Multihance (Multihance)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceHadobenic acidHadobenic acid
Similar drugsTo uncover
  • Multihance
    solution in / in 
    Brakko Imajing SpA     Italy
    • Dosage form: & nbspsolution for intravenous administration
    Composition:

    Per 1 ml:

    Active components: dicomglumine 529.0 mg prepared from gadolinium oxide 91.77 mg, BORTA (4-carboxy-5,8,11-tris (carboxymethyl) -1-phenyl-2-oxa-5,8,11-triazatridecane-13 -ic acid) 256.7 mg, meglumine 195.2 mg (equivalent: gadobenic acid 334.0 mg, meglumine 195.0 mg).

    Auxiliary components: water for injection up to 1 ml.

    Description:Transparent colorless or slightly yellowish liquid.
    Pharmacotherapeutic group:contrast agent for MRI
    ATX: & nbsp

    V.08.C.A   Paramagnetic contrast media

    Pharmacodynamics:

    When researching the liver

    Multianhance allows detecting lesions that are not visualized by magnetic resonance imaging before the introduction of contrast medium in patients with established or suspected hepatocellular cancer or metastatic liver damage.

    The gadolinium chelate complex, gadobenic acid, shortens the time of longitudinal (T1) and, to a lesser extent, transverse (T2) relaxation of water protons in tissues.

    The relaxing capacity (r) of the hapoenic acid in aqueous solutions is: r1 = 4.39 and r2 = 5.56 mmol-1from-1 at 20 MHz.

    When changing from an aqueous solution to solutions containing whey proteins, a significant increase in the relaxing capacity of gadobenic acid occurs, while the indices r1 and r2 in human blood plasma were 9.7 and 12.5, respectively.

    In the liver, the drug provides a persistent and prolonged increase in the intensity of the signal of normal parenchyma in obtaining T1-weighted images. The increase in signal intensity is maintained at a high level for at least 2 h after administration of the drug in a dose of both 0.05 and 0.10 mmol / kg. The contrast difference between focal lesions of the liver and normal parenchyma on T1-weighted dynamic images becomes noticeable almost immediately after the bolus administration of the drug (within 2-3 min). Contrast has a tendency to a subsequent decrease, which is due to a nonspecific increase in the contrast of liver damage. However, it is believed that continued leaching of the drug from the foci of lesions and the persistent intensity of the signal of normal parenchyma may contribute to better detection of lesions and a decrease in the detection threshold of lesions between 40 and 120 min after administration.

    The results of phase II and III clinical trials involving patients with liver cancer showed that the average sensitivity and specificity of magnetic resonance imaging are 95% and 80%, respectively.

    When conducting magnetic resonance imaging of the brain and spinal cord the drug enhances the contrast of healthy tissues in which there is no blood-brain barrier, tumors located outside the brain, and areas with damage to the blood-brain barrier. In clinical studies of the third phase, performed in parallel groups, an increase in diagnostic information was shown when using Multihance by 32-69%, and by 35-69% with the use of the reference preparation. In two intra-individual clinical studies in adults performed with cross-comparison, Multioence use at a dose of 0.1 mmol / kg compared to the reference preparation at a dose of 0.1 mmol / kg (gadopentetic acid or gadodiamide) was accompanied by a significantly higher (p <0.001) level of contrasting pathological formations, signal-to-noise ratio, and pathological focus-healthy tissue ratio,as well as better visualization of pathological CNS formations (p <0.001) using a 1.5 T scanner.

    Visualization of foci in the central nervous system

    The difference Multihance / gadopentetic acid (n = 151) study MH-109

    p

    The difference Multihance / gadodiamide (n = 113) the MH-130 study

    p

    Determination of the prevalence of the pathological process

    From 25% to 30%

    < 0,001

    From 24% to 25%

    < 0,001

    Visualization of focal morphology

    From 29% to 34%

    < 0,001

    From 28% to 32%

    < 0,001

    Clarity of focal boundaries

    From 37% to 44%

    < 0,001

    From 35% to 44%

    < 0,001

    Contrasting foci

    From 50% to 66%

    < 0,001

    From 58% to 67%

    < 0,001

    General diagnostic evaluation

    From 50% to 68%

    < 0,001

    From 56% to 68%

    < 0,001

    In the studies of MN-109 and MN-130, the effect of improving the quality of imaging of foci in the CNS with the use of MultiHence for further management of the patient was not evaluated.

    When conducting magnetic resonance angiography the drug improves image quality by increasing the signal-to-noise ratio of blood as a result of a reduction in T1 blood, reduces the number of artifacts associated with movement, by reducing the time of the study, and also eliminates flow artifacts.

    When carrying out MRI of the mammary glands Multihance enhances the difference in contrast between the tumor and normal breast tissue, increasing the likelihood of finding a tumor.

    Pharmacokinetics:

    Adults.

    The reproduction of the pharmacokinetics in humans has been adequately described using a bi-exponential decay model. The apparent half-lives and half-lives are in the range from 0.085 to 0.117 and from 1.17 to 1.68, respectively. Since the composition of the drug includes auxiliary substances, and the pharmacokinetics is studied only for active, the apparent volume of distribution in the range from 0.170 to 0.248 l / kg of body weight indicates that the drug is distributed in the plasma and in the extracellular space.

    The ion of hapoenic acid is rapidly excreted from the body mainly by the kidneys and in less quantity with bile. The total clearance from the plasma, ranging from 0.098 to 0.133 l / h per kg of body weight, and the renal clearance, ranging from 0.082 to 0.104 l / h per kg of body weight, indicate that the mixture is mainly excreted at the expense of glomerular filtration. The indices of plasma concentration and the area under the concentration-time curve indicate the presence of a statistically significant linear dependence on the administered dose. The ion of hapoenic acid is excreted by the kidneys unchanged in the amount of 78-94% of the administered dose within 24 hours.2 to 4% of the dose is released through the intestine.

    The ion of hapoenic acid does not penetrate the blood-brain barrier and therefore does not accumulate in unchanged brain tissue and in the affected areas with a preserved blood-brain barrier. However, impaired penetration of the blood-brain barrier or damage to the vessels creates conditions for the penetration of the ion of gadobenic acid into the affected area.

    Pharmacokinetics in some categories of patients

    Children aged 2 years with tumors of the central nervous system

    Pharmacokinetics studies were performed in a group of 80 people (40 adults and 40 children) aged 2 to 47 years (intravenous administration). Pharmacokinetics, beginning at the age of 2, is described by a two-compartment model with standard allometric coefficients and the effect of creatinine clearance on the rate of gadolinium excretion. The pharmacokinetic parameters in adults corresponded to the values ​​described earlier. The volume of distribution and clearance were lower in adolescents and children due to less body weight, which was taken into account by normalizing the values ​​for body weight. Thus, the administration of Multiohance to children in doses,calculated for kg body weight, shows a similar profile for the adult profile of the concentration-time curve (AUC) and the maximum concentration (C max). These data confirm the absence of the need for dose reduction in children aged 2 years.

    Renal failure. When administering a single intravenous dose of gadobenic acid (0.2 mmol / kg body weight) in patients with chronic renal failure with a creatinine clearance of> 30 to <60 mL / min, the average half-life is approximately 3 to 9 hours. acute renal failure (creatinine clearance> 10 to <30 mL / min), the average half-life is 6.5 to 12.5 hours. For comparison, in healthy people, the average half-life is between 1.0 and 2.0 hours. However, the total elimination time of gadobenic acid is not related with renal insufficiency. Also, there were no differences in severity or adverse reactions in patients with renal insufficiency compared to healthy volunteers, and there was no renal impairment in patients who received the Multienhance drug.

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

    Liver failure. In patients with impaired liver function with the introduction of a single intravenous dose of gadobenic acid (0.1 mmol / kg body weight), the pharmacokinetics of the drug varies insignificantly compared with healthy people.

    Floor. There were no significant differences in the effect of gadobenic acid on people of different sexes.

    Age. The rate of removal of gadobenic acid from the body decreases slightly with age. Since these changes are at the limit of normal, it is not recommended to change the dose for the older age group of patients.

    Race. Pharmacokinetic differences associated with race, in clinical studies have not been studied.

    Physicochemical characteristics

    Osmolarity at 37 ° C: 1.97 Osm / kg of water, viscosity at 37 ° C: 5.3 MPa∙from

    Indications:

    MultiHence is used only for diagnostic purposes.The drug is a contrast agent for magnetic resonance imaging (MRI) and magnetic resonance angiography, is shown for:

    - MRI of the liver, in order to detect focal lesions in patients with suspected or confirmed primary liver cancer (hepatocellular carcinoma) or metastatic liver damage.

    - MRI of the brain and spinal cord, to detect focal lesions and obtain additional diagnostic information in comparison with MRI without contrasting.

    - Magnetic resonance angiography for detection of wall-occlusive lesions of peripheral arteries and branches of the abdominal aorta.

    - MRI of the mammary glands for the detection of malignant neoplasms in patients with suspected development of malignant neoplasms according to mammography or ultrasound examination of the mammary glands.

    Contraindications:
    Hypersensitivity to the drug components, gadolinium chelate complexes, benzyl alcohol, age up to 2 years for central nervous system (MRI of the brain and spinal cord), children under 18 years (liver MRI, magnetic resonance angiography), severe renal failure glomerular filtration <30 ml / min / 1.73m2)
    Carefully:In patients with moderate renal insufficiency (glomerular filtration rate 30-59 ml / min / 1.73 m2). With caution should be administered to patients with cardiovascular diseases and other diseases associated with the risk of arrhythmia or taking drugs that have pro-arrhythmogenic effect. Avoid administration of the drug to patients with acute renal failure of any severity within the hepatic renal syndrome, as well as in the pre- and postoperative period of liver transplantation, unless diagnostic information is crucial and can not be obtained by other methods.
    Pregnancy and lactation:Data of clinical studies of the use of gadobenic acid in pregnant women are absent. Therefore, do not use the drug MultiHence pregnant women, unless it is dictated by obvious clinical need. It is recommended to abstain from breastfeeding within 24 hours after the introduction.
    Dosing and Administration:

    Adults.

    With MRI of the liver: the recommended dose of MultiHence in adults is 0.05 mmol / kg body weight, which corresponds to 0.1 ml / kg body weight 0.5 M solution.

    With MRI of the brain and spinal cord: the recommended dose of MultiHence in adults and children aged 2 years is 0.1 mmol / kg body weight, which corresponds to 0.2 ml / kg body weight 0.5 M solution.

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

    With MRI of the mammary glands: the recommended dose in adults is 0.1 mmol / kg body weight, which corresponds to 0.2 ml / kg body weight 0.5 M solution.

    The drug should be injected into the syringe immediately before use. Breeding is not required. The unused product must be disposed of. Do not use the remnants of the drug in subsequent magnetic resonance studies.

    To minimize the risk of getting the drug into soft tissues with intravenous administration, it is important to make sure that the needle or cannula is inserted correctly.

    In studies of the liver, brain and spinal cord: the drug should be administered intravenously bolus or by slow infusion (10 ml / min).

    When MP angiography: the drug should be administered intravenously bolus by hand or using an automatic injector.

    After the administration of the drug, the cannula is washed with 0.9% sodium chloride solution.

    Image acquisition after contrast agent administration:

    Liver

    Dynamic research

    immediately after bolus administration

    Study with delay

    between 40 and 120 minutes after administration

    Head and spinal cord

    in the period up to 60 min after administration

    Magnetic resonance angiography

    immediately after the introduction with a scan delay calculated by the test bolus or automatically. To calculate the required time for scanning, it is necessary to insert a test bolus ≤2 ml.

    MRI of mammary glands

    Dynamic T1-weighted image, scanning immediately after bolus administration followed by repetition after 2, 4, 6 and 8 minutes.

    Elderly patients.

    In patients older than 65 years there is no need to reduce the dose.

    Children from 2 years old.

    Children under the age of 2 years do not need a dose reduction. 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 the age of 18 years.

    Side effects:

    Adults.

    In the studies of 2,637 patients, the following adverse reactions were detected, the frequency of none of the reactions exceeded 2%.

    Group

    Frequent

    (≥ 1/100)

    Infrequent

    (≥ 1/1000, <1/100)

    Rare

    (≥ 1/10000, <1/1000)

    Infections and invasions


    Nasopharyngitis


    From the nervous system

    Headache

    Dizziness, fainting, parosmia

    Hypersthesia, tremor, increased intracranial pressure, hemiplegia

    From the side of the organs of sight



    conjunctivitis

    From the organs of hearing and balance



    Tinnitus

    From the side of the cardiovascular system


    Tachycardia, atrial fibrillation, atrioventicular blockade I degree, ventricular extrasystoles, sinus bradycardia, increase and decrease in blood pressure

    Arrhythmia, myocardial ischemia, lengthening of the interval PR

    From the respiratory system


    Rhinitis

    Shortness of breath, laryngospasm, stagnation of blood in the lungs, pulmonary edema

    From the digestive system

    Nausea

    Dryness in the rue, perversion of taste, diarrhea, vomiting, indigestion, drooling, abdominal pain

    Constipation, fecal incontinence, pancreatic necrosis

    From the skin


    Itching, rash, face swelling, urticaria, increased sweating


    From the side of the connective tissue and the musculoskeletal system


    Back and Muscle Pain


    From the urinary system



    Urinary incontinence, mandatory urge to urinate

    Systemic complications and complications at the site of administration

    Reaction in the area of ​​injection, a feeling of heat

    Asthenia, anemia, fever, chills, pain (including in the chest, at the injection site), hemorrhage in the area of ​​injection, extravasation

    Inflammation in the area of ​​injection

    Measurements of laboratory and instrumental indicators


    Deviation of laboratory parameters, ECG changes, lengthening of the interval QT

    Deviation of laboratory indicators: hypochromic anemia, leukocytosis, leukopenia, basophilia, hypoproteinemia, hypocalcemia, hypercalcemia, albuminuria, glucosuria, hematuria, hyperlipidemia, hyperbilirubinemia, elevated serum iron concentrations, increased serum transaminase, alkaline phosphatase, lactate dehydrogenase, and increased creatinine concentration

    ECG changes: blockade of the foot of the bundle of Giss, complete atrioventricular block, atrioventricular block of the first degree, inverted tooth T, long interval PR, long interval QT, short interval QT.

    Anaphylactic reactions are possible, incl. development of anaphylactic shock.

    Children from 2 years old. In clinical studies, the following adverse reactions were observed: vomiting (1.4%), hyperthermia (0.9%) and increased sweating (0.9%). The frequency and nature of adverse reactions in children was similar to that of adult patients.

    Overdose:No cases of overdose have been reported, so the symptoms of an overdose are unknown. Doses up to 0.4 mmol / kg were used in healthy volunteers without any serious adverse reactions. Use in doses that are higher than allowed is not recommended. Treatment of overdose should be aimed at maintaining the vital functions of the body and the rapid appointment of symptomatic therapy. The drug can be removed from the body by hemodialysis. It is not known whether hemodialysis is a measure of the prevention of nephrogenic systemic fibrosis.
    Interaction:MultiHence should not be mixed with other drugs in one syringe. Special precautions should be taken in patients who receive such medications as cisplatin, anthracyclines (doxorubicin, daunorubicin), vincristine, methotrexate, etoposide, tamoxifen, paclitaxel and others.
    Special instructions:

    For 15 minutes after the administration of the drug, patients should be monitored. The patient should remain in the hospital for 1 hour after the administration of the drug.

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

    Particular attention should be paid to patients with cardiovascular diseases. 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.

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

    In patients with moderate renal insufficiency (glomerular filtration rate 30-59 ml / min / 1.73 m2) the use of the drug is possible only after a careful assessment of the potential benefit and possible risk from the study and should be limited to the introductionstandard dose (0.1 mmol / kg body weight for MRI of the brain and spinal cord, MRA and not> 0.05 mmol / kg body weight for MRI of the liver), and the interval between repeated injections should be at least 7 days.

    In patients with acute or chronic severe renal failure (glomerular filtration rate <30ml / min / 1.73m2) development of nephrogenic systemic fibrosis is possible. The risk of developing nephrogenic systemic fibrosis in patients with moderate renal insufficiency (glomerular filtration rate 30-59 ml / min / 1.73 m2) is not known, so the drug in such patients should be used with caution.

    To remove the drug from the body immediately after its introduction, it is possible to use hemodialysis. It is not known whether hemodialysis is a measure of the prevention of nephrogenic systemic fibrosis.

    You should inject the drug intravenously with caution to avoid extravasation. In the event that extravasation has occurred, the patient's observation and treatment require all cases of local reactions development.

    Effect on the ability to drive transp. cf. and fur:Based on the data of pharmacokinetics and pharmacodynamics, Multiohance does not affect the abilitymanage vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. 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:
    The solution for intravenous administration is 529 mg / ml.
    Packaging:
    10 ml, 15 ml or 20 ml in flasks of colorless glass type I, corked with an elastomer plug (butyl rubber), crimped aluminum and a flip-off flap consisting of an aluminum ring and a central disk of polypropylene in various colors. Aluminum break-in and an aluminum ring of the flip-off type cover constitute one element of the package. Each label is labeled. One bottle is placed in a cardboard box together with instructions for use.
    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002084
    Date of registration:31.05.2013
    Expiration Date:31.05.2018
    The owner of the registration certificate:Brakko Imajing SpABrakko Imajing SpA Italy
    Manufacturer: & nbsp
    Representation: & nbspIMEX, CJSCIMEX, CJSCRussia
    Information update date: & nbsp30.05.2018
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