ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Hypersensitivity Reactions: Hypersensitivity reactions occurring approximately 2% of patients and include life-threatening anaphylactic reactions with respiratory distress, shock, angioedema, urticaria, pruritus. death has been reported following I.V. administration of similar compound (6). To report SUSPECTED ADVERSE REACTIONS, contact AuroMedics Pharma LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Postmarketing Experience. Hypersensitivity Reactions: Case series report an overall incidence of hypersensitivity reactions in approximately 2% of patients. Life-threatening anaphylactic reactions have occurred. Manifestations include respiratory distress, shock, angioedema, urticaria, pruritus. death has been reported following administration of similar compound employed to estimate the depth of severe burn. Reactions are more likely to occur in patients with personal or family history of bronchial asthma, significant allergies, drug reactions or previous reactions to triphenylmethane dyes [see Warnings and Precautions (5)]. Laboratory Tests: Isosulfan blue 1% interferes with measurements of oxygen saturation by pulse oximetry and of methemoglobin by gas analyzer [see Warnings and Precautions (5)]. Skin: transient or long-term (tattooing) blue coloration.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Teratogenic Effects. Pregnancy Category C. Animal reproduction studies have not been conducted with isosulfan blue 1%. It is not known whether isosulfan blue 1% can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Isosulfan blue 1% should be given to pregnant woman only if clearly needed.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been performed to evaluate the carcinogenic potential of isosulfan blue 1%. Reproduction studies in animals have not been conducted and, therefore, it is unknown if problem concerning mutagenesis or impairment of fertility in either males or females exists.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.2 Pharmacodynamics. Following subcutaneous administration, isosulfan blue 1% binds to serum proteins and is picked up by the lymphatic vessels. Thus, the lymphatic vessels are delineated by the blue dye.. 12.3 Pharmacokinetics. Up to 10% of the subcutaneously administered dose of isosulfan blue 1% is excreted unchanged in the urine in 24 hours in human.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Isosulfan blue injection 1% is contraindicated in those individuals with known hypersensitivity to triphenylmethane or related compounds.. Hypersensitivity to triphenylmethane or related compounds (4).

DESCRIPTION SECTION.

11 DESCRIPTION. The chemical name of isosulfan blue is N-[4-[[4-(diethylamino)phenyl] (2,5-disulfophenyl) methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium hydroxide, inner salt, sodium salt. Isosulfan blue is greenish blue color hygroscopic powder. Its structural formula is: Isosulfan blue injection 1% is sterile, non-pyrogenic, aqueous dark blue color solution for subcutaneous administration. Phosphate buffer in water for injection is added in sufficient quantity to yield final pH of 6.8 to 7.4. Each mL of solution contains 10 mg isosulfan blue, 6.6 mg sodium monohydrogen phosphate and 2.7 mg potassium dihydrogen phosphate. The solution contains no preservative. Isosulfan blue injection 1% is contrast agent for the delineation of lymphatic vessels.. Isosulfan Blue Chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Isosulfan blue injection 1% is to be administered subcutaneously, one-half (1/2) mL into three (3) interdigital spaces of each extremity per study. maximum dose of mL (30 mg) isosulfan blue is, therefore, injected (2.1). 2.1 Subcutaneous administration. Isosulfan blue injection 1% is to be administered subcutaneously, one-half (1/2) mL into three (3) interdigital spaces of each extremity per study. maximum dose of mL (30 mg) isosulfan blue is, therefore, injected.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 1% aqueous solution (isosulfan blue). 1% aqueous solution (isosulfan blue).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. No drug interactions have been identified with isosulfan blue 1%.. No drug interactions have been identified for isosulfan blue 1% (7).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Isosulfan blue injection 1% is sterile, non-pyrogenic, aqueous dark blue color solution and is supplied as follows: Isosulfan blue injection 1% 50 mg per mL (10 mg mL): mL Single Dose Vialsin Carton of NDC 55150-240-06 Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature]. Avoid excessive heat. Discard Unused Portion. The vial stoppers are not made with natural rubber latex.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Isosulfan blue injection 1% upon subcutaneous administration, delineates the lymphatic vessels draining the region of injection. It is an adjunct to lymphography in: primary and secondary lymphedema of the extremities; chyluria, chylous ascites or chylothorax; lymph node involvement by primary or secondary neoplasm; lymph node response to therapeutic modalities (1.1). 1.1 Lymphatic Vessel Delineation. Isosulfan blue injection 1% upon subcutaneous administration, delineates lymphatic vessels draining the region of injection. It is an adjunct to lymphography in: primary and secondary lymphedema of the extremities; chyluria, chylous ascites or chylothorax; lymph node involvement by primary or secondary neoplasm; and lymph node response to therapeutic modalities.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Inform patients that urine color may be blue for 24 hours following administration of isosulfan blue injection 1%. Manufactured by: Aurobindo Pharma Limited IDA, Pashamylaram 502307 India Distributed by: AuroMedics Pharma LLC Wheeling Road Dayton, NJ 08810 NOVAPLUS is registered trademark of Vizient Inc.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been performed to evaluate the carcinogenic potential of isosulfan blue 1%. Reproduction studies in animals have not been conducted and, therefore, it is unknown if problem concerning mutagenesis or impairment of fertility in either males or females exists.. 13.2 Teratogenic Effects. Pregnancy Category C. Animal reproduction studies have not been conducted with isosulfan blue 1%. It is not known whether isosulfan blue 1% can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Isosulfan blue 1% should be given to pregnant woman only if clearly needed.

NURSING MOTHERS SECTION.

8.3 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 isosulfan blue 1% is administered to nursing mother.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Do not exceed indicated recommended dosage as overdosage levels have not been identified for isosulfan blue 1%.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL 1% [50 mg per mL (10 mg mL)] Container Label. NDC 55150-240-06 Rx only Isosulfan Blue Injection 1% Sterile mL Non-Pyrogenic Single Dose Vial 50 mg per mL (10 mg mL) For Subcutaneous Use Only For Lymphography NOVAPLUS(R) PACKAGE LABEL-PRINCIPAL DISPLAY PANEL 1% [50 mg per mL (10 mg mL)] Container Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of isosulfan blue 1% in children have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Following subcutaneous administration, isosulfan blue 1% binds to serum proteins and is picked up by the lymphatic vessels. Thus, the lymphatic vessels are delineated by the blue dye.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Up to 10% of the subcutaneously administered dose of isosulfan blue 1% is excreted unchanged in the urine in 24 hours in human.

SPL UNCLASSIFIED SECTION.

1.1 Lymphatic Vessel Delineation. Isosulfan blue injection 1% upon subcutaneous administration, delineates lymphatic vessels draining the region of injection. It is an adjunct to lymphography in: primary and secondary lymphedema of the extremities; chyluria, chylous ascites or chylothorax; lymph node involvement by primary or secondary neoplasm; and lymph node response to therapeutic modalities.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Caution should be exercised when isosulfan blue 1% is administered to nursing mothers (8.3). Safety and effectiveness of isosulfan blue 1% in children has not been established (8.4). Caution should be exercised when isosulfan blue 1% is administered to nursing mothers (8.3). Safety and effectiveness of isosulfan blue 1% in children has not been established (8.4). 8.3 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 isosulfan blue 1% is administered to nursing mother.. 8.4 Pediatric Use. Safety and effectiveness of isosulfan blue 1% in children have not been established.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Life-threatening anaphylactic reactions have occurred after isosulfan blue 1% administration. Monitor patients closely for at least 60 minutes after administration of isosulfan blue 1% (5.1). The admixture of isosulfan blue 1% with local anesthetics results in an immediate precipitation of to 9% drug complex. Use separate syringe for anesthetics (5.2). Isosulfan blue 1% interferes with measurements in peripheral blood pulse oximetry. Arterial blood gas analysis may be needed (5.3). Life-threatening anaphylactic reactions have occurred after isosulfan blue 1% administration. Monitor patients closely for at least 60 minutes after administration of isosulfan blue 1% (5.1). The admixture of isosulfan blue 1% with local anesthetics results in an immediate precipitation of to 9% drug complex. Use separate syringe for anesthetics (5.2). Isosulfan blue 1% interferes with measurements in peripheral blood pulse oximetry. Arterial blood gas analysis may be needed (5.3). 5.1 Hypersensitivity Reactions. Life-threatening anaphylactic reactions (respiratory distress, shock, angioedema) have occurred after isosulfan blue 1% administration. Reactions are more likely to occur in patients with history of bronchial asthma, allergies, drug reactions or previous reactions to triphenylmethane dyes. Monitor patients closely for at least 60 minutes after administration of isosulfan blue 1%. Trained personnel should be available to administer emergency care including resuscitation.. 5.2 Precipitation of Isosulfan Blue 1% by Lidocaine. The admixture of isosulfan blue 1% (with local anesthetics (i.e. lidocaine)) in the same syringe results in an immediate precipitation of to 9% drug complex. Use separate syringe to administer local anesthetic.. 5.3 Interference with Oxygen Saturation and Methemoglobin Measurements. Isosulfan blue 1% interferes with measurements of oxygen saturation in peripheral blood by pulse oximetry and can cause falsely low readings. The interference effect is maximal at 30 minutes and minimal generally by four hours after administration. Arterial blood gas analysis may be needed to verify decreased arterial partial pressure of oxygen. Isosulfan blue 1% may also cause falsely elevated readings of methemoglobin by arterial blood gas analyzer. Therefore, co-oximetry may be needed to verify methemoglobin level.