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    Other Imaging Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral tricarbocyanine dye and optical imaging agent
    Used for determining cardiac output, hepatic function and liver blood flow, ophthalmic angiography, and visualization of extrahepatic biliary ducts, lymph nodes and lymphatic vessels in setting of cervical and uterine tumors, and vessels, blood flow, and tissue perfusion around several surgical procedures
    Associated with severe hypersensitivity reactions

    COMMON BRAND NAMES

    IC Green

    HOW SUPPLIED

    IC Green Intravenous Inj Pwd F/Sol: 25mg

    DOSAGE & INDICATIONS

    For use as an aid in cardiac function diagnosis.
    For determining cardiac output using indicator-dilution studies.
    NOTE: See FDA-approved labeling for calibrating dye curves to quantitate the patient-specific dilution curves.
    Intravenous Dosage (IC-Green)
    Adults

    5 mg IV. An average of 5 dilution curves is recommended for diagnostic cardiac catheterization. Do not exceed the maximum total dose of 2 mg/kg.[48809]

    Children and Adolescents

    2.5 mg IV. An average of 5 dilution curves is recommended for diagnostic cardiac catheterization. Do not exceed the maximum total dose of 2 mg/kg.

    Infants

    1.25 mg IV. An average of 5 dilution curves is recommended for diagnostic cardiac catheterization. Do not exceed the maximum total dose of 2 mg/kg.[48809]

    For visualization of micro- and macro-vasculature, blood flow, and tissue perfusion before, during, and after vascular, gastrointestinal, organ transplant, and plastic micro- and reconstructive surgeries (including general minimally invasive procedures).
    Intravenous Dosage (Spy Agent Green)
    Adults

    1.25 to 5 mg IV for a single image sequence or 3.75 to 10 mg IV for visualization of perfusion in extremities through the skin. Additional doses may be administered to obtain imaging sequences during the procedure. Do not exceed the maximum total dose of 2 mg/kg.

    Infants, Children, and Adolescents

    1.25 to 5 mg IV for a single image sequence. Lower doses may be administered in younger patients and in those with lower body weight. Additional doses may be administered to obtain imaging sequences during the procedure. Do not exceed the maximum total dose of 2 mg/kg.

    For use as an aid in determining hepatobiliary system dysfunction diagnosis.
    For hepatic function studies using ear densitometry or photometric analysis.
    Intravenous Dosage (IC-Green)
    Adults

    0.5 mg/kg IV.

    For visualization of extrahepatic biliary ducts.
    Intravenous Dosage (Spy Agent Green)
    Adults

    2.5 mg IV as a single dose at least 45 minute prior to surgery. Additional doses may be administered to obtain imaging sequences during the procedure. Do not exceed the maximum total dose of 2 mg/kg.

    Children and Adolescents 12 years and older

    2.5 mg IV as a single dose at least 45 minute prior to surgery. Additional doses may be administered to obtain imaging sequences during the procedure. Do not exceed the maximum total dose of 2 mg/kg.

    For use as a diagnostic agent during ophthalmic angiography.
    NOTE: Because excessive dye extravasation does not occur in the highly fenestrated choroidal vasculature, indocyanine green is useful in both absorption and fluorescence infrared angiography of the choroidal vasculature when using appropriate filters and film in a fundus camera.
    Intravenous Dosage (IC-Green)
    Adults

    Up to 40 mg IV via the antecubital vein depending on the imaging equipment and technique used.

    For visualization of lymph nodes and lymphatic vessels during sentinel lymph node mapping for cervical and uterine tumors.
    Interstitial Cervical Dosage (Spy Agent Green)
    Adult Females

    5 mg interstitially into the cervix as four 1 mL injections at the 3 o'clock and 9 o'clock positions with a superficial (1 to 3 mm) and a deep (1 to 2 cm) injection at each position.[63781]

    MAXIMUM DOSAGE

    Adults

    2 mg/kg IV; 5 mg interstitially into the cervix.

    Geriatric

    2 mg/kg IV; 5 mg interstitially into the cervix.

    Adolescents

    2 mg/kg IV.

    Children

    2 mg/kg IV.

    Infants

    2 mg/kg IV.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific dosing recommendations in patients with hepatic impairment are not available; it appears no dosage adjustment is needed.

    Renal Impairment

    Specific dosing recommendations in patients with renal impairment are not available; it appears no dosage adjustment is needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution
    Under sterile conditions, dissolve the indocyanine green powder with Sterile Water for Injection. The amount of Sterile Water for Injection to be used is determined by the procedure to be performed.
    For hepatic function studies, dilute 25 mg indocyanine green with 5 mL of Sterile Water for Injection (5 mg/mL).
    For visualization of vessels, blood flow, tissue perfusion, and extrahepatic biliary ducts, dilute 25 mg indocyanine green with 10 mL of Sterile Water for Injection (2.5 mg/mL).
    For ophthalmic angiograms, dilute up to 40 mg indocyanine green with 2 mL of Sterile Water for Injection (up to 20 mg/mL).
    For lymphatic mapping, dilute 25 mg indocyanine green with 20 mL of Sterile Water for Injection (1.25 mg/mL).
    Discard the solution if the product precipitates.
    Storage: Indocyanine green is unstable in aqueous solution and must be used within 6 hours. The dye is stable in whole blood and plasma, so samples obtained during testing may be read hours later.[48809] [63781]
     
    Intravenous Bolus Injection
    Indocyanine green is administered as a rapid IV bolus.
    For hepatic function studies, administer into the lumen of an arm vein as rapidly as possible, without allowing the dye to escape outside the vein. Study the patient in a fasting, basal state. Changing concentrations of indocyanine green can be monitored by ear densitometry or by obtaining blood specimens at timed intervals (i.e., photometric method). The normal percentage disappearance rate in healthy subjects is 18% to 24% per minute.
    For visualization of vessels, blood flow, and tissue perfusion, administer via a central or peripheral venous line using a 3-way stopcock attached to an injection port on the infusion line. Immediately after indocyanine green injection, switch the access on the stopcock and flush the line with 10 mL of 0.9% Sodium Chloride Injection. Adjust the amount and type of flush to avoid volume and/or sodium overload in pediatric patients.
    For cardiac output studies, administer via the cardiac catheter. Rinse the syringe that will be used for the injection with the Sterile Water for Injection provided. Use isotonic saline to flush the residual dye from the cardiac catheter to avoid hemolysis.
    For ophthalmic angiography studies, administer into the antecubital vein. Inject a 5 mL IV bolus of 0.9% Sodium Chloride Injection immediately after the indocyanine green.[48809] [63781]
     
    Interstitial Cervical Injection
    For lymphatic mapping, administer as 4 interstitial injections into the cervix at the 3 and 9 o'clock positions with a superficial (1 to 3 mm) and a deep (1 to 2 cm) injection at each position.[63781]

    STORAGE

    IC Green:
    - Discard reconstituted product if not used within 6 hours
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Iodine hypersensitivity

    Indocyanine green contains sodium iodide and is contraindicated in patients with iodine hypersensitivity. Anaphylaxis or other allergic reactions may occur.

    Dialysis, renal failure, uremia

    Indocyanine green should be used with caution in patients with renal failure or uremia, and those who are on dialysis. In 1 case report, anaphylactoid reactions with various manifestations occurred in 4 of 43 (9.3%) patients on hemodialysis who received indocyanine green for cardiac output studies. Specific reactions included dyspnea, palpitations, anxiety, nausea, edema, and hypotension. Reasons for these adverse effects in this vulnerable patient population are unclear; however, patients that reacted to indocyanine green were found to have significantly higher eosinophil counts than those who did not react (937 +/- 271 vs. 378 +/- 67; p less than 0.025).

    Laboratory test interference

    Indocyanine green may cause laboratory test interference with radioactive iodine uptake studies. Because indocyanine green contains iodine, the iodine-binding capacity of thyroid tissue may be reduced for at least 1 week after indocyanine green administration. Do not perform radioactive iodine uptake studies for at least 1 week after the administration of indocyanine green.

    Pregnancy

    There are no adequate, well-controlled studies with indocyanine green during pregnancy. Available data from a small number of scientific literature studies with indocyanine green use in pregnant women have not reported any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Data from a single small study suggest there is no placental transfer of indocyanine green. Maternal doses of indocyanine green ranging from 0.5 to 5 mg/kg were administered during stage 1 or 2 of labor in 9 pregnant women. Blood samples were obtained from the mother and the fetal scalp at baseline, 2 to 4 minutes, and 6 to 8 minutes after dye injection. No indocyanine green was found in the fetal blood of all 9 infants or the umbilical vein blood of 4 infants. Animal reproduction studies have not been conducted with indocyanine green.[48809] [49707]

    Breast-feeding

    No adverse events have been observed in the breast-fed infant in 17 cases of indocyanine green use in breast-feeding women reported in the literature. However, there are no data on the presence of indocyanine green in human milk or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for indocyanine green and any potential adverse effects on the breast-fed infant from indocyanine green or the underlying maternal condition.

    ADVERSE REACTIONS

    Severe

    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    cyanosis / Early / Incidence not known
    cardiac arrest / Early / Incidence not known
    laryngospasm / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    visual impairment / Early / Incidence not known

    Moderate

    edema / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    peripheral vasodilation / Rapid / Incidence not known
    erythema / Early / Incidence not known
    wheezing / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    confusion / Early / Incidence not known
    dyspnea / Early / Incidence not known

    Mild

    flushing / Rapid / Incidence not known
    syncope / Early / Incidence not known
    weakness / Early / Incidence not known
    agitation / Early / Incidence not known
    headache / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    nausea / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    anxiety / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    diaphoresis / Early / Incidence not known
    cough / Delayed / Incidence not known
    skin discoloration / Delayed / Incidence not known

    DRUG INTERACTIONS

    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Phenobarbital may increase the clearance indocyanine green. The half-life of indocyanine green was lower in patients taking the drugs concomitantly compared to patients with normal and abnormal liver function taking no concomitant medications. The mechanism of interaction is unclear; those proposed in the medical literature include increased indocyanine green uptake by the liver cell, enhanced binding by specific hepatic carrier proteins, or more rapid excretion into bile.
    Haloperidol: (Moderate) Haloperidol may increase the clearance of indocyanine green. The half-life of indocyanine green was lower in patients taking the drugs concomitantly compared to patients with normal and abnormal liver function taking no concomitant medications. The mechanism of interaction is unclear; those proposed in the medical literature include increased indocyanine green uptake by the liver cell, enhanced binding by specific hepatic carrier proteins, or more rapid excretion into bile.
    Heparin: (Moderate) Heparin products that contain sodium bisulfite may reduce the absorption peak of indocyanine green. Collection of blood samples for analysis should be performed with anticoagulants that do not contain sodium bisulfite.
    Nifedipine: (Moderate) In a study of 9 healthy adults given 0.5 mg/kg of indocyanine green, nifedipine increased indocyanine green clearance by 14%.
    Nitrofurantoin: (Moderate) Nitrofurantoin may increase the clearance of indocyanine green. The half-life of indocyanine green was lower in patients taking the drugs concomitantly compared to patients with normal and abnormal liver function taking no concomitant medications. The mechanism of interaction is unclear; those proposed in the medical literature include increased indocyanine green uptake by the liver cell, enhanced binding by specific hepatic carrier proteins, or more rapid excretion into bile.
    Phenobarbital: (Moderate) Phenobarbital may increase the clearance indocyanine green. The half-life of indocyanine green was lower in patients taking the drugs concomitantly compared to patients with normal and abnormal liver function taking no concomitant medications. The mechanism of interaction is unclear; those proposed in the medical literature include increased indocyanine green uptake by the liver cell, enhanced binding by specific hepatic carrier proteins, or more rapid excretion into bile.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Phenobarbital may increase the clearance indocyanine green. The half-life of indocyanine green was lower in patients taking the drugs concomitantly compared to patients with normal and abnormal liver function taking no concomitant medications. The mechanism of interaction is unclear; those proposed in the medical literature include increased indocyanine green uptake by the liver cell, enhanced binding by specific hepatic carrier proteins, or more rapid excretion into bile.
    Primidone: (Moderate) Primidone may increase the clearance indocyanine green. The half-life of indocyanine green was lower in patients taking the drugs concomitantly compared to patients with normal and abnormal liver function taking no concomitant medications. The mechanism of interaction is unclear; those proposed in the medical literature include increased indocyanine green uptake by the liver cell, enhanced binding by specific hepatic carrier proteins, or more rapid excretion into bile.
    Propranolol: (Minor) In a study of 9 healthy adults given 0.5 mg/kg of indocyanine green, propranolol decreased clearance by 21%.
    Propranolol; Hydrochlorothiazide, HCTZ: (Minor) In a study of 9 healthy adults given 0.5 mg/kg of indocyanine green, propranolol decreased clearance by 21%.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate, well-controlled studies with indocyanine green during pregnancy. Available data from a small number of scientific literature studies with indocyanine green use in pregnant women have not reported any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Data from a single small study suggest there is no placental transfer of indocyanine green. Maternal doses of indocyanine green ranging from 0.5 to 5 mg/kg were administered during stage 1 or 2 of labor in 9 pregnant women. Blood samples were obtained from the mother and the fetal scalp at baseline, 2 to 4 minutes, and 6 to 8 minutes after dye injection. No indocyanine green was found in the fetal blood of all 9 infants or the umbilical vein blood of 4 infants. Animal reproduction studies have not been conducted with indocyanine green.[48809] [49707]

    No adverse events have been observed in the breast-fed infant in 17 cases of indocyanine green use in breast-feeding women reported in the literature. However, there are no data on the presence of indocyanine green in human milk or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for indocyanine green and any potential adverse effects on the breast-fed infant from indocyanine green or the underlying maternal condition.

    MECHANISM OF ACTION

    Indocyanine green enables intravascular imaging through fluorescence. When bound to proteins in plasma or lymph fluid, indocyanine green absorbs light in the near-infrared region at 806 nm, and emits fluorescence (light) at a slightly longer wavelength, with peak emission at 830 nm. Fluorescence imaging devices provide external energy as near-infrared light for indocyanine green to absorb, resulting in excitation of indocyanine green; emitted fluorescence is transferred from the field of view to an image on a monitor. Its visual color is created from microbubbles produced from shaking during product reconstitution, rather than the chemical composition of the dye itself. Approximately 0.01 mL of air is injected with each 1 mL of prepared indocyanine green dye.[48809] [48816]

    PHARMACOKINETICS

    Indocyanine green is administered parenterally as intravenous or interstitial cervical injections. Once in systemic circulation, indocyanine green binds to plasma (98%) or lymphatic proteins (including albumin and alpha-1 lipoproteins), which confines the drug to the intravascular compartment. No extrahepatic or enterohepatic circulation occurs, and there is negligible renal, peripheral, lung, or cerebrospinal uptake. Indocyanine green is not metabolized. The drug is removed from plasma almost exclusively by hepatic parenchymal cells and is subsequently excreted unchanged in bile. The peak absorption and emission of indocyanine green lie in a region of 800 to 850 nm where transmission of energy by the pigment epithelium is more efficient than in the region of visible light energy.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Intravenous Route

    Fluorescence is visible in the blood vessels within 5 to 15 seconds postinjection. The time from injection to appearance of indocyanine green in bile ranges from 8 to 15 minutes. Peak concentrations in bile occur at 120 minutes.

    Other Route(s)

    Interstitial Route
    After interstitial injection, indocyanine green is taken up by the lymphatic vessels and lymph nodes. Fluorescence is visible in the lymphatic vessels and lymph nodes within 1 minute postinjection.[63781]