Iso-sulfan Blue

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.

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. A maximum dose of 3 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. A maximum dose of 3 mL (30 mg) isosulfan blue is, therefore, injected. Discard unused portion. 2.2 Instructions for Preparation and Administration of the 1 mL or 3 mL Pre-filled Syringe To be prepared and administered by a healthcare provider only. For subcutaneous injection only. Do not inject by any other route. As a precaution, always wear gloves. Inspect isosulfan blue injection for particulate matter and discoloration prior to administration. Figure A shows an annotated drawing of the 3 mL syringe. Appearance may differ for the 1 mL syringe. Figure A 1) Grip the syringe at the luer lock collar and remove the tip cap from the prefilled syringe by twisting the cap anticlockwise and pulling upwards ( See Figure B ) Figure B 2) Hold the luer lock collar and attach the needle to the syringe with a firm clockwise twisting motion ( See Figure C ). Figure C 3) Remove the needle sheath with a straight pull. Do not twist the sheath as the needle may become loosened from the syringe ( See Figure D ) Figure D 4) Hold the syringe with the attached needle in an upright position. Prime the syringe by tapping the syringe barrel and moving the plunger stopper carefully forward to the first graduation mark (this may expel air and excess solution) ( See Figure E ) Figure E 5) Administer one-half (1/2) mL subcutaneously, into three (3) interdigital spaces of each extremity per study. 6) Dispose of the used supplies in an approved sharps container in accordance with local hospital procedures. Figure A Figure B Figure C Figure D Figure E

WARNINGS AND PRECAUTIONS • Life threatening anaphylactic reactions have occurred after isosulfan blue injection 1% administration. Monitor patients closely for at least 60 minutes after administration of isosulfan blue injection 1% ( 5.1 ). • The admixture of isosulfan blue injection 1% with local anesthetics results in an immediate precipitation of 4% to 9% drug complex. Use a separate syringe for anesthetics ( 5.2 ). • Isosulfan blue injection 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 injection 1% administration. Reactions are more likely to occur in patients with a history of bronchial asthma, allergies, drug reactions or previous reactions to tri-phenylmethane dyes. Monitor patients closely for at least 60 minutes after administration of isosulfan blue injection 1%. Trained personnel should be available to administer emergency care including resuscitation. 5.2 Precipitation of Isosulfan Blue Injection 1% by Lidocaine The admixture of isosulfan blue injection 1% (with local anesthetics (i.e. lidocaine)) in the same syringe results in an immediate precipitation of 4% to 9% drug complex. Use a separate syringe to administer a local anesthetic. 5.3 Interference with Oxygen Saturation and Methemoglobin Measurements Isosulfan blue injection 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 4 hours after administration. Arterial blood gas analysis may be needed to verify decreased arterial partial pressure of oxygen. Isosulfan blue injection 1% may also cause falsely elevated readings of methemoglobin by arterial blood gas analyzer. Therefore, cooximetry may be needed to verify methemoglobin level.

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 ).

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

ADVERSE REACTIONS Hypersensitivity Reactions: Hypersensitivity reactions occurring in approximately 2% of patients and include life-threatening anaphylactic reactions with respiratory distress, shock, angioedema, urticaria, pruritus. A death has been reported following IV administration of a similar compound ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 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. A death has been reported following administration of a similar compound employed to estimate the depth of a severe burn. Reactions are more likely to occur in patients with a 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 injection 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.

CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Following subcutaneous administration, isosulfan blue injection 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 injection 1% is excreted unchanged in the urine in 24 hours in humans.