Indocyanine green

Clinical Pharmacology:

Following intravenous injection, Indocyanine Green is rapidly bound to plasma protein, of which albumin is the principle carrier (95%). Indocyanine Green undergoes no significant extrahepatic or enterohepatic circulation; simultaneous arterial and venous blood estimations have shown negligible renal, peripheral, lung or cerebro-spinal uptake of the dye. Indocyanine Green is taken up from the plasma almost exclusively by the hepatic parenchymal cells and is secreted entirely into the bile. After biliary obstruction, the dye appears in the hepatic lymph, independently of the bile, suggesting that the biliary mucosa is sufficiently intact to prevent diffusion of the dye, though allowing diffusion of bilirubin. These characteristics make Indocyanine Green a helpful index of hepatic function.

The plasma fractional disappearance rate at the recommended 0.5 mg/kg dose has been reported to be significantly greater in women than in men, although there was no significant difference in the calculated value for clearance.

Indications and Usage:

For determining cardiac output, hepatic function and liver blood flow, and for ophthalmic angiography.

Contraindications:

Indocyanine Green for Injection USP contains sodium iodide and should be used with caution in patients who have a history of allergy to iodides.

Warnings:

Anaphylactic deaths have been reported following Indocyanine Green for Injection USP administration during cardiac catheterization.

Precautions:

General:

Indocyanine Green Powder and Solution: Indocyanine Green is unstable in aqueous solution and must be used within 6 hours. However, the dye is stable in plasma and whole blood so that samples obtained in discontinuous sampling techniques may be read hours later. Sterile techniques should be used in handling the dye solution as well as in the performance of the dilution curves.

Indocyanine Green powder may cling to the vial or lump together because it is freeze-dried in the vials.

Drug Interactions:

Heparin preparations containing sodium bisulfite reduce the absorption peak of Indocyanine Green in blood and, therefore, should not be used as an anticoagulant for the collection of samples for analysis.

Drug/Laboratory Test interactions:

Radioactive iodine uptake studies should not be performed for at least a week following the use of Indocyanine Green.

Carcinogenesis, Mutagenesis, Impairment or Fertility:

No studies have been performed to evaluate the carcinogenicity, mutagenicity, or impairment of feritility

Pregnancy: Teratogenic Effects: Pregnancy Category C:

Animal Reproduction studies have not been conducted with Indocyanine Green. It is also not known whether Indocyanine Green can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Indocyanine Green should be given to a pregnant woman only if clearly indicated.

Nursing Mothers:

lt is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Indocyanine Green is administered to a nursing woman.

Pediatric Use:

Safety and effectiveness in pediatric patients have been established.

Side Effects:

Anaphylactic or urticarial reactions have been reported in patients with or without history of allergy to iodides. If such reactions occur, treatment with the appropriate agents (e.g., epinephrine, antihistamines, and corticosteroids) should be administered.

Overdosage:

There are no data available describing the signs, symptoms, or laboratory findings accompanying overdosage. The LD₅₀ after I.V. administration ranges between 60 and 80 mg/kg in mice, 50 and 70 mg/kg in rats and 50 and 80 mg/kg in rabbits.

Dosage and Administration:

Indicator-Dilution Studies:

Indocyanine Green permits recording of the indicator-dilution curves for both diagnostic and research purposes independently of fluctuations in oxygen saturation. In the performance of dye dilution curves, a known amount of dye is usually 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 systematic arterial sampling site.

Under sterile conditions, the Indocyanine Green for Injection USP powder should be dissolved with Sterile Water for Injection, USP, and the solution used within 6 hours after it is prepared. If a precipitate is present, discard the solution. The amount of solvent to be used can be calculated from the dosage form which follows. It is recommended that the syringe used for injection of the dye be rinsed with this diluent. Saline is used in all other parts of the catheterization procedure.

This matter of rinsing the dye syringe with distilled water may not be critical, since it is known that an amount of sodium chloride sufficient to make an isotonic solution may be added to dye that has first been dissolved in distilled water. This procedure has been used for constant-rate injection techniques without precipitation of the dye.

The usual doses of Indocyanine Green which have been used for dilution curves are as follows:

•   - Adults-5 mg
•   - Children-2.5 mg
•   - Infants-1.25 mg

These doses of the dye are usually injected in a 1-mL volume. An average of five dilution curves is required in the performance of a diagnostic cardiac catheterization. The total dose of dye injected should be kept below 2 mg/kg.

Calibrating Dye Curves:

To quantitate the dilution curves, standard dilutions of Indocyanine Green in whole blood are made as follows: It is strongly recommended that the same dye that was used for the injections be used in the preparation of these standard dilutions. The most concentrated dye solution is made by accurately diluting 1 mL of the 5-mg/mL dye with 7 mL of distilled water. This concentration is then successively halved by diluting 4 mL of the previous concentration with 4 mL of distilled water. (If a 2.5 mg/mL concentration was used for the dilution curves, 1 mL of the 2.5 mg/mL dye is added to 3 mL of distilled water to make the most concentrated "standard' solution. This concentration is then successively halved by diluting 2. mL of the previous concentration with 2 mL of distilled water.) Then 0.2-mL portions (accurately measured from a calibrated syringe) of these dye solutions are added to 5-mL aliquots of the subject's blood, giving final concentrations of the dye in blood beginning with 24 mg/liter, approximately (actual concentration depends on the exact volume of dye added). This concentration is, of course, successively halved in the succeeding aliquots of the subject's blood. These aliquots of blood containing known amounts of dye, as well as a blank sample to which 0.2 mL of saline containing no dye has been added, are then passed through the detecting instrument and a calibration curve is constructed from the deflections recorded.

Hepatic Function Studies:

Due to its absorption spectrum, changing concentrations of Indocyanine Green in the blood can be monitored by ear densitometry or by obtaining blood specimens at timed intervals. The technique for both methods is as follows. The patient should be studied in a fasting, basal state. The patient should be weighed and the dosage calculated on the basis of 0.5 mg/kg of body weight.

Under sterile conditions, the Indocyanine Green for Injection USP powder should be dissolved with Sterile Water for Injection, USP. Exactly 5 mL of Sterile Water for Injection, USP, should be added to the 25-mg vial, giving 5 mg of dye per mL of solution.

Inject the correct amount of dye into the lumen of an arm vein as rapidly as possible, without allowing the dye to escape outside the vein, (If the photometric method is used, prior to injecting Indocyanine Green, withdraw 6 mL of venous blood from the patient's arm for serum blank and standard curve construction, and through the same needle, inject the correct amount of dye.)

Ear Densitometry:

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 which has a compensatory photo-electric cell to correct for changes in blood volume and hematocrit, and a detection photocell which 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 provide a reliable index of plasma removal kinetics after single injections or continuous infusions of Indocyanine Green. This technique was employed in newborn infants, healthy adults and in children and adults with liver disease. The normal subject has a removal rate of 18-24% per minute. Due to the absence of extra-hepatic removal, Indocyanine Green was found to be ideally suited for serial study of severe chronic liver disease and to provide a stable measurement of hepatic blood flow. In larger doses, Indocyanine Green has proven to be particularly valuable in detecting drug-induced alterations of hepatic function and in the detection of mild liver injury.

Using the ear densitometer, a dosage of 0.5 mg/kg in normal subjects gives the following clearance pattern.