1 ml on 1 kg of body weight is sufficient (that is equivalent to 0,1 mmol/kg of body weight).

In addition for cranial and spinal MRT
As a rule, intravenous administration of Gadovist (1 mmol/ml) in a dose of 0,1 ml on 1 kg of body weight is sufficient (that is equivalent to 0,1 mmol/kg of body weight). If at the same time there are suspicions about existence of defeats or more exact information on number, the size and prevalence of defeats is necessary, then diagnostic efficiency of a research can be increased, having in addition entered Gadovist's solution (0,1 mmol/ml) in a dose 0,1 or even 0,2 ml on 1 kg of body weight within 30 minutes after the previous injection.
To exclude metastasises or a recurrent tumor, enter Gadovist's solution (0,1 mmol/ml) in a dose of 0,3 ml on 1 kg of body weight that often promotes increase in diagnostic efficiency of a research. It belongs to defeats with weak expressiveness of network of blood vessels, with small extracellular space or a combination of these factors, and also to use when scanning of rather less intensive ^-weighed pulse sequences.
For perfused researches of a brain it is recommended to use an injector and to apply T2* - the weighed pulse sequences in a combination with MRT of a head and spinal cord to identification of volume defeats or local ischemia in the absence of assumptions of volume educations. For carrying out this research it is recommended to use an injector; Gadovist's solution (1 mmol/ml) enter in a dose 0,3 ml on 1 kg of body weight with a speed of 3-5 ml/sec.

• Magnetic and resonant angiography.
One area of scanning:
7,5 ml for body weight less than 75 kg
10 ml for the body weight of 75 kg and more
(there correspond 0,1 - 0,15 mmol/kg of body weight) Two and more areas of scanning: 15 ml for the body weight less than 75 kg of 20 ml for the body weight of 75 kg and more (there correspond 0,2-0,3 mmol/kg of body weight)

Use for children:
For children 2 years are more senior and teenagers the recommended Gadovist's dose makes 0,1 mmol/kg of body weight (0,1 ml/kg of body weight) according to all indications (see the section "Indications" are equivalent).
The Gadovist is not recommended for use for children under 2 years in connection with insufficiency of data on efficiency and safety.

Features of use:

• Hypersensitivity with the known hypersensitivity to drug or its components is required From patients especially careful assessment of a ratio risk/advantage of use of Gadovist. As well as at use of other contrast intravenous agents, Gadovist's use can be followed by hypersensitivity manifestations - the anaphylactoid reactions and other manifestations of an idiosyncrasy which are characterized by reactions from cardiovascular, respiratory system or the skin reactions turning into serious conditions including shock. The majority of these reactions develop within 0.5-1 hour after introduction.
The delayed allergic reactions are seldom observed (in several hours - days after introduction).
After holding a diagnostic procedure with Gadovist (also as well as after use of other contrast means), observation of a condition of the patient is recommended.
At a research it is necessary to have medicines and equipment for holding resuscitation actions.
The risk of development of hypersensitivity reactions is higher in cases of the previous reaction to contrast means, bronchial asthma and allergic diseases in the anamnesis.
The patients accepting beta adrenoblockers can be rezistentna to drugs, possessing beta and agonistic action, applied to treatment of reactions of hypersensitivity.
• Heavy renal failures
It is necessary to estimate with special care a ratio risk/advantage of use of drug for patients with heavy renal failures as in similar cases removal of a contrast agent is slowed down. In especially hard cases it is necessary to remove гадобутрол from an organism by means of a hemodialysis. After three courses of dialysis about 98% of a gadobutrol are brought out of an organism.
It was reported about cases of development of the nephrogenic system fibrosis (NSF) in connection with introduction of gadoliniysoderzhashchy contrast means to patients with the following diseases / states:
- acute or chronic heavy renal failure (glomerular filtration rate <30 ml/min. / 1,73 sq.m) and
- the acute renal failure of any weight caused by a hepatonephric syndrome or during the period before transplantation of a liver.
In spite of the fact that Gadovist has very high stability of a complex, thanks to its macrocyclic structure, there is a possibility of development of NSF when using Gadovist's. Therefore at such patients it is necessary to use Gadovist only after careful assessment of a ratio advantage/risk.
Before Gadovist's introduction all patients it is necessary to check regarding dysfunction of kidneys by means of collecting anamnestic data and/or carrying out laboratory analyses.
The Gadovist can be removed from an organism by a hemodialysis. Concerning patients who at the time of Gadovist's introduction already receive hemodialysis treatment it is necessary to consider expediency of the immediate beginning of a hemodialysis after Gadovist's introduction for the purpose of acceleration of elimination of contrast means.
• Convulsive states
Extra care is required at Gadovist's appointment, as well as other contrast means containing gadolinium chelate, to patients with a low threshold of convulsive readiness.
• Serious cardiovascular illness
At patients with a serious cardiovascular illness of Gadovist it is necessary to apply only after careful assessment of a ratio risk/advantage as information concerning this category of patients is limited.
Results of preclinical trials of safety (studying of system toxicity, genotoxicity and potential of contact sensitivity) showed what гадобутрол is not the substance having any danger to the person.
Influence on ability to manage car and to use difficult mechanisms
Influences on ability to manage car and to use difficult mechanisms, it is not revealed.

Side effects:

Frequency of each individual side effect did not exceed the size "infrequently". At conduct of clinical trials side effects were estimated more than at 2900 patients. In most cases side effects were characterized by weak or moderate intensity. The list of undesirable reactions which, according to the doctor, were connected with the studied drug is included below.

System of bodies              Infrequently (> 1/1000, <1/100)                             it is rare (<1/1000)
Immune system                                                                        Anaphylactoid reactions
Nervous system            Headache, dizziness,
                                                dysgeusia,                      Parosmiya's paresthesia
Vessels                              Vasodilatation                                  Hypotension
Respiratory                                                                             Asthma system
Gastrointestinal
                                           Nausea Vomiting system                                              
Skin and hypodermic fabric                                                                    Urticaria, rash
General pathology and Bol's changes in the place of an injection,
 in an injection site                  reaction in the place of an injection 

Allergic reactions: the delayed allergic reactions (in several hours or days).
Local reactions: in the place of an injection owing to a venipuncture or administration of contrast agent sometimes perhaps short-term weak or moderate cryesthesia, heat or pain. Accidental introduction of Gadovist to okolososudisty fabrics can cause pain duration up to several minutes.

•   The side reactions revealed after a conclusion drug on the market are included below
System of bodies Seldom (<1/1000)
Immune system acute anaphylaxis
Nervous system loss of consciousness, spasms
The organ of sight conjunctivitis, swelled a century
Cardiovascular system cardiac standstill, tachycardia
Vessels collapse, inflows
Respiratory system apnoea, bronchospasm, cyanosis, orofaringealny hypostasis, cough, nose congestion
Skin and hypodermic fabric throat hypostasis, hyperhidrosis, itch, erythema
General pathology and changes in an injection site feeling of heat, febricula
Data are given in a basis of classification of systems of bodies for MedDRA (The medical Dictionary for Regulatory Activity). The most suitable medical terms (MedDRA 8.0 version) are listed. Synonyms or faithful states are not given, but have to be also taken into account.

Interaction with other medicines:

It is not necessary to mix Gadovist with other drugs as data on compatibility are absent.
Interactions with other medicines are not revealed.

Contraindications:

There are no absolute contraindications for Gadovist's use (see. "Special instructions").
With care
Gadovist it is necessary to apply with care at the following states:
- hypersensitivity to one of drug ingredients
- heavy renal failures
- serious cardiovascular illness
- low threshold of convulsive readiness.

Pregnancy and lactation
• Pregnancy
In experiments on animals neither embriotoksichesky, nor teratogenic action of diagnostic doses of Gadovist was revealed. At a research of repeated doses of a gadobutrol, only introduction by a pregnant animal of the toxic doses (exceeding a diagnostic dose by 8 - 17 times) caused an arrest of development of embryos and their lethality, but did not result in teratogenecity.
However, data of clinical trials of use of a gadobutrol at pregnancy are absent. Therefore Gadovist should not be entered to pregnant women if only it is not dictated by obvious need
• Lactation
So far the possibility of hit of a gadobutrol in milk of the feeding woman is not studied.
As show experiments on animals, Gadovist in the minimum quantities (less than 0,01% of the entered dose) gets to breast milk. After Gadovist's introduction feeding by a breast should be interrupted at least for 24 hours.

Overdose:

So far cases of intoxication connected with Gadovist's overdose at his clinical use were not noted. On the basis of results of researches of acute toxicity the risk of developing of acute intoxication in connection with Gadovist's use is extremely improbable.
In cases of inadvertent overdose of Gadovist it can be brought out of an organism by means of extracorporal dialysis (see the section "Special Instructions"). At overdose  as  a precautionary measure  monitoring of functions of cardiovascular system (including an ECG) and control of function of kidneys is recommended. The maximum tested dose of solution of Gadovist (1,0 mmol/ml) making 1,5 ml/kg of body weight at people was transferred well.

Storage conditions:

Period of validity - 3 years.
Not to use after the period of validity specified on packaging.
After the bottle was open in aseptic conditions, Gadovist remains stable within, at least, 8 hours at the room temperature. At a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous administration of 1 mmol/ml. On 15 ml or 30 ml in bottles from colourless glass like I, with the rubber bungs which are pressed out by the aluminum caps supplied with plastic covers. On 1 bottle on 30 ml or on 5 bottles on 15 ml together with the application instruction place in a cardboard pack. On 5 ml or 7,5 ml in the glass syringe from colourless glass like I. On 1 syringe in the blister from PVC and the laminated paper. On 5 blisters together with the application instruction place in a cardboard pack.
On 15 ml in plastic cartridges with a capacity of 65 ml. On 5 cartridges together with the application instruction place in a cardboard pack.
On 30 ml in plastic cartridges with a capacity of 65 ml. On 5 cartridges together with the application instruction place in a cardboard pack.