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  • CLASSES

    Other Imaging Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral diagnostic aid
    Used to determine cardiac output, hepatic function, and liver blood flow, as well as during ophthalmic angiography
    Lyophilized green tricarbocyanine dye

    COMMON BRAND NAMES

    IC Green

    HOW SUPPLIED

    IC Green Intravenous Inj Pwd F/Sol: 25mg

    DOSAGE & INDICATIONS

    For use as a diagnostic aid in cardiac function diagnosis, to determine cardiac output using indicator-dilution studies.
    NOTE: An average of 5 dilution curves are needed for a diagnostic cardiac catheterization. The total amount of indocyanine green administered should be less than 2 mg/kg.
    NOTE: See prescribing information for creating calibrating dye curves to quantitate the patient-specific dilution curves.
    NOTE: Indocyanine green should be mixed with the Sterile Water for Injection solvent provided. The resulting solution should be used within 6 hours of preparation and should not be used if a precipitate is present. It is recommended that the syringe used for the injection of the dye be rinsed with Sterile Water for Injection; however, 0.9% Sodium Chloride Injection should be used in all other parts of the catheterization procedure.
    Intravenous dosage
    Adults

    5 mg IV rapid bolus. A known amount of dye is injected as a single bolus as rapidly as possible via a cardiac catheter into selected sites in the vascular system. A recording instrument (oximeter or densitometer) is attached to a needle or catheter for sampling of the dye-blood mixture from a systemic arterial sampling site.

    Adolescents and Children

    2.5 mg IV rapid bolus. A known amount of dye is injected as a single bolus as rapidly as possible via a cardiac catheter into selected sites in the vascular system. A recording instrument (oximeter or densitometer) is attached to a needle or catheter for sampling of the dye-blood mixture from a systemic arterial sampling site.

    Infants

    1.25 mg IV rapid bolus. A known amount of dye is injected as a single bolus as rapidly as possible via a cardiac catheter into selected sites in the vascular system. A recording instrument (oximeter or densitometer) is attached to a needle or catheter for sampling of the dye-blood mixture from a systemic arterial sampling site.

    For use as a diagnostic aid in determining hepatobiliary system dysfunction diagnosis.
    NOTE: The patient should be studied in a fasting, basal state.
    Using ear densitometry.
    Intravenous Dosage
    Adults

    0.5 mg/kg IV bolus. The patient should be weighed just prior to the procedure. Inject the dye into the lumen of an arm vein as rapidly as possible, without allowing the dye to escape outside of the vein. 25 mg of indocyanine green powder should be dissolved in exactly 5 mL of the aqueous solvent provided to create a 5 mg/mL dye solution. Ear oximetry has also been used and makes it possible to monitor the appearance and disappearance of indocyanine green without the necessity of withdrawal and spectrophotometric analysis of blood samples for calibration. An ear densitometer that has a compensatory photoelectric cell to correct for changes in blood volume and hematocrit, and a detection photocell that registers levels has been described. This device permits simultaneous measurement of cardiac output, blood volume, and hepatic clearance of indocyanine green and was found to be a reliable index of plasma removal kinetics after single injections or continuous infusions of indocyanine green. This technique has been employed in newborn infants, healthy adults, and in in children and adults with liver disease. A normal subject has a removal rate of 18% to 24%/minute. In larger doses, indocyanine green is particularly helpful in detecting drug-induced alterations of hepatic function and in the detection of mild liver injury. See manufacturer labeling for a graph of the normal clearance pattern of indocyanine green.

    Using photometric analysis.
    Intravenous Dosage
    Adults

    0.5 mg/kg IV bolus. The patient should be weighed just prior to the procedure. Inject the dye into the lumen of an arm vein as rapidly as possible, without allowing the dye to escape outside of the vein. 25 mg of indocyanine green powder should be dissolved in exactly 5 mL of the aqueous solvent provided to create a 5 mg/mL dye solution. A blood sample, drawn at 20 minutes after dye injection, should be allowed to clot, it should be centrifuged, and its optical density determined at 805 nm using the patient's normal serum as a blank. A single 20-minute sample in healthy subjects should contain no more than 4% of the initial concentration of the dye. A plot of dye concentrations vs. optical density, which demonstrates the percent retention of indocyanine green in a patient, can be found in the manufacturer labeling. If more accurate results are desired, a plot using the patient's blood and a vial of indocyanine green can be constructed; instructions on this method can be found in the manufacturer labeling. Hemolysis does not interfere with the results. If the disappearance rate of the dye is to be determined, samples should be obtained at 5, 10, 15, and 20 minutes after injecting the dye. Prepare each sample as outlined above. The optical densities should be read at 805 nm. The indocyanine green concentration on each timed sample can be determined by using the concentration curve in the prescribing information. The values should be plotted on logarithmic paper. All samples should be read at the same temperature. Percentage disappearance in healthy subjects is 18% to 24% per minute with a normal biological half-time of 2.5 to 3 minutes.

    For use as a diagnostic agent during ophthalmic angiography.
    NOTE: 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.
    NOTE: 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
    Adults

    Dosages of up to 40 mg in 2 mL of aqueous solvent administered IV bolus into the antecubital vein have been found to give optimal angiograms, although 25 mg IV is often injected. A 5 mL IV bolus of normal saline should be injected immediately following the injection of indocyanine green. One author suggests photographing 7 to 10 minutes after injection with late photographs at 20 and 40 minutes.

    MAXIMUM DOSAGE

    Adults

    Maximum dosage limits are not available.

    Geriatric

    Maximum dosage limits are not available.

    Adolescents

    Maximum dosage limits are not available.

    Children

    Maximum dosage limits are not available.

    Infants

    Maximum dosage limits are not available.

    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
    Dissolve the indocyanine green powder with the Sterile Water for Injection solvent provided. The amount of solvent to be used should be determined based on the procedure to be performed. For hepatic function studies, a 25 mg vial should be diluted with 5 mL solvent. For ophthalmic angiograms, up to 40 mg indocyanine green in 2 mL solvent may be used.
    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.
    IV Push
    Indocyanine green is administered as a rapid IV bolus.
    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, so as 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 afterward.
    For hepatic function studies, administer into the lumen of an arm vein.

    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

    General Information

    Radioactive iodine uptake studies should not be conducted for a minimum of 1 week following the use of indocyanine green.

    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 < 0.025).

    Neonates

    The safety and effectiveness of indocyanine green have not been established in neonates.

    Pregnancy

    Indocyanine green is classified as FDA pregnancy category C. No well controlled studies have assessed the effect of indocyanine green on the fetus or female reproduction capacity. A small study in 9 pregnant patients examined placental transfer of indocyanine green during labor. Maternal doses of indocyanine green ranging from 0.5—5 mg/kg were administered during stage 1 or 2 of labor. Blood samples were obtained from the mother and the fetal scalp at baseline, 2—4 minutes, and 6—8 minutes following dye injection. No indocyanine green was found in the fetal blood of all 9 infants or the umbilical vein blood of 4 infants, thus demonstrating no placental transfer.

    Breast-feeding

    According to the manufacturer, it is not known if indocyanine green is excreted in human milk. Caution is advised when administering indocyanine green to a nursing woman. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

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

    Moderate

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

    Mild

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

    DRUG INTERACTIONS

    Atropine; Hyoscyamine; Phenobarbital; 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.
    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.
    Hydrochlorothiazide, HCTZ; Propranolol: (Minor) In a study of 9 healthy adults given 0.5 mg/kg of indocyanine green, propranolol decreased clearance by 21%.
    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.
    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%.

    PREGNANCY AND LACTATION

    Pregnancy

    Indocyanine green is classified as FDA pregnancy category C. No well controlled studies have assessed the effect of indocyanine green on the fetus or female reproduction capacity. A small study in 9 pregnant patients examined placental transfer of indocyanine green during labor. Maternal doses of indocyanine green ranging from 0.5—5 mg/kg were administered during stage 1 or 2 of labor. Blood samples were obtained from the mother and the fetal scalp at baseline, 2—4 minutes, and 6—8 minutes following dye injection. No indocyanine green was found in the fetal blood of all 9 infants or the umbilical vein blood of 4 infants, thus demonstrating no placental transfer.

    According to the manufacturer, it is not known if indocyanine green is excreted in human milk. Caution is advised when administering indocyanine green to a nursing woman. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Indocyanine green dye enables intravascular imaging through fluorescence, with a maximal spectral absorption between 800—850 nm. 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.

    PHARMACOKINETICS

    Indocyanine green is administered intravenously. Following administration, it immediately and completely binds to plasma proteins, including albumin and alpha-one lipoproteins. Albumin is the primary carrier, transporting approximately 95% of the dye. Indocyanine green does not cross the placenta, and it is not known if the dye is excreted in breast milk. 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.

    Intravenous Route

    Reports estimate that the time from injection to appearance of indocyanine green in bile ranges from 8—15 minutes. Peak concentrations in bile occur at 120 minutes.