Multihance (Solution) Instructions for Use

Marketing Authorization Holder

Bracco Imaging S.p.A. (Italy)

Manufactured By

Patheon Italia, S.P.A. (Italy)

ATC Code

V08CA08 (Gadobenic acid)

Active Substance

Gadobenic acid (Rec.INN registered by WHO)

Dosage Form

Multihance

Solution for intravenous administration 529 mg/1 mL: fl. 10 mL, 15 mL or 20 mL

Dosage Form, Packaging, and Composition

Solution for intravenous administration in the form of a clear, colorless or slightly yellowish liquid.

* obtained from gadolinium oxide – 91.77 mg, BOPTA (4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oic acid) – 256.7 mg, meglumine – 195.2 mg (equivalent to: Gadobenic acid – 334 mg, meglumine – 195 mg).

Excipients: water for injections – up to 1 mL.

Osmolarity at 37°C (98.6°F): 1.97 Osm/kg water, viscosity at 37°C (98.6°F): 5.3 mPa·s.

10 mL – colorless glass vials (1) – cardboard packs.
15 mL – colorless glass vials (1) – cardboard packs.
20 mL – colorless glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Contrast diagnostic agent for magnetic resonance imaging

Pharmacotherapeutic Group

Contrast agent for MRI

Pharmacological Action

In liver studies

Multihance allows for the detection of lesions that are not visualized by MRI before the administration of the contrast agent in patients with established or suspected hepatocellular carcinoma or metastatic liver lesions.

The gadolinium chelate complex, Gadobenic acid, shortens the longitudinal (T1) and, to a lesser extent, transverse (T2) relaxation times of water protons in tissues. The relaxivity (r) of gadobenic acid in aqueous solutions is: r₁ = 4.39 and r₂ = 5.56 mmol^-1s^-1 at 20 MHz.

When moving from an aqueous solution to solutions containing serum proteins, a significant increase in the relaxivity of gadobenic acid occurs, with r₁ and r₂ values in human plasma being 9.7 and 12.5, respectively. In the liver, the drug provides a persistent and prolonged increase in signal intensity of the normal parenchyma on T1-weighted images. The increase in signal intensity remains at a high level for at least 2 hours after administration of the drug at doses of both 0.05 and 0.10 mmol/kg. The difference in contrast between focal liver lesions and normal parenchyma on T1-weighted dynamic images becomes noticeable almost immediately after bolus administration of the drug (within 2-3 minutes). The contrast tends to decrease subsequently, which is due to non-specific enhancement of liver lesions. However, it is believed that the continued washout of the drug from the lesions and the persistent signal intensity of the normal parenchyma may contribute to better lesion detection and a lower detection threshold for lesions between 40 and 120 minutes after administration.

Results of Phase II and III clinical trials involving patients with liver cancer showed that the average sensitivity and specificity of MRI were 95% and 80%, respectively.

During MRI of the brain and spinal cord, the drug enhances the contrast of healthy tissues lacking a blood-brain barrier, tumors located outside the brain, and areas with blood-brain barrier damage.

During magnetic resonance angiography, the drug improves image quality by increasing the blood signal-to-noise ratio due to shortening of blood T1, reduces motion-related artifacts by shortening the examination time, and eliminates flow artifacts.

Pharmacokinetics

Adults

The reproduction of pharmacokinetics in humans was adequately described using a biexponential decay model. The apparent distribution and elimination half-lives range from 0.085 to 0.117 and from 1.17 to 1.68 hours, respectively. Since the drug composition includes excipients and pharmacokinetics is studied only for the active substances, the apparent volume of distribution ranging from 0.170 to 0.248 L/kg body weight indicates that the drug is distributed in plasma and in the extracellular space.

The gadobenic acid ion is rapidly eliminated from the body mainly by the kidneys and to a lesser extent in the bile. The total plasma clearance, ranging from 0.098 to 0.133 L/h per kg body weight, and renal clearance, ranging from 0.082 to 0.104 L/h per kg body weight, indicate that the mixture is mainly eliminated by glomerular filtration. Plasma concentration values and area under the concentration-time curve indicate a statistically significant linear dependence on the administered dose. The gadobenic acid ion is excreted by the kidneys unchanged in an amount of 78-94% of the administered dose within 24 hours. From 2 to 4% of the dose is excreted through the intestines.

The gadobenic acid ion does not cross the intact blood-brain barrier and therefore does not accumulate in unchanged brain tissue and in lesions with an intact blood-brain barrier. However, impaired blood-brain barrier permeability or vascular damage create conditions for the gadobenic acid ion to penetrate the lesion area.

Pharmacokinetics in specific patient categories

Children aged 2 years and older with CNS tumors

Pharmacokinetic studies were conducted in a group of 80 subjects (40 adults and 40 children) aged 2 to 47 years (intravenous administration). Pharmacokinetics, starting from 2 years of age, is described by a two-compartment model with standard allometric coefficients and the influence of creatinine clearance on the rate of gadolinium elimination. Pharmacokinetic parameters in adults corresponded to values described previously. The volume of distribution and clearance were lower in adolescents and children due to lower body weight, which was accounted for by normalizing values for body weight. Thus, administration of Multihance to children in doses calculated per kg of body weight demonstrates a similar area under the curve (AUC) and maximum concentration (Cmax) profile as in adults. These data confirm that there is no need to reduce the dose in children aged 2 years and older.

Renal impairment. After administration of a single intravenous dose of gadobenic acid (0.2 mmol/kg body weight) in patients with chronic renal failure with creatinine clearance from >30 to <60 mL/min, the mean elimination half-life is approximately 3 to 9 hours. For patients with acute renal failure (creatinine clearance from >10 to <30 mL/min), T_1/2 ranges from 6.5 to 12.5 hours. For comparison, in healthy individuals, T_1/2 ranges from 1.0 to 2.0 hours. However, the total elimination time of gadobenic acid is not associated with renal failure. Also, no differences were observed in either the severity or the nature of adverse reactions in patients with renal failure compared to healthy volunteers, and there was no impairment of renal function in patients who were prescribed Multihance.

Hemodialysis. In patients with severe renal failure requiring hemodialysis, after administration of a single intravenous dose of gadobenic acid (0.2 mmol/kg body weight), T_1/2 is approximately 1 hour during hemodialysis, while without hemodialysis it increases to 18-66 hours.

Hepatic impairment. In patients with impaired liver function after administration of a single intravenous dose of gadobenic acid (0.1 mmol/kg body weight), the pharmacokinetics of the drug change insignificantly compared to healthy individuals.

Gender. No significant differences in the exposure to gadobenic acid were found between people of different genders.

Age. The rate of elimination of gadobenic acid from the body slightly decreases with age. Since these changes are within the normal range, it is not recommended to change doses for the older age group of patients.

Race. Pharmacokinetic differences related to race have not been systematically studied.

Indications

Multihance is used for diagnostic purposes only. The drug is a contrast agent for MRI and magnetic resonance angiography, indicated for

• MRI of the liver, for the detection of focal lesions in patients with suspected or confirmed primary liver cancer (hepatocellular carcinoma) or metastatic liver lesions;
• MRI of the brain and spinal cord, for the detection of focal lesions and to obtain additional diagnostic information compared to non-contrast MRI;
• Magnetic resonance angiography for the detection of steno-occlusive lesions of peripheral arteries and branches of the abdominal aorta.

ICD codes

Dosage Regimen

Adults

For MRI of the liver, the recommended dose of Multihance in adults is 0.05 mmol/kg body weight, which corresponds to 0.1 mL/kg body weight of the 0.5 M solution.

For MRI of the brain and spinal cord, the recommended dose of Multihance in adults and children aged 2 years and older is 0.1 mmol/kg body weight, which corresponds to 0.2 mL/kg body weight of the 0.5 M solution.

For magnetic resonance angiography, the recommended dose of Multihance in adults is 0.1 mmol/kg body weight, which corresponds to 0.2 mL/kg body weight of the 0.5 M solution.

The drug should be drawn into a syringe immediately before use. Dilution is not required. Unused drug must be disposed of. Do not use drug residues in subsequent magnetic resonance studies.

To minimize the risk of possible leakage of the drug into the soft tissues during intravenous administration, it is important to ensure that the needle or cannula is correctly inserted.

For liver, brain, and spinal cord studies: the drug should be administered intravenously as a bolus or by slow infusion (10 mL/min).

For MR angiography, the drug should be administered intravenously as a bolus manually or using an automatic injector.

After administration of the drug, the cannula should be flushed with 0.9% sodium chloride solution.

Image acquisition after contrast administration

Elderly patients

In patients over 65 years of age, there is no need to reduce the dose.

Children aged 2 years and older

In children aged 2 years and older, there is no need to reduce the dose. Use for MRI of the brain and spinal cord is not recommended in children under 2 years of age. Use for MRI of the liver and magnetic resonance angiography is not recommended in children under 18 years of age.

Adverse Reactions

Infections and infestations nasopharyngitis.

Nervous system disorders headache, dizziness, syncope, parosmia, hyperesthesia, tremor, increased intracranial pressure, hemiplegia.

Eye disorders conjunctivitis.

Ear and labyrinth disorders tinnitus.

Cardiac disorders tachycardia, atrial fibrillation, first-degree atrioventricular block, ventricular extrasystoles, sinus bradycardia, hypotension, hypertension, arrhythmia, myocardial ischemia, prolonged PR interval.

Respiratory, thoracic and mediastinal disorders rhinitis, dyspnea, laryngospasm, pulmonary congestion, pulmonary edema.

Gastrointestinal disorders nausea, dry mouth, taste perversion, diarrhea, vomiting, dyspepsia, salivation, abdominal pain, constipation, fecal incontinence, necrotizing pancreatitis.

Skin and subcutaneous tissue disorders pruritus, rash, facial edema, urticaria, hyperhidrosis.

Musculoskeletal and connective tissue disorders back pain and muscle pain.

Renal and urinary disorders urinary incontinence, urinary urgency.

General disorders and administration site conditions injection site reaction, feeling hot, asthenia, anemia, pyrexia, chills, pain (including chest pain, injection site pain), injection site hemorrhage, extravasation, injection site inflammation.

Investigations abnormal laboratory tests, ECG changes, prolonged interval.

Allergic reactions anaphylactic reactions, including the development of anaphylactic shock.

ECG changes bundle branch block, complete atrioventricular block, first-degree atrioventricular block, inverted T wave, prolonged PR interval, prolonged QT interval, short QT interval.

Abnormal laboratory tests hypochromic anemia, leukocytosis, leukopenia, basophilia, hypoproteinemia, hypocalcemia, hypercalcemia, albuminuria, glucosuria, hematuria, hyperlipidemia, hyperbilirubinemia, increased serum iron concentration, increased activity of serum transaminases, alkaline phosphatase, LDH, as well as creatinine concentration.

Children aged 2 years and older.

In clinical studies, the following adverse reactions were observed: vomiting (1.4%), pyrexia (0.9%), and hyperhidrosis (0.9%). The frequency and nature of adverse reactions in children were similar to those in adult patients.

Contraindications

• Hypersensitivity to the components of the drug, gadolinium chelate complexes, benzyl alcohol;
• Age under 2 years for CNS studies (MRI of the brain and spinal cord);
• Children under 18 years of age (MRI of the liver, magnetic resonance angiography).

With caution

In patients with moderate renal impairment (glomerular filtration rate 30-59 mL/min/1.73m²). The drug should be administered with caution to patients taking medications or suffering from metabolic, cardiac, or other disorders that may provoke cardiac arrhythmias. Administration of the drug should be avoided in patients with acute renal failure of any severity as part of hepatorenal syndrome, as well as in the pre- and postoperative period of liver transplantation, unless the diagnostic information is critical and cannot be obtained by other methods.

Use in Pregnancy and Lactation

There are no clinical data on the use of gadobenic acid in pregnant women. Therefore, Multihance should not be used in pregnant women unless dictated by obvious clinical necessity. Refraining from breastfeeding for 24 hours after administration is recommended.

Use in Hepatic Impairment

Administration of the drug should be avoided in patients in the pre- and postoperative period of liver transplantation, unless the diagnostic information is critical and cannot be obtained by other methods.

Use in Renal Impairment

In patients with acute or chronic severe renal failure (glomerular filtration rate <30 mL/min/1.73m²), nephrogenic systemic fibrosis may develop. The risk of developing nephrogenic systemic fibrosis in patients with moderate renal impairment (glomerular filtration rate 30-59 mL/min/1.73m²) is unknown, so the drug should be used with caution in such patients. Administration of the drug should be avoided in patients with acute renal failure of any severity as part of hepatorenal syndrome.

Pediatric Use

Use for MRI of the brain and spinal cord is not recommended in children under 2 years of age. Use for MRI of the liver and magnetic resonance angiography is not recommended in children under 18 years of age.

Geriatric Use

In patients over 65 years of age, there is no need to reduce the dose.

Special Precautions

Patients should be under observation for 15 minutes after administration of the drug. The patient should remain in a hospital setting for 1 hour after administration of the drug.

The use of the drug should also be accompanied by compliance with generally accepted safety rules for magnetic resonance imaging, which include the exclusion of the use of ferromagnetic products, such as pacemakers or aneurysm clips.

Special attention should be paid to patients with cardiovascular diseases. The use of the drug should be limited to clinics equipped for emergency care, where everything necessary for cardiopulmonary resuscitation is available in the shortest possible time.

Magnetic resonance imaging with contrast agents containing other gadolinium chelate complexes should not be performed within 7 hours after using the drug.

In patients with acute or chronic severe renal failure (glomerular filtration rate <30 mL/min/1.73m²), nephrogenic systemic fibrosis may develop. The risk of developing nephrogenic systemic fibrosis in patients with moderate renal impairment (glomerular filtration rate 30-59 mL/min/1.73m²) is unknown, so the drug should be used with caution in such patients.

Hemodialysis can be used to remove the drug from the body immediately after its administration. It is not known whether hemodialysis is a measure to prevent nephrogenic systemic fibrosis.

The drug should be administered intravenously with precautions to avoid extravasation. If extravasation occurs, all cases of local reactions require patient observation and treatment.

Effect on the ability to drive vehicles and operate machinery

Based on pharmacokinetic and pharmacodynamic data, the drug Multihance does not affect the ability to drive vehicles or engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. However, considering the possibility of side effects such as dizziness and fainting, such activities should be avoided for 24 hours after the drug administration.

Overdose

No cases of overdose have been reported, so the symptoms of overdose are unknown. Doses up to 0.4 mmol/kg were used in healthy volunteers without any serious adverse reactions. The use of doses exceeding the approved ones is not recommended.

Treatment of overdose should be aimed at maintaining vital body functions and the rapid administration of symptomatic therapy. The drug can be removed from the body by hemodialysis. It is not known whether hemodialysis is a measure to prevent nephrogenic systemic fibrosis.

Drug Interactions

Multihance must not be mixed with other medicines in the same syringe. Special precautions should be observed in patients receiving drugs such as cisplatin, anthracyclines (doxorubicin, daunorubicin), vincristine, methotrexate, etoposide, tamoxifen, paclitaxel and others.

Storage Conditions

At a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.