Multihance

Gadobenate dimeglumine is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting during your MRI.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when the medicine is injected.

Your doctor or other healthcare provider may want to watch you for a short time after your test is over. This is to make sure you do not have any unwanted side effects or delayed reactions.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Since gadobenate dimeglumine is used only during your MRI, you will not be on a dosing schedule.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

This medication can harm the kidneys in certain people, and this effect may be increased if you also use other medicines harmful to the kidneys. Many other drugs (including some over-the-counter medicines) can harm your kidneys. You may need dose adjustments or special tests if you have recently used any of these medications, such as:

• lithium (Eskalith, Lithobid);

• methotrexate (Rheumatrex, Trexall);

• pain or arthritis medicines such as aspirin (Anacin, Excedrin), acetaminophen (Tylenol), ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others;

• medicines used to treat ulcerative colitis, such as mesalamine (Pentasa) or sulfasalazine (Azulfidine);

• medicines used to prevent organ transplant rejection, such as cyclosporine (Gengraf, Neoral, Sandimmune), sirolimus (Rapamune) or tacrolimus (Prograf);

• IV antibiotics such as amphotericin B (Amphotec, AmBisome, Abelcet), amikacin (Amikin), bacitracin (Baci IM), capreomycin (Capastat), gentamicin (Garamycin), kanamycin (Kantrex), streptomycin, or vancomycin (Vancocin, Vancoled);

• antiviral medicines such as acyclovir (Zovirax), adefovir (Hepsera), cidofovir (Vistide), foscarnet (Foscavir), ganciclovir (Cytovene), valacyclovir (Valtrex), or valganciclovir (Valcyte); or

• cancer medicine such as aldesleukin (Proleukin), carmustine (BiCNU, Gliadel), cisplatin (Platinol), ifosfamide (Ifex), oxaliplatin (Eloxatin), streptozocin (Zanosar), or tretinoin (Vesanoid).

There may be other drugs that can affect gadobenate dimeglumine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• A heartbeat that does not feel normal.
• This medicine may cause tissue damage if the drug leaks from the vein. Tell your nurse if you have any redness, burning, pain, swelling, blisters, skin sores, or leaking of fluid where the drug is going into your body.

• If you need to store MultiHance at home, talk with your doctor, nurse, or pharmacist about how to store it.

  MRI of the Central Nervous System (CNS)

MultiHance is indicated for intravenous use in magnetic resonance imaging (MRI) of the central nervous system (CNS) in adults and children over 2 years of age to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine, and associated tissues.

  MRA of Renal and Aorto-ilio-femoral Vessels

MultiHance is indicated for use in magnetic resonance angiography (MRA) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease.

The following adverse reactions are discussed in greater detail in other sections of the label:

• Nephrogenic systemic fibrosis [see Warnings and Precautions (5.1)]
• Hypersensitivity reactions [see Warnings and Precautions (5.2)]

  Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult

In all clinical trials with MultiHance, a total of 4967 adult subjects (137 healthy volunteers and 4830 patients) received MultiHance at doses ranging from 0.005 to 0.4 mmol/kg. There were 2838 (57%) men and 2129 (43%) women with a mean age of 56.5 years (range 18 to 93 years). A total of 4403 (89%) subjects were Caucasian, 134 (3%) Black, 275 (6%) Asian, 40 (1%) Hispanic, 70 (1%) in other racial groups, and for 45 (1%) subjects, race was not reported.

The most commonly reported adverse reactions in adult subjects who received MultiHance were nausea (1.3%) and headache (1.2%). Most adverse reactions were mild to moderate in intensity. One subject experienced a serious anaphylactoid reaction with laryngeal spasm and dyspnea [see Warnings and Precautions (5.2)]. Serious adverse reactions consisting of convulsions, pulmonary edema, acute necrotizing pancreatitis, and anaphylactoid reactions were reported in 0.1% of subjects in clinical trials.

Adverse reactions that occurred in at least 0.5% of 4967 adult subjects who received MultiHance are listed below (Table 2), in decreasing order of occurrence within each system.

The following adverse reactions occurred in less than 0.5% of the 4967 adult subjects who received MultiHance. Serious adverse reactions described above are not repeated below.
Blood and Lymphatic System Disorders: Basophilia;
Cardiac Disorders: Atrioventricular block first degree;
Eye Disorders: Eye pruritus, eye swelling, ocular hyperemia, visual disturbance;
Gastrointestinal Disorders: Abdominal pain or discomfort, diarrhea, dry mouth, lip swelling, paraesthesia oral, tongue edema, vomiting;
General Disorders and Administration Site Conditions: Chest pain or discomfort, chills, malaise;
Immune System Disorders: Hypersensitivity;
Investigations: Nonspecific changes in laboratory tests (including hematology, blood chemistry, liver enzymes and urinalysis), blood pressure and electrocardiogram parameters (including PR, QRS and QT intervals and ST-T segment changes).
Musculoskeletal and Connective Tissue Disorders: Myalgia;
Nervous System Disorders: Parosmia, tremor;
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, laryngospasm, nasal congestion, sneezing, wheezing;
Skin and Subcutaneous Tissue Disorders: Hyperhidrosis, pruritus, rash, swelling face, urticaria.

Pediatric

In clinical trials of MultiHance in MRI of the CNS, 217 pediatric subjects received MultiHance at a dose of 0.1 mmol/kg. A total of 112 (52%) subjects were male and the overall mean age was 8.3 years (range 4 days to 17 years). A total of 168 (77%) subjects were Caucasian, 12 (6%) Black, 12 (6%) Asian, 24 (11%), Hispanic, and 1 (<1%) in other racial groups.

Adverse reactions were reported for 14 (6.5%) of the subjects. The frequency and the nature of the adverse reactions were similar to those seen in the adult patients. The most commonly reported adverse reactions were vomiting (1.4%), pyrexia (0.9%), and hyperhidrosis (0.9%). No subject died during study participation. A serious adverse reaction of worsening of vomiting was reported for one (0.5%) patient with a brain tumor (glioma) for which a causal relationship to MultiHance could not be excluded.

  Post-marketing Experience

The following adverse reactions have been identified during post approval use of MultiHance. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Anaphylactic, anaphylactoid and hypersensitivity reactions manifested with various degrees of severity up to anaphylactic shock, loss of consciousness and death. The reactions generally involved signs or symptoms of respiratory, cardiovascular, and/or mucocutaneous abnormalities.

Extravasation of MultiHance may lead to injection site reactions, characterized by local pain or burning sensation, swelling, blistering, and necrosis [see Warnings and Precautions (5.4)]

  Mechanism of Action

Gadobenate dimeglumine is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The large magnetic moment produced by the paramagnetic agent results in a large local magnetic field, which can enhance the relaxation rates of water protons in its vicinity leading to an increase of signal intensity (brightness) of tissue.

In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxation time in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.

  Pharmacodynamics

Unlike other tested paramagnetic contrast agents (See Table 3), MultiHance demonstrates weak and transient interactions with serum proteins that causes slowing in the molecular tumbling dynamics, resulting in strong increases in relaxivity in solutions containing serum proteins. The improved relaxation effect can contribute to increased contrast-to-noise ratio and lesion-to-brain ratio, which may improve visualization.

Disruption of the blood-brain barrier or abnormal vascularity allows enhancement by MultiHance of lesions such as neoplasms, abscesses, and infarcts. Uptake of MultiHance into hepatocytes has been demonstrated.

  Pharmacokinetics

Three single-dose intravenous studies were conducted in 32 healthy male subjects to assess the pharmacokinetics of gadobenate dimeglumine. The doses administered in these studies ranged from 0.005 to 0.4 mmol/kg. Upon injection, the meglumine salt is completely dissociated from the gadobenate dimeglumine complex. Thus, the pharmacokinetics is based on the assay of gadobenate ion, the MRI contrast effective ion in gadobenate dimeglumine. Data for plasma concentration and area under the curve demonstrated linear dependence on the administered dose. The pharmacokinetics of gadobenate ion following intravenous administration can be best described using a two-compartment model.

Distribution
Gadobenate ion has a rapid distribution half-life (reported as mean ± SD) of 0.084 ± 0.012 to 0.605 ± 0.072 hours. Volume of distribution of the central compartment ranged from 0.074 ± 0.017 to 0.158 ± 0.038 L/kg, and estimates of volume of distribution by area ranged from 0.170 ± 0.016 to 0.282 ± 0.079 L/kg. These latter estimates are approximately equivalent to the average volume of extracellular body water in man. In vitro studies showed no appreciable binding of gadobenate ion to human serum proteins.

Elimination
Gadobenate ion is eliminated predominately via the kidneys, with 78% to 96% of an administered dose recovered in the urine. Total plasma clearance and renal clearance estimates of gadobenate ion were similar, ranging from 0.093 ± 0.010 to 0.133 ± 0.270 L/hr/kg and 0.082 ± 0.007 to 0.104 ± 0.039 L/hr/kg, respectively. The clearance is similar to that of substances that are subject to glomerular filtration. The mean elimination half-life ranged from 1.17 ± 0.26 to 2.02 ± 0.60 hours. A small percentage of the administered dose (0.6% to 4%) is eliminated via the biliary route and recovered in feces.

Metabolism
There was no detectable biotransformation of gadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelating agent being recovered alone in feces.

Pharmacokinetics in Special Population

Renal Impairment: A single intravenous dose of 0.2 mmol/kg of MultiHance was administered to 20 subjects with impaired renal function (6 men and 3 women with moderate renal impairment [urine creatinine clearance >30 to <60 mL/min] and 5 men and 6 women with severe renal impairment [urine creatinine clearance >10 to <30 mL/min]). Mean estimates of the elimination half-life were 6.1 ± 3.0 and 9.5 ± 3.1 hours for the moderate and severe renal impairment groups, respectively as compared with 1.0 to 2.0 hours in healthy volunteers.

Hemodialysis: A single intravenous dose of 0.2 mmol/kg of MultiHance was administered to 11 subjects (5 males and 6 females) with end-stage renal disease requiring hemodialysis to determine the pharmacokinetics and dialyzability of gadobenate. Approximately 72% of the dose was recovered by hemodialysis over a 4-hour period. The mean elimination half-life on dialysis was 1.21 ± 0.29 hours as compared with 42.4 ± 24.4 hours when off dialysis.

Hepatic Impairment: A single intravenous dose of 0.1 mmol/kg of MultiHance was administered to 11 subjects (8 males and 3 females) with impaired liver function (Class B or C modified Child-Pugh Classification). Hepatic impairment had little effect on the pharmacokinetics of MultiHance with the parameters being similar to those calculated for healthy subjects.

Gender, Age, Race: A multiple regression analysis performed using pooled data from several pharmacokinetic studies found no significant effect of sex upon the pharmacokinetics of gadobenate. Clearance appeared to decrease slightly with increasing age. Since variations due to age appeared marginal, dosage adjustment for geriatric population is not recommended. Pharmacokinetic differences due to race have not been systematically studied.

Pediatric: A population pharmacokinetic analysis incorporated data from 25 healthy subjects (14 males and 11 females) and 15 subjects undergoing MR imaging of the central nervous system (7 males and 8 females) between ages of 2 and 16 years. The subjects received a single intravenous dose of 0.1 mmol/kg of MultiHance. The geometric mean Cmax was 62.3 μg/mL (n=16) in children 2 to 5 years of age, and 64.2 μg/mL (n=24) in children older than 5 years. The geometric mean AUC 0-∞ was 77.9 μg-h/mL in children 2-5 years of age (n=16) and 82.6 μg-h/mL in children older than 5 years (n=24). The geometric mean half-life was 1.2 hours in children 2 to 5 years of age and 0.93 hours in children older than 5 years. There was no significant gender-related difference in the pharmacokinetic parameters in the pediatric patients. Over 80% of the dose was recovered in urine after 24 hours.

How Supplied

MultiHance (gadobenate dimeglumine) is a clear, colorless to slightly yellow solution containing 529 mg gadobenate dimeglumine per mL. MultiHance is supplied in glass vials; each single dose vial is rubber stoppered with an aluminum seal and the contents are sterile. MultiHance is supplied in boxes of:

Five 5 mL single dose 10 mL vials              (NDC 0270-5164-12)
Five 10 mL single dose 20 mL vials           (NDC 0270-5164-13)
Five 15 mL single dose 20 mL vials           (NDC 0270-5164-14)
Five 20 mL single dose 20 mL vials           (NDC 0270-5164-15)

Storage and Handling
Inspect the MultiHance vial visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. Do not mix intravenous medications or parenteral nutrition solutions with MultiHance. Do not administer other medications in the same intravenous line with MultiHance because of the potential for chemical incompatibility.

Draw MultiHance into a syringe and inject using sterile technique. MultiHance vials are intended for single use only. Administer immediately after opening and discard any unused product.

Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Do not freeze.

Applies to gadobenate dimeglumine: intravenous solution

Along with its needed effects, gadobenate dimeglumine (the active ingredient contained in Multihance) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking gadobenate dimeglumine:

• Abdominal or stomach pain
• anxiety
• back pain
• black, tarry stools
• bladder pain
• bloody or cloudy urine
• blue lips and fingernails
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain or discomfort
• chills
• confusion
• convulsions
• cough
• coughing that sometimes produces a pink frothy sputum
• dark urine
• decreased urination
• deep or fast breathing with dizziness
• difficult or labored breathing
• difficult, burning, or painful urination
• difficult, fast, or noisy breathing, sometimes with wheezing
• difficulty with breathing or swallowing
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• excessive muscle tone
• fainting
• fast, slow, or irregular heartbeat
• fever
• frequent urge to urinate
• general feeling of discomfort or illness
• headache
• hives
• inability to move the legs or arms
• increased sweating
• itching
• lightheadedness, dizziness, or fainting
• lower back or side pain
• muscle stiffness
• muscle tension or tightness
• nausea
• nervousness
• numbness of the feet, hands, and around the mouth
• pain in the shoulders, arms, jaw, or neck
• pain or redness at the injection site
• pale skin
• pale skin at the injection site
• paralysis of one side of the body
• pounding heartbeat
• pounding in the ears
• problems with speech or speaking
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• reddening of the skin, especially around the ears
• shakiness in the legs, arms, hands, or feet
• shortness of breath
• skin rash
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• sudden shortness of breath or troubled breathing
• sugar in the urine
• sweating
• swelling in the legs and ankles
• swelling of the eyes, face, or inside of the nose
• swollen glands
• tightness in the chest
• tiredness
• trembling or shaking of the hands or feet
• unusual bleeding or bruising
• unusual tiredness or weakness
• wheezing
• yellow eyes or skin

Some side effects of gadobenate dimeglumine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• feeling hot

• Acid or sour stomach
• bad, unusual, or unpleasant (after) taste
• belching
• blurred or loss of vision
• change in sense of smell
• change in taste
• continuing ringing or buzzing or other unexplained noise in the ears
• decreased awareness or responsiveness
• diarrhea
• difficulty having a bowel movement (stool)
• difficulty with moving
• disturbed color perception
• double vision
• dry mouth
• ear pain
• feeling unusually cold
• halos around lights
• hearing loss
• heartburn
• hives or welts
• indigestion
• joint pain
• lack or loss of strength
• loss of bowel control
• muscle aches or cramps
• muscle spasms
• night blindness
• overbright appearance of lights
• redness of the eye
• redness of the skin
• severe sleepiness
• shivering
• stomach discomfort, upset, or pain
• stuffy nose
• swelling of the eyelid
• swollen joints
• tunnel vision
• vomiting