Indocyanine green is a parenteral tricarbocyanine dye and optical imaging agent indicated for determining cardiac output, hepatic function and liver blood flow, for ophthalmic angiography, and for visualization of extrahepatic biliary ducts, lymph nodes and lymphatic vessels in setting of breast, cervical, and uterine cancers, and vessels, blood flow, and tissue perfusion around several surgical procedures. Severe hypersensitivity reactions, including deaths due to anaphylaxis, have been associated with intravenous administration of indocyanine green; cardiopulmonary resuscitation personnel and equipment must be readily available.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific 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 to yield 5 mg/mL.
-For lymphatic mapping of breast cancer, dilute 25 mg indocyanine green with 10 mL of Sterile Water for Injection to yield 2.5 mg/mL.
-For lymphatic mapping of cervical and uterine cancer, dilute 25 mg indocyanine green with 20 mL of Sterile Water for Injection to yield 1.25 mg/mL.
-For ophthalmic angiograms, dilute up to 40 mg indocyanine green with 2 mL of Sterile Water for Injection to yield 20 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 to yield 2.5 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.
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.
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 3 cm) injection at each position.
Intradermal Breast Injection
-For lymphatic mapping, administer as 2 intradermal injections into the peri-areolar area of the breast at the 12 and 9 o'clock positions for the right breast or at the 12 and 3 o'clock positions for the left breast. If a peri-tumoral dose is necessary, administer as 3 intradermal injections at the 12 o'clock, 3 o'clock, and 9 o'clock positions.
Anaphylactoid reactions to indocyanine green have been reported in patients with and without reported sensitivity to iodide and irrespective of prior exposure. Anaphylactic shock leading to death has been reported after the administration of indocyanine green 5 mg IV during cardiac catheterization, with shock leading to pulmonary congestion and hemorrhagic edema. In this case, other contributing factors to death were identified, including severe coronary atherosclerosis and thrombus, cardiomegaly, and liver congestion. Various manifestations of anaphylactoid reactions have been reported after indocyanine green use at doses ranging from 5 mg to 50 mg IV. Immediate reactions (within approximately 1 to 2 minutes after drug administration) include cardiac arrest, sinus tachycardia, palpitations, respiratory arrest, laryngospasm, dyspnea, wheezing, bronchospasm, pruritus, edema, diaphoresis, flushing, headache, weakness, and nausea. Significant hypotension was reported in 2 patients as early as 20 seconds after indocyanine green administration. One patient received 2 doses of indocyanine green 5 mg IV, with corresponding decreases in blood pressure to 95/70 mm Hg and 30/5 mm Hg after the first and second doses, respectively. A second report of hypotension occurred after receipt of indocyanine green 50 mg IV, with blood pressure falling to 55/40 mm Hg. Both patients were treated with supportive care and recovered. Other reported reactions that had slightly later onset include generalized urticaria, erythema, cyanosis, peripheral vasodilation, syncope, agitation, anxiety, confusion, vomiting, pharyngitis, and cough. Indocyanine green should be administered cautiously in all patients, regardless of previous allergy history. Management of anaphylactoid symptoms from indocyanine green should include necessary supportive care including administration of epinephrine, corticosteroids, and antihistamines. Resuscitative equipment should be readily available. The exact physiological mechanism by which indocyanine green causes hypersensitivity reactions is unknown and debated in medical literature. It has been proposed that these reactions are more likely due to nonimmunologic histamine release, rather than to an antigen-antibody response. Most reactions appear to be idiosyncratic and pseudoallergic; however, prior sensitization to indocyanine green (resulting in immune-mediated reactions) may also occur, as progressive worsening of symptoms has resulted with consecutive administrations. After reactions, scratch and intradermal skin tests have been negative, and no precipitating antibodies were found in the serum of a patient who experienced an anaphylactoid reaction with severe hypotension (30/5 mm Hg).
Skin discoloration was reported after an accidental subcutaneous injection of indocyanine green. Skin discoloration including injection site discoloration was also reported in 1.4% of subjects in a clinical trial for lymphatic mapping of breast cancer.
Indocyanine green has been associated with visual impairment, in the form of visual field defects. A retrospective case series of 7 patients, who underwent vitrectomy with indocyanine green-assisted internal limiting membrane (ILM) peeling for macular holes, examined long-term development of visual defects. Intraoperatively, patients received a total of 0.1 to 0.8 mL of 0.5% indocyanine green. The dye was injected into fluid-filled eyes and was allowed to remain for 1 to 3 minutes, after which it was removed by extensive washout with irrigation fluid. The ILM was then lifted and peeled off. Mean follow-up time was 60.7 months, during which 6 nasal and 1 extensive visual field constriction defects occurred (1 in each patient). The average mean deviation (the mean difference in decibels between the normal expected range of vision and the patient's demonstrated range) was worse at 3 years than at 1 year after surgery, indicating that the visual field deteriorated for at least 3 years. The exact intravitreal toxicity mechanism of indocyanine green is unknown; however, there are proposed mechanisms which include gene expression alteration, apoptosis, direct injury to retinal pigment epithelium or ganglion/neuroretinal cells, direct injury to superficial retinal vessels, the osmolarity effect of the dye on the vitreoretinal interface, biomechanical damage to the ILM or inner retina, and light toxicity induced by indocyanine green. Research does support dose-dependent retinal toxic effects; therefore, use lowest dye concentration possible. Minimize the time that indocyanine green is in the vitreous cavity (in contact with retinal tissue).
Indocyanine green contains sodium iodide and is contraindicated in patients with iodine hypersensitivity. Hypersensitivity reactions including deaths due to anaphylaxis have been reported after intravenous administration of indocyanine green. Ensure cardiopulmonary resuscitation personnel and equipment are readily available and monitor all persons for hypersensitivity reactions.
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).
Indocyanine green may cause diagnostic 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.
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.
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.
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.
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.
-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 visualization of lymph nodes and lymphatic vessels during sentinel lymph node mapping for cervical and uterine cancer:
Interstitial Cervical Dosage (Spy Agent Green):
Adults: 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 3 cm) injection at each position.
-for visualization of lymph nodes and lymphatic vessels during sentinel lymph node mapping for breast cancer:
Intradermal dosage (Spy Agent Green):
Adults: 0.25 mg intradermally into the peri-areolar area of the breast as two 0.05 mL injections at the 12 o'clock and the 9 o'clock positions for the right breast or at the 12 o'clock or 3 o'clock positions for the left breast. If lymphatic flow towards the axillary lymph nodes is not visualized, a subsequent peri-tumoral dose of 0.375 mg intradermally as three 0.05 mL injections at the 12 o'clock, 3 o'clock, and 9 o'clock positions is recommended.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
Specific dosing recommendations in patients with hepatic impairment are not available; it appears no dosage adjustment is needed.
Patients with Renal Impairment Dosing
Specific dosing recommendations in patients with renal impairment are not available; it appears no dosage adjustment is needed.
*non-FDA-approved indication
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%.
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 with peak absorption at 805 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.
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
-Route-Specific Pharmacokinetics
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.
-Special Populations
Gender Differences
The fractional plasma disappearance rate of indocyanine green is significantly greater in females compared to males when the recommend dose of 0.5 mg/kg is administered. There are no significant differences in calculated clearance.