Gadovist^® (Solution) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Manufactured By

Bayer, AG (Germany)

Or

Polisan NTFF, LLC (Russia)

ATC Code

V08CA09 (Gadobutrol)

Active Substance

Gadobutrol (Rec.INN registered by WHO)

Dosage Form

Gadovist®

Solution for intravenous administration 1 mmol/ml: syringes 5 ml or 7.5 ml 5 pcs., vials 15 ml 5 pcs. or 30 ml 1 pcs., cartridges 15 ml or 30 ml 5 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous administration transparent, free of particles.

Excipients : calcoxide sodium, hydrochloric acid 1N, trometamol, water for injections.

5 ml – syringes of colorless glass (1) – blisters (5) – cardboard packs^×.
7.5 ml – syringes of colorless glass (1) – blisters (5) – cardboard packs^×.
5 ml – syringes of colorless cycloolefin polymer (1) – blisters (5) – cardboard packs^×.
7.5 ml – syringes of colorless cycloolefin polymer (1) – blisters (5) – cardboard packs^×.
15 ml – vials of colorless glass (5) – cardboard packs^×.
30 ml – vials of colorless glass (1) – cardboard packs^×.
15 ml – cartridges of colorless cycloolefin polymer (5) – cardboard packs^×.
30 ml – cartridges of colorless cycloolefin polymer (5) – cardboard packs^×.

^× the presence of first-opening control (perforation and/or label) is allowed.

Clinical-Pharmacological Group

Contrast diagnostic agent for magnetic resonance imaging

Pharmacotherapeutic Group

Contrast agent for MRI

Pharmacological Action

Paramagnetic contrast agent for magnetic resonance imaging (MRI).

Gadobutrol is a neutral complex of gadolinium (III) with a macrocyclic ligand – dihydroxy-hydroxymethylpropyltetraazacyclododecanetriacetic acid (butrol).

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

Gadobutrol, even at low concentrations, causes a significant shortening of relaxation time. The ability to change T1 and T2 relaxation times, determined by the effect on the spin-lattice and spin-spin relaxation times of protons in plasma at pH=7 and temperature 40°C (104°F), is quantitatively approximately 5.6 l/mmol × s and 6.5 l/mmol × s respectively. The ability to influence relaxation time depends only to a small extent on the magnetic field strength.

Pharmacokinetics

Pharmacokinetic parameters in humans are proportional to the administered dose of gadobutrol. Intravenously administered Gadobutrol is rapidly distributed in the extracellular space and is excreted by the kidneys via glomerular filtration in unchanged form. It does not bind to plasma proteins.

If the dose of gadobutrol does not exceed 0.4 mmol/kg body weight, after the initial distribution phase, an elimination phase begins and its plasma level decreases with a T_1/2 of 1.81 h (1.33-2.13 h), which corresponds to the renal excretion rate. At a gadobutrol dose of 0.1 mmol/kg body weight, 2 minutes after injection, its plasma level was 0.59 mmol/l, and 60 minutes after injection – 0.3 mmol/l. Within 2 hours, more than 50% of the administered dose is excreted in the urine, and within 12 hours – more than 90%. If the administered dose of gadobutrol is 0.1 mmol/kg body weight, then 100.3±2.6% of this dose is eliminated from the body within 72 hours. The renal clearance of gadobutrol in healthy individuals ranges from 1.1 to 1.7 ml/min × kg; thus, it is comparable to the clearance of inulin, which indicates the predominant excretion of gadobutrol by glomerular filtration. Less than 0.1% of the administered substance is excreted from the body in feces. The extrarenal excretion of the drug is so insignificant that it can be disregarded.

Metabolites are not detected in plasma and urine.

The T_1/2 of gadobutrol in patients with impaired renal function increases proportionally to the degree of reduction 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

To enhance contrast during MRI, including: contrast enhancement during cranial and spinal MRI; contrast enhancement during MRI of the head and neck area; contrast enhancement during MRI of the chest area; contrast enhancement during MRI of the mammary glands; contrast enhancement during MRI of the abdominal cavity (including the pancreas, liver, and spleen); contrast enhancement during MRI of the pelvic area (including the prostate gland, bladder, and uterus); contrast enhancement during MRI of the retroperitoneal space (including the kidneys); contrast enhancement during MRI of the musculoskeletal system and extremities; contrast enhancement during magnetic resonance angiography (MRA); contrast enhancement during cardiac MRI (including for the assessment of myocardial perfusion under pharmacological stress and diagnosis of tissue viability “delayed contrast enhancement”).

Spinal MRI: conducting differential diagnosis between intra- and extramedullary tumors, identifying the boundaries of solid tumors in the spinal canal, and determining the extent of intramedullary tumors.

For perfusion studies: in the diagnosis of stroke, recognition of focal cerebral ischemia, or assessment of tumor blood supply.

ICD codes

Dosage Regimen

Intended exclusively for diagnostic purposes.

Administer as a single intravenous bolus injection.

For adults, the standard diagnostic dose is 0.1 ml/kg body weight (0.1 mmol/kg).

Do not exceed a maximum single dose of 0.3 ml/kg body weight.

For children over 7 years of age, use the recommended dose of 0.1 ml/kg body weight (0.1 mmol/kg).

For perfusion MRI in adults, administer a dose of 0.1 ml/kg at a high injection rate.

For magnetic resonance angiography (MRA) in adults, administer a dose of 0.1 ml/kg.

For cardiac MRI, use a dose of 0.1 ml/kg for assessment of myocardial perfusion and viability.

Flush the intravenous line with sodium chloride 0.9% after injection to ensure complete administration.

Calculate the exact volume based on patient body weight immediately prior to administration.

Inspect the solution visually for particulate matter and discoloration; do not use if present.

Use the product immediately after opening the primary container.

Discard any unused portion.

Adverse Reactions

Nervous system disorders uncommon – headache, dizziness, dysgeusia, paresthesia; rare – parosmia, loss of consciousness, seizures.

Gastrointestinal disorders uncommon – nausea; rare – vomiting.

Cardiovascular disorders: uncommon – vasodilation; rare – arterial hypotension, cardiac arrest, tachycardia, collapse, flushing.

Respiratory system disorders : rare – dyspnea, respiratory arrest, bronchospasm, cyanosis, oropharyngeal edema, cough, nasal congestion, laryngeal edema.

Eye disorders rare – conjunctivitis, eyelid edema.

Immune system disorders rare – anaphylactoid reactions, anaphylactic shock.

Skin and subcutaneous tissue disorders: rare – urticaria, rash, hyperhidrosis, pruritus, erythema.

Allergic reactions delayed allergic reactions (after several hours or days).

Local reactions uncommon – pain at the injection site, reaction at the injection site.

General disorders and administration site conditions rare – feeling of heat, general malaise.

Contraindications

Hypersensitivity to gadobutrol.

Use in Pregnancy and Lactation

There are no data on the use of gadobutrol during pregnancy. It is not recommended for use during pregnancy except in cases of extreme necessity.

Experimental animal studies have not revealed embryotoxic or teratogenic effects of gadobutrol at diagnostic doses. In studies of gadobutrol in repeated doses, only administration to pregnant animals at toxic doses (exceeding the diagnostic dose by 8-17 times) caused delayed embryonic development and lethality, but did not lead to teratogenicity. Experimental studies have established that Gadobutrol is excreted in breast milk in minimal amounts (less than 0.01% of the administered dose).

To date, the possibility of gadobutrol passing into human breast milk has not been studied. Therefore, after the administration of gadobutrol, breastfeeding should be interrupted for at least 24 hours.

Special Precautions

In patients with known hypersensitivity to gadobutrol, a particularly careful assessment of the risk-benefit ratio of use is required.

The use of gadobutrol (like other contrast agents for intravenous administration) 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, progressing to severe conditions, including shock. Most of these reactions develop within 0.5-1 hour after administration.

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

During a study using gadobutrol (like other contrast agents for intravenous administration), it is necessary to have medications and equipment for resuscitation measures.

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

The risk/benefit ratio of using the drug should be especially carefully assessed in patients with severe renal impairment, since in such cases the excretion of the contrast agent is slowed. In particularly severe cases, Gadobutrol should be removed from the body by hemodialysis. After three dialysis sessions, approximately 98% of gadobutrol is eliminated from the body.

Cases of nephrogenic systemic fibrosis have been reported in association with the administration of gadolinium-containing contrast agents to patients with acute or chronic severe renal failure (glomerular filtration rate <30 ml/min/1.73 m²); patients with acute renal failure of any severity caused by hepatorenal syndrome, or in the period before and after liver transplantation.

Although due to its macrocyclic structure, Gadobutrol has very high complex stability, there is a possibility of developing nephrogenic systemic fibrosis with the use of gadobutrol. Therefore, in such patients, Gadobutrol should be used only after a careful assessment of the benefit/risk ratio.

Before administering gadobutrol, renal function should be monitored (medical history and/or laboratory tests).

Gadobutrol can be removed from the body by hemodialysis. For patients who are already on hemodialysis at the time of gadobutrol administration, the advisability of immediately initiating hemodialysis after gadobutrol administration to accelerate the elimination of the contrast agent should be considered.

Special caution is required when using in patients with a low seizure threshold.

In patients with severe cardiovascular diseases, Gadobutrol should be used only after a careful assessment of the risk/benefit ratio, because information concerning this category of patients is limited.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.