PREGNANCY SECTION.

Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal Reproduction studies have not been conducted with IC-GREEN(TM). It is also not known whether IC-GREEN(TM) can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. IC-GREEN(TM) should be given to pregnant woman only if clearly indicated.

SPL UNCLASSIFIED SECTION.

(indocyanine green for injection, USP)SterileRx only.

STORAGE AND HANDLING SECTION.

STORAGE:. Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Rx onlyManufactured by: Akorn, Inc. Lake Forest, IL 60045Manufactured for: Novadaq Technologies Inc. Mississauga, ON Canada L4W 4L5NVIG00NRev. 07/09.

WARNINGS SECTION.

WARNINGS. Anaphylactic deaths have been reported following IC-GREEN(TM) administration during cardiac catheterization.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been performed to evaluate the carcinogenicity, mutagenicity, or impairment of fertility.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Following intravenous injection, IC-GREEN(TM) is rapidly bound to plasma protein, of which albumin is the principle carrier (95%). IC-GREEN(TM) 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. IC-GREEN(TM) 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 IC-GREEN(TM) 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.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. IC-GREEN(TM) contains sodium iodide and should be used with caution in patients who have history of allergy to iodides.

DESCRIPTION SECTION.

DESCRIPTION. IC-GREEN(TM) is sterile, lyophilized green powder containing 25 mg of indocyanine green with no more than 5% sodium iodide. It is packaged with Aqueous Solvent consisting of Sterile Water for Injection used to dissolve the indocyanine green. IC GREEN(TM) is to be administered intravenously.Indocyanine green is water soluble, tricarbocyanine dye with peak spectral absorption at 800 nm. The chemical name for Indocyanine Green is H Benz[e]indolium, 2-[7-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5- heptatrienyl]-1,1-dimethyl-3-(4-sulfobutyl)-,hydroxide, inner salt, sodium salt. IC-GREEN(TM) has pH of approximately 6.5 when reconstituted. Each vial of IC-GREEN(TM) contains 25 mg of indocyanine green as sterile lyophilized powder.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. INDICATOR-DILUTION STUDIES: IC-GREEN(TM) permits recording of the indicator-dilution curves for both diagnostic and research purpose independently of fluctuations in oxygen saturation. In the performance of dye dilution curves, known amount of dye is usually injected as single bolus as rapidly as possible via cardiac catheter into selected sites in the vascular system. recording instrument (oximeter or densitometer) is attached to needle or catheter for sampling of the dye-blood mixture from systemic arterial sampling site.Under sterile conditions, the IC-GREEN(TM) powder should be dissolved with the Aqueous Solvent provided for this product, and the solution used within hours after it is prepared. If 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. Isotonic saline should be used to flush the residual dye from the cardiac catheter into the circulation so as to avoid hemolysis. With the exception of the rinsing of the dye injection syringe, 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 IC-GREEN(TM) which have been used for dilution curves are as follows: Adults 5.0 mg Children 2.5 mg Infants 1.25 mgThese doses of the dye are usually injected in mL volume. An average of five dilution curves are required in the performance of diagnostic cardiac catheterization. The total dose of dye injected should be kept below mg/kg.. Adults 5.0 mg. Children 2.5 mg. Infants 1.25 mg. Calibrating Dye Curves: To quantitate the dilution curves, standard dilutions of IC GREEN(TM) 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 mL of the mg/mL dye with mL of distilled water. This concentration is then successively halved by diluting mL of the previous concentration with mL of distilled water. (If 2.5 mg/mL concentration was used for the dilution curves, mL of the 2.5 mg/mL dye is added to mL of distilled water to make the most concentrated standard solution. This concentration is then successively halved by diluting mL of the previous concentration with mL of distilled water.) Then 0.2 mL portions (accurately measured from calibrated syringe) of these dye solutions are added to mL aliquots of the subjects blood, giving final concentrations of the dye in blood beginning with 24.0 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 subjects blood. These aliquots of blood containing known amounts of dye, as well as blank sample of which 0.2 mL of saline containing no dye has been added, are then passed through the detecting instrument and calibration curve is constructed from the deflections recorded.. HEPATIC FUNCTION STUDIES: Due to its absorption spectrum, changing concentrations of IC-GREEN(TM) (indocyanine green for injection) 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 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 IC-GREEN(TM) powder should be dissolved with the Aqueous Solvent provided. Exactly mL of aqueous solvent should be added to the 25 mg vial giving 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 IC GREEN(TM), withdraw mL of venous blood from the patients 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 IC-GREEN(TM) without the necessity of withdrawal and spectrophotometric analysis of blood samples for calibration. An ear densitometer which has compensatory photo-electric cell to correct for changes in blood volume and hematocrit, and detection photocell which registers levels has been described. This device permits simultaneous measurement of cardiac output, blood volume and hepatic clearance of IC-GREEN(TM) and was found to provide reliable index of plasma removal kinetics after single injections or continuous intrusions of IC-GREEN(TM). This technique was employed in newborn infants, healthy adults and in children and adults with liver disease. The normal subject has removal rate of 18-24% per minute. Due to the absence of extra-hepatic removal, IC-GREEN(TM) was found to be ideally suited for serial study of severe chronic liver disease and to provide stable measurement of hepatic blood flow. In larger doses, IC-GREEN(TM) 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, dosage of 0.5 mg/kg in normal subjects gives the following clearance pattern.Dichromatic earpiece densitometer supplied by The Waters Company, Rochester, Minnesota.. Figure. Figure.

DRUG & OR LABORATORY TEST INTERACTIONS SECTION.

Drug/ Laboratory Test Interactions: Radioactive iodine uptake studies should not be performed for at least week following the use of IC-GREEN(TM).

DRUG INTERACTIONS SECTION.

Drug Interactions: Heparin preparations containing sodium bisulfite reduce the absorption peak of IC-GREEN(TM) in blood and, therefore, should not be used as an anticoagulant for the collection of samples for analysis.

GENERAL PRECAUTIONS SECTION.

General: IC-GREEN(TM) Powder and Solution: IC-GREEN(TM) is unstable in aqueous solution and must be used within 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.IC-GREEN(TM) (indocyanine green for injection) powder may cling to the vial or lump together because it is freeze-dried in the vials.

GERIATRIC USE SECTION.

Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients.

HOW SUPPLIED SECTION.

HOW SUPPLIED:. IC-GREEN(TM) is supplied in kit (NDC 66259-701-02) containing six 25 mgIC-GREEN(TM) vials and six 10 mL Aqueous Solvent ampules: NDC 66259-701-25 IC-GREEN(TM) vial. 25 mg fill in 20 mL vial. NDC 17478-701-10 Aqueous Solvent ampule. 10 mL fill in 10 mL ampule.. NDC 66259-701-25 IC-GREEN(TM) vial. 25 mg fill in 20 mL vial.. NDC 17478-701-10 Aqueous Solvent ampule. 10 mL fill in 10 mL ampule.. STORAGE:. Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Rx onlyManufactured by: Akorn, Inc. Lake Forest, IL 60045Manufactured for: Novadaq Technologies Inc. Mississauga, ON Canada L4W 4L5NVIG00NRev. 07/09.

INDICATIONS & USAGE SECTION.

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

NURSING MOTHERS SECTION.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when IC-GREEN(TM) is administered to nursing woman.

OVERDOSAGE SECTION.

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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

NDC 66259-701-2525 mgIC-GREEN(R)(indocyanine greenFor injection, USP)After reconstitution, use within hours.Rx only SterileManufactured by:Akorn, Inc.Manufactured for: Novadaq Technologies, Inc.. Principal Display Panel.

PEDIATRIC USE SECTION.

Pediatric Use: Safety and effectiveness in pediatric patients have been established.

PRECAUTIONS SECTION.

PRECAUTIONS. General: IC-GREEN(TM) Powder and Solution: IC-GREEN(TM) is unstable in aqueous solution and must be used within 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.IC-GREEN(TM) (indocyanine green for injection) 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 IC-GREEN(TM) 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 week following the use of IC-GREEN(TM).. Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been performed to evaluate the carcinogenicity, mutagenicity, or impairment of fertility.. Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal Reproduction studies have not been conducted with IC-GREEN(TM). It is also not known whether IC-GREEN(TM) can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. IC-GREEN(TM) should be given to pregnant woman only if clearly indicated.. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when IC-GREEN(TM) is administered to nursing woman.. Pediatric Use: Safety and effectiveness in pediatric patients have been established.. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients.