Clariscan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLARISCAN (CLARISCAN)

Composition:

active substance: gadoterinic acid;

1 ml of solution contains 279.3 mg of gadoteric acid (as meglumine gadoterate), equivalent to 0.5 mmol/ml;

excipients: meglumine, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or slightly yellowish solution, practically free from mechanical particles.

Pharmacotherapeutic group. Paramagnetic contrast agents. Gadoteric acid.

ATC code V08CA02.

Pharmacological properties.

Pharmacodynamics.

Gadoteric acid has paramagnetic properties that enhance contrast in magnetic resonance imaging (MRI). Gadoteric acid has no specific pharmacodynamic activity and is highly biologically inert.

Pharmacokinetics.

After intravenous injection, gadoteric acid distributes into extracellular fluids of the body. Gadoteric acid does not bind to plasma albumin.

In patients with normal renal function, the plasma half-life is approximately 90 minutes. Gadoteric acid is excreted unchanged via glomerular filtration. In renal impairment, plasma clearance is reduced.

In animals, the level of excretion of gadoteric acid into milk is low, and penetration across the placental barrier is slow.

To date, there are no data on the pharmacokinetics in elderly people, children, pregnant women, breastfeeding women, or patients with hepatic impairment.

Clinical characteristics.

Indications.

Used exclusively for diagnostic purposes when magnetic resonance imaging (MRI) without contrast enhancement is not feasible.

Adult patients

Contrast enhancement in MRI.

MRI of the brain and spinal cord: detection of brain tumors, detection of spinal cord tumors and surrounding tissues, detection of intervertebral disc herniations, and diagnosis of infectious diseases.

Whole-body MRI, including visualization of kidney, heart, uterine, ovarian pathology, thoracic and abdominal organs, and bone-joint pathology.

Angiography.

Children (0–18 years)

• Contrast enhancement in MRI.
• MRI of the brain and spinal cord: detection of brain tumors, detection of spinal tumors and surrounding tissues, detection of intervertebral disc herniations, and diagnosis of infectious diseases.
• Whole-body MRI, including visualization of kidney, heart, uterine, ovarian pathology, thoracic and abdominal organs, and bone-joint pathology.

Contraindications.

Hypersensitivity to gadoteric acid, meglumine, or to any medicinal product containing gadolinium.

Interaction with other medicinal products and other forms of interaction.

No interaction with other medicinal products has been observed. Adequate studies on drug interactions have not been conducted.

Concomitant medicinal products to be considered. Beta-blockers, vasoactive substances, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists – these medicinal products reduce the effectiveness of cardiovascular compensatory mechanisms in arterial pressure disturbances. Prior to administration of gadolinium-based agents, the radiologist must be informed if the patient is taking any of the listed drugs, and resuscitation equipment should be prepared in advance.

Special precautions for use.

Gadoteric acid must not be administered intrathecally. Serious, life-threatening, and fatal events, predominantly with neurological reactions (e.g., coma, encephalopathy, seizures), have been reported following intrathecal administration. Gadoteric acid should be administered exclusively by intravenous injection. Extravasation may lead to local intolerance reactions requiring conventional local treatment.

Standard precautions must be taken during MRI procedures: the presence of cardiac pacemakers, ferromagnetic vascular clips, infusion pumps, neurostimulators, cochlear implants, or suspicion of intracorporeal metallic foreign bodies, especially in the eye, are contraindications to MRI.

Hypersensitivity

• As with other gadolinium-containing contrast agents, hypersensitivity reactions, including life-threatening reactions, may occur. Hypersensitivity reactions may be allergic (described as anaphylactic reactions if identified as severe) or non-allergic. Reactions may be immediate (within less than 60 minutes) or delayed (up to 7 days). Anaphylactic reactions occur immediately and may be fatal. Anaphylactic reactions are dose-independent, may occur even after the first dose of the agent, and are often unpredictable.
• Regardless of the administered dose, there is always a risk of hypersensitivity reactions.
• Patients who have previously experienced a reaction during prior administration of a gadolinium-containing contrast agent have an increased risk of another reaction upon subsequent administration of the same agent or possibly other agents; therefore, such patients are at high risk of allergic reactions.
• Administration of gadoteric acid may exacerbate symptoms of pre-existing asthma. In patients whose asthma has worsened following administration of the agent, the decision to use gadoteric acid should be made only after careful assessment of the risk-benefit ratio.
• It is known that patients receiving beta-blockers, especially those with concomitant bronchial asthma, may experience exacerbated hypersensitivity reactions to iodinated contrast agents. These patients may be refractory to standard treatment of hypersensitivity reactions with beta-agonists.
• Prior to injection of any contrast agent, the patient's allergy history (e.g., allergy to seafood, hay fever, urticaria), sensitivity to contrast agents, and presence of bronchial asthma should be assessed, as a higher incidence of adverse reactions to contrast agents has been reported in patients with these conditions. Premedication with antihistamines and/or corticosteroids may be considered.
• The examination must be performed under close medical supervision. If a hypersensitivity reaction occurs, administration of the contrast agent should be stopped immediately and specific therapy should be initiated as needed. Intravenous access must be maintained throughout the examination period. Appropriate medications (e.g., epinephrine and antihistamines), an endotracheal tube, and a respirator must be readily available to initiate emergency measures immediately.

Renal impairment

All patients should be evaluated for renal dysfunction prior to administration of gadoteric acid, with interpretation of laboratory test results.

Nephrogenic systemic fibrosis (NSF), associated with the use of certain gadolinium-containing contrast agents, has been reported in patients with acute or chronic severe renal impairment (GFR <30 mL/min/1.73 m²). Patients undergoing liver transplantation are at particularly high risk due to the high incidence of acute renal failure in this group. Since there is a possibility that NSF may also occur following administration of gadoteric acid, the agent should be used in patients with severe renal insufficiency and in patients before and after liver transplantation only after careful assessment of the risk-benefit ratio and when diagnostic information is essential and cannot be obtained by non-contrast MRI.

Hemodialysis may be used after administration of gadoteric acid to remove the agent from the body. There is no evidence to recommend hemodialysis for the prevention or treatment of NSF in patients who have not yet undergone hemodialysis.

Elderly patients

Since renal clearance of gadoteric acid may be reduced in elderly patients (aged 65 years and older), it is particularly important to monitor these patients for the development of renal function impairment.

Children

Neonates and young children

Due to immature renal function in neonates up to 4 weeks of age and children under 1 year of age, gadoteric acid should be administered to these patients only after careful evaluation of all risks.

Central nervous system disorders

As with other gadolinium-containing contrast agents, special precautions are necessary in patients with a low seizure threshold. Precautionary measures, such as close monitoring of the patient, should be taken. All equipment and medications necessary for seizure management should be prepared and readily available.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of gadolinium-based contrast agents, including gadoteric acid, in pregnant women are limited. Gadolinium may cross the placenta. It is unknown whether gadolinium exposure is associated with adverse fetal outcomes.

Animal studies do not indicate a direct or indirect harmful effect on reproductive function. Gadoteric acid should not be used during pregnancy unless the clinical condition of the woman necessitates its use.

Breastfeeding period

Gadolinium-containing contrast agents are excreted in small amounts in breast milk. Considering the small amount of the agent excreted in milk and poor gastrointestinal absorption, no effect on the newborn is expected following clinical doses. The decision to continue or interrupt breastfeeding for 24 hours after administration of gadoteric acid should be left to the discretion of the physician and the breastfeeding mother.

Ability to influence reaction rate when driving or operating machinery.

No studies on the effect of the drug on the ability to drive vehicles or operate machinery have been conducted. Patients receiving the drug on an outpatient basis should be aware that nausea may occur suddenly while driving vehicles or operating machinery.

Method of Administration and Dosage

The medicinal product Clariscan must be administered only by a qualified healthcare professional experienced in performing and interpreting MRI studies using gadolinium-based contrast agents.

Method of Administration

The lowest dose providing sufficient contrast enhancement for diagnostic purposes should be used.

The dose should be calculated based on the patient's body weight. This dose must not exceed the recommended dose per kilogram of body weight, as described in detail in this section.

Adults, including elderly patients

Brain and spinal cord MRI. In most cases, the recommended dose is 0.1 mmol/kg, i.e. 0.2 mL/kg, which is sufficient to achieve diagnostically adequate contrast enhancement.

If clinical suspicion of a lesion persists despite normal MRI findings, a subsequent injection of 0.2 mmol/kg, i.e. 0.4 mL/kg, within 30 minutes may improve tumor visualization and assist in selecting appropriate treatment strategies.

Whole-body MRI and angiography

An intravenous dose of 0.1 mmol/kg, i.e. 0.2 mL/kg, is recommended to achieve diagnostically adequate contrast enhancement.

Angiography. In exceptional cases (e.g., inability to obtain high-quality images of a large vascular territory), administration of a second consecutive injection of 0.1 mmol/kg, i.e. 0.2 mL/kg, may be justified. However, if two consecutive doses of Clariscan are planned for separate angiographic regions (such as leg arteries or pulmonary vessels), administration of 0.05 mmol/kg, i.e. 0.1 mL/kg per dose, may be considered, depending on the available image-processing equipment.

Special Populations

Renal Impairment

For patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m²), the standard adult dose is recommended.

Clariscan should be administered to patients with severe renal insufficiency (eGFR < 30 mL/min/1.73 m²) and to patients before and after liver transplantation only after careful risk-benefit assessment, and only if the diagnostic information is essential and cannot be obtained by non-contrast MRI. If Clariscan is required, the dose must not exceed 0.1 mmol/kg body weight. No more than one dose should be administered during a single scanning session. Due to lack of data on repeated administration, injections of gadoterate acid should not be repeated if the interval between doses is less than 7 days.

Elderly Patients

No dose adjustment is required for elderly patients (aged 65 years and older); however, Clariscan should be prescribed with caution in this age group.

Hepatic Impairment

The standard adult dose is recommended for patients with hepatic impairment. However, caution is advised, particularly in the perioperative period of liver transplantation.

Children (0–18 years)

Brain and spinal cord MRI / Whole-body MRI

The recommended maximum dose of gadoterate acid is 0.1 mmol/kg body weight. No more than one dose should be administered during a single scanning session.

Due to immature renal function in neonates up to 4 weeks of age and children under 1 year of age, Clariscan should be administered only after careful consideration of all risk factors, at a dose not exceeding 0.1 mmol/kg body weight. Due to lack of data on repeated administration, Clariscan should not be re-administered if the interval between injections is less than 7 days.

Angiography

Gadoterate acid is not recommended for angiography in children under 18 years of age due to insufficient data on efficacy and safety for this indication.

Method of Administration

The product is intended for intravenous use only.

Intravenous administration of contrast agents should, whenever possible, be performed with the patient in a supine position. After administration, the patient should remain under observation for at least 30 minutes, as clinical experience shows that most adverse reactions occur within this period.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and storage conditions during use are the responsibility of the user, typically not exceeding 24 hours at a temperature of 2 °C to 8 °C, except when opened under controlled and validated aseptic conditions.

Paediatric Population

Depending on the calculated dose of gadoterate acid to be administered to a child, Clariscan vials with a volume adapted to that amount should be used to ensure administration of the most accurate possible volume of the product.

In neonates and infants, the required dose should be administered manually.

Children.

Due to immature renal function in neonates up to 4 weeks of age and children under 1 year of age, gadoterate acid should be administered to these patients only after careful assessment of all risks.

Overdose.

Gadoterate acid may be removed by hemodialysis. However, there is no evidence that hemodialysis is effective in preventing nephrogenic systemic fibrosis (NSF).

Adverse reactions

Adverse reactions associated with the use of gadoteric acid are usually mild to moderate in intensity and transient. The most commonly observed reactions are injection site reactions, nausea, and headache.

During clinical trials, the most frequently reported adverse reactions were nausea, headache, injection site reactions, chills, hypotension, somnolence, dizziness, hot flushes, burning sensation, rash, asthenia, dysgeusia, and hypertension, with an incidence classified as uncommon (≥1/1000 to <1/100).

In post-marketing studies, the most common adverse reactions following administration of gadoteric acid were nausea, vomiting, pruritus, and hypersensitivity reactions.

Among hypersensitivity reactions, skin reactions were the most frequently observed, which may be localised, widespread, or generalised.

These reactions most commonly occur immediately (during injection or within one hour after the start of injection), and sometimes delayed (from one hour to several days after injection), manifesting in such cases as skin changes.

Immediate-type hypersensitivity reactions include one or more effects appearing simultaneously or sequentially, and most commonly involve disorders of the skin, respiratory system, gastrointestinal tract, joints, and/or cardiovascular system.

Each symptom may be a warning sign of the onset of shock and very rarely leads to a fatal outcome.

Individual cases of NSF have been reported with the use of gadoteric acid, most of which occurred in patients who had received other gadolinium-containing contrast agents concomitantly.

The table lists adverse reactions by system organ class and frequency, as follows: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Data are derived from clinical trials.

The following adverse reactions have been reported with the use of other intravenous MRI contrast agents.

Adverse reactions in children

The safety of gadoteric acid in children was evaluated in clinical and post-marketing studies. Compared to adults, the safety profile of gadoteric acid did not show any specific differences in children. Most reactions were gastrointestinal symptoms or hypersensitivity reactions.

Reporting of potential adverse reactions

It is important to report potential adverse reactions after the medicinal product has been marketed. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any potential adverse reactions through the national reporting system or to the marketing authorization holder.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging.

10 ml, 15 ml, 20 ml of injection solution in glass vials closed with a rubber stopper and an aluminum cap with a plastic disc.

50 ml, 100 ml of injection solution in polypropylene bottles closed with a rubber stopper and a screw cap with a tamper-evident plastic disc.

10 glass or 10 polypropylene vials in a cardboard box labeled in Ukrainian.

Prescription status.

Prescription only.

Manufacturer.

GE Healthcare AS, Norway.

Manufacturer's address and location of operations.

Nycoveien 1, NO-0485 Oslo, Norway.