Gadovist - instructions for use, dose, side effects, contraindications

Active substanceGadobutrolGadobutrol

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Gadovist®

solution in / in

Bayer Pharma AG Germany

Dosage form: & nbspsolution for intravenous administration

Composition:

In 1 ml of solution contains:

Active substance: 604.72 mg (1.0 mmol) of gadobutrol;

Excipients: sodium cobalkrolrol 0.513 mg, trometamol 1.211 mg, hydrochloric acid 0.1 M to pH 7.2 ± 0.2, water for injection up to 1 ml.

Description:

Transparent liquid, free from particles.

Pharmacotherapeutic group:Contrast agent for MRI

ATX: & nbsp

V.08.C.A Paramagnetic contrast media

Pharmacodynamics:

The drug Gadovist® is a paramagnetic contrast agent for magnetic resonance imaging.

The enhancement of the image contrast is due to its active component gadobutrol, which is a neutral (nonionic) gadolinium (III) complex with a macrocyclic ligand-dihydroxy-hydroxymethylpropyl-tetraazacyclododecane-triacetic acid (butrolole).

Using T₁-weighted pulse sequences during the magnetic resonance study, the shortening of the spin-lattice relaxation time of excited atomic nuclei induced by gadolinium ions leads to an increase in the signal intensity and, as a result, to an increase in the contrast of the image of certain tissues. However, when using T₂* -weighted 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 injection) leads to a decrease in the signal.

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

There was no inhibition of activity of enzymes by gadobutrol.

Pharmacokinetics:

The behavior of gadobutrol in the body is similar to the behavior of other highly hydrophilic biologically inert substances released by the kidneys (eg, mannitol or inulin).

Suction and distribution

After intravenous administration gadobutrol rapidly distributed in the extracellular space. Binding to plasma proteins is negligible. After administration of 0.1 mmol gadobutrol / kg body weight, the average concentration of gadobutrol in plasma,equal to 0.59 mmol / l, is determined 2 minutes after the injection, and a concentration of 0.3 mmol / l - 60 minutes after the injection.

Metabolism

Gadobutrol is not metabolized.

Excretion

Gadobutrol is excreted from the plasma with a half-life of 1.81 hours (1.33 to 2.13 hours).

Gadobutrol is excreted by the kidneys in unmodified form. Extracellular elimination is insignificant. The kidney clearance of gadobutrol in healthy individuals ranges from 1.1 to 1.7 ml / min / kg and, thus, it is comparable to the clearance of inulin, which indicates the preferential removal of gadobutrol by glomerular filtration. More than 50% of the administered dose is excreted by the kidneys 2 hours after intravenous administration. Gadobutrol fully output within 24 hours. Less than 0.1% is excreted from the body through the intestine.

Linearity / Nonlinearity

Some indicators of the pharmacokinetics of gadobutrol in humans are proportional to the administered dose (eg, C_mOh, AUC), and some are dose-independent (for example, V_ss, t_1/2).

Additional information for specific patient groups

Elderly patients

Due to age-related physiological changes in renal function in healthy elderly volunteers (over 65 years), systemic exposure was increased by approximately 33% (in men) and 54% (in women), and half-life was increased by approximately 33% (in men) and 58 % (among women).The plasma clearance is reduced by approximately 25% (in men) and by 35% (in women), respectively. Withdrawal of the administered dose by the kidneys was completed within 24 hours for all volunteers. There was no difference between elderly and not elderly healthy volunteers.

Patients of childhood

The pharmacokinetics of gadobutrol in the child population <18 years of age and in adults are similar.

It was demonstrated that the pharmacokinetic profile of gadobutrol in children of all age groups is similar to that in adults and shows similar indices of the total concentration in the blood plasma for the entire observation period (AUC), plasma clearance normalized for body weight (CLtot), and the volume of distribution (V_ss), as well as the half-life and the rate of excretion.

Patients with impaired renal function

The half-life of gadobutrol from the plasma in patients with impaired renal function is increased due to reduced glomerular filtration.

The average half-life in the terminal phase increases to 5.8 hours in patients with mild to moderate renal dysfunction (80> CK> 30 ml / min) and up to 17.6 hours in patients with severe renal dysfunction KK <30 ml / min), where KK-clearance of creatinine.

The average clearance of plasma creatinine was reduced to 0.49 ml / min / kg in patients with impaired renal function of mild or moderate severity (80> CK> 30 ml / min) and 0.16 ml / min / kg in patients with severe impairment of kidney function not on dialysis (QC <30 mL / min).

In patients with mild or moderate renal dysfunction, the complete excretion of gadobutrol by the kidneys was observed after 72 hours. In patients with severe renal dysfunction, approximately 80% of the administered dose was excreted by the kidneys within 5 days.

Hemodialysis should be considered necessary if the renal function is dramatically reduced.

Patients in need of hemodialysis, gadobutrol almost completely removed from the plasma after the third dialysis.

Indications:

This drug is intended for diagnostic purposes only. The drug Gadovist® is shown to adults and children of any age, including full-term newborns, to increase the contrast of the image when performing a magnetic resonance imaging of the entire body, including:

- enhanced image contrast in the conduct of cranial and spinal MRI,including differential diagnosis between intra- and extramedullary tumors, detection of solid tumors in the spinal canal and determination of the prevalence of intramedullary tumors;

- increased contrast in the image during the MRI of the head and neck;

- increased contrast of the image during MRI of the chest area;

- increased contrast of the image during MRI of the mammary glands;

- increased contrast of the image during MRI of the abdominal region (including pancreas, liver and spleen);

- increased contrast of the image during MRI of the pelvic area (including the prostate, bladder and uterus);

- increased contrast of the image during MRI of the retroperitoneal space (including kidneys);

- increased contrast of the image when performing MRI of the musculoskeletal system and limbs;

- increased contrast of the image during magnetic resonance angiography (MRA);

- increased contrast of the image during MRI of the heart (including for evaluation of myocardial perfusion under conditions of pharmacological stress and diagnosis of tissue viability - "delayed contrasting").

Contraindications:

Hypersensitivity to the active substance or any of the auxiliary components of the drug.

Carefully:

The drug Gadovist® should be used with caution in the presence of the following conditions:

- hypersensitivity to similar contrast agents based on gadolinium (CSOG) in history;

- a history of bronchial asthma;

- allergic diseases in the anamnesis;

- severe renal dysfunction, incl. acute and chronic renal failure with GFR <30 mL / min / 1.73 m²;

- severe cardiovascular diseases;

- at a low threshold of convulsive activity;

- in patients with acute renal insufficiency of any severity against the background of hepatorenal syndrome;

- in patients in the perioperative period of liver transplantation;

- in children under one year.

Pregnancy and lactation:

Pregnancy

Data on clinical studies of gadobutrol during pregnancy are not available.

With repeated administration in animal experiments, there was no evidence of reproductive toxicity in clinically relevant doses.

Do not use the drug to examine pregnant women,when MRI with contrast enhancement seems to be extremely necessary and the intended benefit to the mother from its use exceeds the potential risk to the fetus.

Breastfeeding period

Until now, the possibility of getting gadobutrol into breast milk has not been studied.

As experiments on animals show, the drug Gadovist® in minimal amounts (less than 0.1% of the administered dose) enters the breast milk, absorption through the gastrointestinal tract is negligible (about 5% of the dose with ingestion is excreted by the kidneys). After the administration of Gadovist®, the question of the possibility of interrupting breastfeeding for 24 hours should be addressed.

Dosing and Administration:

general information

The drug is used only for intravenous use.

The required dose is administered intravenously in the form of a bolus. To perform perfusion studies of the brain in the diagnosis of stroke, recognition of focal cerebral ischemia or evaluation of blood supply to the tumor, it is recommended to use an automatic injector. Magnetic resonance imaging with contrast enhancement can be started immediately (shortly after the injection, depending on the pulse sequence used and the study protocol).

Optimum signal increase is observed during the first passage through the arterial vessels during MRA with contrast enhancement and for a period of 15 minutes after the administration of Gadovist® in other studies, including CNS studies (the time depends on the type of injury / tissue ).

For studies with contrasting T₁-weighted pulse sequences are the most suitable.

When conducting magnetic resonance imaging, general safety rules must be observed.

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® should only be taken into the syringe just before administration. The rubber stopper of the bottle should not be pierced more than 1 time.

The drug Gadovist® 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® in cartridges should be administered by a specialist in accordance with the instructions supplied with the equipment for the use of cartridges.

The administration of the drug should be carried out in accordance with the generally accepted precautions when performing magnetic resonance imaging with contrast enhancement.

Part of the drug unused during one study should be destroyed.

Do not mix Gadovist® with other drugs, as there is no compatibility data.

Dosing regimen

Adults

The dose depends on the indications. A single intravenous injection of gadobutrol at a dose of 0.1 mmol / kg (equivalent to 0.1 ml of Gadovist® per 1 kg of body weight) is usually sufficient. The maximum dose of gadobutrol is 0.3 mmol per 1 kg of body weight (equivalent to 0.3 ml of Gadovist® per 1 kg of body weight).

MRI of the whole body (except MRA)

Typically, intravenous administration of the drug Gadovist® at a dose of 0.1 ml per 1 kg of body weight (equivalent to 0.1 mmol per kg of body weight) is sufficient.

Additional recommendations for cranial and spinal MRI

If there are suspicions about the presence of lesions or more accurate information is needed aboutnumber, size, and extent of lesions, diagnostic efficiency studies can be increased by introducing additional Gadovist® solution of the drug in doses of from 0.1 ml to 0.2 ml per 1 kg body weight for 30 minutes after the last injection.

To exclude metastases or recurrence of the tumor, a solution of Gadovist® 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 use when 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^®, which is administered in a dose of 0.1-0.3 ml per 1 kg of body weight at a rate of 3-5 ml / sec.

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)

More than one scan area:

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).

In patients under one year, patients in the perioperative period of liver transplantation, as well as in patients with severe renal impairment (GFR <30 mL / min / 1.73 m²), the use of the drug should be limited to one standard dose (0.1 mmol / kg body weight) and the repeated administration should not be performed earlier than 7 days later.

Additional information for individual patient groups

Use in children

For children of all ages, including full-term newborns, the recommended dose of gadobutrol is 0.1 mmol / kg of body weight (equivalent to 0.1 ml of Gadovist® preparation per 1 kg of body weight) for all indications (see Indication section).

Elderly patients

In clinical studies, there was no difference in safety and efficacy between older patients (65 years and over) and younger patients. Other reports of clinical experience indicate that there is no difference in response to drug administration between older and younger patients. It is believed that there is no need to adjust the dose.

Patients with impaired hepatic function

Due to the fact that gadobutrol completely unchanged is excreted by the kidneys, there is no need to adjust the dose (see section "Pharmacological properties")

Patients with impaired renal function

In patients with impaired renal function gadobutrol but dosage adjustment is not recommended to guarantee the receipt of diagnostic imaging (see "Special instructions" and "Pharmacological properties").

Side effects:

The overall safety profile of Gadovist® is based on clinical trial data from more than 6,300 patients, as well as from post-marketing surveillance data.

The most frequent unwanted drug reactions (NLR) (≥ 0.5%) that were observed in patients receiving Gadovist® include: headache, nausea and dizziness.

The most serious adverse reactions in patients receiving Gadovist® are cardiac arrest and severe anaphylactoid reactions. Delayed allergic reactions (within 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® are presented in Table 1. The data are based on the classification of organ systems by MedDRA (Medical Dictionary for Regulatory Activities). The most appropriate medical terms (version MedDRA 14.1). Undesirable reactions are classified according to the frequency of manifestation. The frequency grouping was 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".

Table 1. Undesirable reactions reported during clinical trials and during postmarketing studies in patients receiving Gadovist®

System-Organ classes	Often	Infrequently	Rarely	Frequency unknown
Immune system disorders		Hypersensitivity / anaphylactoid reactions^# (anaphylactoid shock^§, cardiovascular failure^§, respiratory arrest^§, pulmonary edema^§, bronchospasm^§, cyanosis ^§, oropharyngeal edema^§, laryngeal edema^§, hypotension^, increased blood pressure^§, chest pain^§, urticaria, edema of the face, angioedema^§, conjunctivitis^§, edema of the eyelids, "hot flashes", intense sweating^§, coughing^§, sneezing^§, a feeling of heat^§, pallor^§)
Disturbances from the nervous system	Head pain	Dizziness, dysgeusia, paresthesia	Loss of consciousness (fainting)^*, convulsions, parosmia
Violations from sides of the heart			Tachycardia, heart palpitations	Heart failure*
Violations from side of the respiratory system, chest and mediastinal organs		Dyspnea*
Violations from side of the gastrointestinal tract	Nausea	Vomiting	Dry mouth
Disturbances from the skin and subcutaneous tissues		Erythema, pruritus (including generalized form), rash (including maculopapular rash with itching)		Nephrogenic systemic fibrosis (NSF)
General disorders and changes in the site of administration		Reaction at the site of administration⁰, a feeling of heat	Malaise, chills

^*Cases related to the threat to life and / or fatal in connection with this an undesirable reaction.

^#None of the individual symptoms of adverse reactions,listed in the point of hypersensitivity reactions / anaphylactoid reactions revealed by clinical studies, did not reach higher frequency values than the value of "rare" (except for urticaria).

^§Hypersensitivity / anaphylactoid reactions, which were detected only in post-marketing studies (frequency is unknown).

⁰Reactions at the site of administration (of various types) include the following: extravasation 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 or rash at the injection site, pain at the injection site, hematoma at the injection site.

Additional information for individual patient groups

Children

Based on the results of two studies I/III phase with a single administration of the drug in 138 cases in children from 2 to 17 years and in 44 cases in the group from 0 to 2 years, the frequency, nature, characteristics and severity of adverse reactions in children of all ages, including full-term newborns, corresponded to the profile of adverse reactions , known in adults. This was confirmed in the Phase IV study, which includes more than 1,100 children of childhood, as well as postmarketing observational studies.

Overdose:

One-time administration of the drug Gadovist® at a dose of 1.5 mmol / kg body weight was tolerated well. To date, no symptoms of intoxication associated with an overdose of Gadovist® in clinical use have been reported.

In case of unintentional overdose, it is recommended to monitor cardiovascular functions (including ECG) and kidney function monitoring as a precautionary measure.

The drug Gadovist® can be removed from the body by hemodialysis (see section "Special instructions").

Interaction:

Do not mix Gadovist® with other drugs, as there is no compatibility data.

Interactions with other drugs have not been identified.

Special instructions:

Expressed states of excitement, anxiety and pain can increase the adverse reactions or intensity of reactions associated with the use of contrast media.

Hypersensitivity

As with the use of other contrast agents for intravenous administration, the use of the drug Gadovist® may be accompanied by manifestations of hypersensitivity - anaphylactoid reactions and other manifestations of idiosyncrasy,characterized by reactions from the cardiovascular, respiratory systems or skin reactions, which turn into severe conditions, including shock.

The risk of developing hypersensitivity reactions is higher in the following cases:

- with a previous reaction to a contrast agent,

- if there is an anamnesis of bronchial asthma,

- with allergic diseases in the anamnesis.

Most of these reactions develop within 0.5-1 hour after administration.

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

In patients with a predisposition to developing allergic reactions, the decision to use Gadovist® should be taken only after a thorough assessment of the risk / benefit ratio.

At the examination it is necessary to have medicines for the treatment of hypersensitivity reactions, as well as equipment for resuscitation.

Rarely observed delayed reactions (a few hours - a day after injection) (see section "Side effect").

Patients taking beta-blockers, when developing a hypersensitivity reaction, can be resistant to the beta-adrenomimetic action of drugs used to treat such reactions.

Renal impairment

Until now, there was no violation of kidney function.

Before the introduction of Gadovist®, all patients should be checked for impaired renal function by collecting anamnesis data and / or conducting laboratory tests.

It is necessary to carefully evaluate the risk / benefit ratio of the drug in patients with severe renal dysfunction, because in such cases, the excretion of contrast medium is slowed down. After three courses of dialysis, about 98% of gadobutrol is excreted from the body. For patients on hemodialysis, the expediency of the immediate onset of hemodialysis after the administration of the drug Gadovist® should be considered in order to accelerate the elimination of the contrast agent.

Cases of development of nephrogenic systemic fibrosis (NSF) have been reported (see the "Side effect" section) due to the introduction of gadolinium-containing contrast agents, including Gadovist®,patients with the following diseases / conditions:

- acute or chronic renal failure (glomerular filtration rate <30 ml / min / 1.73 m²) or

- acute renal failure of any severity, caused by hepatorenal syndrome, or in the period before and after liver transplantation.

Therefore, in such patients, the drug Gadovist® should be used only after a thorough assessment of the benefit / risk ratio.

In patients with impaired renal function gadobutrol must be completely removed from the body before any other contrast agent is re-introduced. Usually, in patients with impaired renal function of mild and moderate severity, complete excretion by the kidney occurs within 72 hours. In patients with severe renal dysfunction, no less than 80% of the prescribed dose is excreted by the kidneys within 5 days.

Convulsions

Particular caution is required when prescribing Gadovist®, as well as other contrast agents containing gadolinium chelate, to patients with a low threshold of convulsive readiness.

The use of the drug should be accompanied by compliance,the generally accepted safety rules for conducting magnetic resonance imaging (including the exclusion of the use of ferromagnetic products, such as a pacemaker or aneurysmal clip).

The use of the drug should be limited to clinics equipped for emergency care, where there is everything necessary for cardiopulmonary resuscitation in the shortest possible time. With the introduction of the drug in patients with epilepsy, CNS lesions or seizures in the anamnesis, there may be a decrease in the threshold of convulsive activity. It is necessary to monitor the patient's condition. The doctor's office should contain medicines, for rapid cessation of seizures.

Due to the fact that patients at the age of 65 and older may have decreased kidney function, it is necessary to evaluate the functional parameters of renal function (including creatinine clearance) before the study.

Solution for injection unused for 1 administration should be destroyed. Physicochemical and microbiological stability is maintained for 24 hours at a temperature of 20-25 ° C. From the microbiological point of view, the drug should be used immediately.If the drug is not used immediately, the medical personnel are responsible for meeting the terms and conditions of storage after opening before use. The time to use should not exceed 24 hours at a temperature of 20-25 ° C.

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

Effects on the ability to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions have not been identified. However, given the likelihood of side effects in the form of dizziness, fainting, such activities should be avoided within 24 hours after the administration of the drug.

Form release / dosage:

Solution for intravenous administration, 1 mmol / ml.

Packaging:For 15 ml or 30 ml in bottles of colorless glass type I, with rubber stoppers, crimped aluminum caps, equipped with plastic caps. For 1 bottle of 30 ml or 5 bottles of 15 ml, along with the instructions for use are placed in a cardboard box.

5 ml or 7.5 ml in a glass or plastic syringe. 1 glass or plastic syringe in a blister.For 5 blisters together with instructions for use are placed in a cardboard box.

For 15 ml in plastic cartridges with a capacity of 65 ml. For 5 cartridges, along with instructions for medical use, put in a cardboard box. For 30 ml in plastic cartridges with a capacity of 65 ml. For 5 cartridges, along with the instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N014546 / 01

Date of registration:29.01.2009 / 24.10.2016

Expiration Date:Unlimited

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

Manufacturer: & nbsp

BAYER PHARMA, AG Germany

Representation: & nbspBAYER, AOBAYER, AO

Information update date: & nbsp03.04.2017

Illustrated instructions

Instructions

Gadovist® (Gadovist®)