SPY AGENT GREEN LYMPHATICS KIT FOR ADVANCED IMAGING MODALITY (AIM) AND PINPOINT

1 Dosing Considerations  The total dose of SPY AGENT™ Green (indocyanine green for injection, USP) injected must be kept to below 2 mg/kg of patient body weight.  Dosing is determined at the discretion of the imaging surgeon.  SPY AGENT™ Green can be reconstituted and prepared for injection either at the beginning of, or during the surgery, depending on the preference of the surgical team.

 Do not use any SPY AGENT™ Green that has been reconstituted for more than 6 hours.  Discard any unused reconstituted SPY AGENT™ Green after each surgery is completed or 6 hours have lapsed since reconstitution. 5 mg/mL solution). 5 mg/mL solution).

Additional doses of SPY AGENT™ Green (2-3 doses) may be administered at the discretion of the imaging surgeon, in order to obtain additional imaging sequences during the procedure. A 10 mL bolus of normal saline should immediately follow the injection of SPY AGENT™ Green.

5 mg/mL solution). Additional doses of SPY AGENT™ Green (2-3 doses) may be administered at the discretion of the imaging surgeon, in order to obtain additional imaging sequences during the procedure. 25 mg/mL solution). Health Canada has not authorized an indication for pediatric use.

5 mg/mL SPY AGENT™ Green solution should be drawn up into appropriate syringes. Page 6 of 20 SPY AGENT™ Green administration is to be performed via a central or peripheral venous line using a three-way stopcock attached to an injection port on the infusion line.

The prepared syringe of SPY AGENT™ Green and a prepared syringe containing 10 mL of saline solution are attached to the stopcock. The prepared SPY AGENT™ Green solution should be injected into the line as a tight bolus. The access on the stopcock should be immediately switched to the syringe containing sterile saline to briskly flush the SPY AGENT™ Green bolus through the line with 10 mL of sterile saline.

Timing of SPY AGENT™ Green Fluorescence Response A fluorescence response should be visible in blood vessels within the field of view of the SPY® Elite or PINPOINT® imaging device within 5 to 15 seconds after injection. 5 mg/mL) should be injected intravenously approximately 45 minutes prior to surgery to allow the indocyanine green to collect into the biliary anatomy.

Timing of SPY AGENT™ Green Fluorescence Response A fluorescence response should be visible in blood vessels within the field of view of the PINPOINT® imaging device approximately 45 minutes after injection. 25 mg/mL) is injected into the cervix of the patient while the patient is under anesthesia.

25 mg injections (four (4) 1 mL injections) and a total dose of 5 mg. Timing of SPY AGENT™ Green Fluorescence Response Fluorescent lymphatic vessels and lymph nodes should begin to be visible within the field of view of the PINPOINT® imaging device within 1 minute after injection.

4 Reconstitution Parenteral Products Under sterile conditions, SPY AGENT™ Green should be reconstituted with the Sterile Water for Injection, USP provided with the SPY AGENT™ Green, as shown in Tables 1 and 2 below. 25 mg/mL  Mix the contents of the SPY AGENT™ Green vial thoroughly and inspect the reconstituted vial for precipitation.

 If precipitation is noted, continue to gently shake the vial until all SPY AGENT™ Green is dissolved in solution.  If precipitation persists after reconstitution, do not use the mixture. Discard the reconstituted vial and prepare a new vial of SPY AGENT™ Green solution.

 The reconstituted solution should be stored at 20ºC to 25ºC and used within 6 hours after it is prepared (Refer to Section 10 Storage, Stability and Disposal).  Any prepared solution remaining after 6 hours must be discarded. 3, Administration, above.

1 Adverse Reaction Overview Anaphylactic or urticarial reactions have been reported in patients with or without history of allergy to iodides. , epinephrine, antihistamines, and corticosteroids. 2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. In an open label, within subject comparison clinical trial, 176 subjects with uterine or cervical malignancies received SPY AGENT™ Green (indocyanine green for injection, USP).

No subjects experienced adverse drug reactions or serious adverse reactions. 3 Post-Market Adverse Reactions Anaphylactic or urticarial reactions have been reported in the literature in patients with or without history of allergy to iodides.

, epinephrine, antihistamines, and corticosteroids. 5 mg has resulted in one report of an anaphylactic reaction to a single intravenous dose of 5 mg indocyanine green.

General Anaphylactic deaths have been reported following administration of SPY AGENT™ Green (indocyanine green for injection, USP) during cardiac catheterization. SPY AGENT™ Green is unstable in aqueous solution and must be used within 6 hours.

However, the dye is stable in plasma and whole blood. Sterile techniques should be used in handling the SPY AGENT™ Green solution. Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Intravenous, interstitial Lyophilized powder for injection / 25 mg Sodium iodide Page 9 of 20 If precipitation persists after reconstitution, do not use the mixture.

Discard the reconstituted vial and prepare a new vial of SPY AGENT™ Green solution. Carcinogenesis and Mutagenesis No studies have been performed to evaluate the carcinogenicity or mutagenicity of SPY AGENT™ Green or indocyanine green.

1 Pregnant Women Animal reproduction studies have not been conducted with SPY AGENT™ Green or 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.

SPY AGENT Green should be given to a pregnant woman only if clearly indicated. There is no experience with exposure to SPY AGENT™ Green in pregnancy during clinical trials. 2 Breast-feeding It is unknown if the drug is excreted in human milk.

Because many drugs are excreted in human milk precaution should be exercised when SPY AGENT™ Green is administered to a nursing woman. 3 Pediatrics The safety and efficacy of SPY AGENT™ Green in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

4 Geriatrics No overall differences in safety or effectiveness have been observed between elderly and younger patients. Of the 176 patients enrolled in the clinical study evaluating SPY AGENT™ Green in identification of lymph nodes during lymphatic mapping in women with uterine and cervical malignancies, 106 (60%) were aged 60 or older.

Review of the clinical data, including evaluation of the frequency of adverse reactions, has not identified differences in safety or efficacy between elderly patients (60-88 years of age) and younger patients (30-59 years of age). Page 10 of 20

Indocyanine green is contraindicated in patients who are hypersensitive to this drug or any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.

 SPY AGENT™ Green (indocyanine green for injection, USP) contains sodium iodide and should not be used in patients who have a history of allergy to iodides because of the risk of anaphylaxis.  SPY AGENT™ Green and the Novadaq SPY® Elite and PINPOINT® Fluorescence Imaging Systems should not be used for procedures with patients who are known to be sensitive to iodides or iodinated imaging contrast agents.

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