Manufacturer: US Sales Office: Sirtex Medical Limited Sirtex Medical Inc Level 33, 101 Miller Street, 300 Unicorn Park Drive, North Sydney NSW 2060, Woburn MA 01801, USA Tel: +61 2 9964 8400 Tel: 1 888 474 7839 www.sirtex.com

4 Warnings • Some patients may experience gastric problems following treatment but H-2 blocking agents may 4.1 Non-Target Delivery of SIR-Spheres be used the day before implantation of SIR- microspheres Spheres microspheres and continued as needed to reduce gastric complications. Inadvertent delivery of SIR-Spheres microspheres to extra-hepatic structures such as the esophagus, • Many patients may experience abdominal pain SIR-Spheres® Y-90 resin stomach, duodenum, gallbladder or pancreas may immediately after administration of SIR-Spheres result in radiation injury to these structures. microspheres and pain relief may be required. microspheres Meticulous angiographic technique must be • SIR-Spheres microspheres demonstrated a mild (Yttrium-90 microspheres) employed to prevent the non-target delivery of SIR- sensitization potential when tested dermally in an Spheres microspheres to any extra-hepatic animal model. structures. 1 Description 4.2 Radioembolization Induced 6 Clinical Trial Results SIR-Spheres microspheres consist of biocompatible microspheres containing yttrium-90 with a size Disease (REILD) In a randomized, controlled clinical trial, a total of 70 patients were studied in two arms, 34 patients with between 20 and 60 microns in diameter. Yttrium-90 Delivery of excessive radiation to the normal liver FUDR chemotherapy (control group), and 36 is a high-energy pure beta-emitting isotope with no parenchyma may result in REILD – see description patients with FUDR plus SIR-Spheres microspheres. primary gamma emission. The maximum energy of in Section 7. The results are shown in the following tables. the beta particles is 2.27 MeV with a mean of

0.93 MeV. The maximum range of emissions in The risk of REILD may also be increased in patients Table 1 – Tumor Response by Volume tissue is 11 mm with a mean of 2.5 mm. The half-life with pre-existing liver disease. Consideration should is 64.1 hours. In therapeutic use, requiring the be given to reducing the prescribed activity of SIR- Response CR PR NC PD Others FUDR only isotope to decay to infinity, 94% of the radiation is Spheres microspheres in the following clinical 1 7 12 9 5 delivered in 11 days. The average number of settings1: (N = 34) 6 particles implanted is 30 – 60 x 10 . SIR-Spheres • Reduced liver functional reserve due to steatosis, FUDR + SIR-Spheres microspheres are a permanent implant. steatohepatitis, hepatitis or 2 16 10 5 3 microspheres (N = 36)* SIR-Spheres microspheres are implanted into a • Elevated baseline bilirubin level hepatic tumor by injection into either the common • Small tumor burden (< 5% liver involvement) *(P = 0.033) hepatic artery or the right or left hepatic artery via the • Small liver volume (< 1.5 L) Tumor response was measured by two consecutive chemotherapy catheter port. The SIR-Spheres • Prior hepatic resection microspheres distribute non-uniformly in the liver, CT scans in a 3 month interval period. primarily due to the unique physiological • Prior liver directed therapy characteristics of the hepatic arterial flow, the tumor • Extensive prior treatment with systemic CR = Complete Response, PR = Partial Response, to normal liver ratio of the tissue vascularity, and the chemotherapy and/or biologic therapies NC = No Change, PD = Progressive Disease, Others size of the tumor. The tumor usually gets higher = No follow-up or unmeasurable density per unit distribution of SIR-Spheres 4.3 Radiation Pneumonitis Table 1 indicates that there is a statistically microspheres than the normal liver. The density of High levels of implanted radiation and/or excessive SIR-Spheres microspheres in the tumor can be as significant improvement of the tumor response rates shunting to the lung may lead to radiation (CR+PR) in the group treated with FUDR plus SIR- high as 5 to 6 times of the normal liver tissue. Once pneumonitis. The lung radiation dose must be limited SIR-Spheres microspheres are implanted into the Spheres microspheres, when compared with the to ≤ 30 Gy. group treated with FUDR only. liver, they are not metabolized or excreted and they stay permanently in the liver. Each device is for single patient use. 5 Precautions Table 2 – Time to First Progressive Disease in the Liver FUDR + • For determining the prescribed activity of SIR- FUDR Only SIR-Spheres 2 Indications for Use Spheres microspheres to administer, the Body microspheres Surface Area (BSA) method is recommended. Number of SIR-Spheres microspheres are indicated for the The Empirical method is not recommended. 34 36 treatment of unresectable metastatic liver tumors Patients For some patients, the Empirical method may Mean Time in 312 Days 510 Days from primary with adjuvant intra- result in excessive activity being prescribed. hepatic artery chemotherapy (IHAC) of FUDR Days +/- SD* +/- 330 +/- 516 For further information on the BSA method, refer Median Time in (Floxuridine). 233 Days 366 Days to Appendix III: Calculation of Individual Dose. Days*

• No studies have been done on the safety and *(P = 0.05) 3 Contraindications effectiveness of this device in pregnant women, nursing mothers or children. SIR-Spheres microspheres are contraindicated in Progressive Disease was defined as more than 25% patients who have: • Due to the radioactivity of this device and the increase of tumor volume, or development of new lesion(s) in the follow up CT scan, when compared • had previous external beam radiation therapy to significant consequences of misplacing the microspheres in situ, this product must be to the pre-treatment CT scan. the liver implanted by doctors with adequate training in the • ascites or are in clinical liver failure handling and implantation technique for this Table 2 indicates that there is a statistically • markedly abnormal synthetic and excretory liver device. significant delay of time to progression of the function tests (LFTs), such as total bilirubin • Sirtex recommends a SPECT scan of the upper disease in the group treated with FUDR plus SIR- > 2.0 mg/dL or albumin < 3.0 g/dL abdomen be performed immediately after Spheres microspheres, when compared with the • > 20% lung shunting of the hepatic artery blood implantation of SIR-Spheres microspheres. The group treated with FUDR only. flow, or > 30 Gy radiation absorbed dose to the SPECT scan will detect the Bremsstrahlung lungs, as estimated by the 99mTc MAA scan radiation from the yttrium-90 to confirm placement 7 Adverse Events • pre assessment angiogram that demonstrates of the microspheres in the liver. When the patient is treated with proper technique, abnormal vascular anatomy that would result in • This product is radioactive. The use of this device without excessive radiation to any organ, the significant reflux of hepatic arterial blood to the is regulated under Title 10 of the Code of Federal common adverse events after receiving the SIR- stomach, pancreas or bowel Regulations Part 35. These regulations must be Spheres microspheres are fever, transient decrease followed when handling this device. • disseminated extra-hepatic malignant disease of hemoglobin, mild to moderate abnormality of liver • been treated with capecitabine within the two • All persons handling, dispensing and implanting function tests (mild increase in SGOT, alkaline previous months, or who will be treated with this device must be familiar with and abide by all phosphatase, bilirubin), abdominal pain, nausea, capecitabine at any time following treatment with Local, State and Federal regulatory requirements vomiting, and diarrhea. SIR-Spheres microspheres governing therapeutic radioactive materials. • portal vein thrombosis Accepted radiation protection techniques should In the Phase III randomized controlled clinical trial be used to protect staff when handling both the with 70 patients, there was a minimal increase of isotope and the patient. Grade 1 and 2 events, mostly transient abnormal

® SIR-Spheres is a Registered Trademark of Sirtex SIR-Spheres Pty Ltd 1 Gil-Alzugaray et al. Hepatology, Vol 57, No. 3, 2013.

SSL-US-13 Date of Issue: February 2017 (CR2189) Page 1 of 3 LFTs and nausea and vomiting in the patients who • Tumor invasion of the hepatic confluence where 10 How Supplied received SIR-Spheres microspheres. There was no the three hepatic veins enter the IVC such that difference in the number of patients who developed none of the hepatic veins could be preserved if the SIR-Spheres microspheres are provided in a vial Grade 3 and 4 adverse events between the two metastases were resected. with water for injection. Each vial contains 3 GBq of Y90 ± 10% (at the time of calibration) in a total of 5 cc groups. No patient died due to the adverse events • Tumor invasion of the porta hepatis such that directly related to SIR-Spheres microspheres. water for injection. Each vial contains 40 – 80 million neither origin of the right or left portal veins could microspheres. The vial is shipped within a 6.4 mm be preserved if resection were undertaken. Table 3 – Adverse Events minimum thickness lead pot. The package consists • Widespread metastases such that resection would of a crimp-sealed SIR-Spheres microspheres glass Grade 1 and 2 Grade 3 and 4 require removal of more liver than is necessary to vial within a lead pot, and a package insert within Events FUDR + SIR- FUDR + SIR- maintain life. Type-A packing bucket. FUDR Spheres FUDR Spheres microspheres microspheres Resectability may be evaluated via imaging with a The vial and its contents should be stored inside its Hemoglobin 4 5 1 0 triple phase contrast angio-portal CAT scan or MRI. transportation container at room temperature Bilirubin 7 2 0 1 Patient Tests Before Treatment with SIR-Spheres (15-25 °C, 59-77 °F). AST (SGOT) 110 109 14 7 microspheres Alk. Phos. 90 188 5 14 The following tests are recommended before The calibration date (for radioactive contents) and Nausea/ the expiration information are quoted on the vial 5 13 2 1 treatment: Vomiting • A hepatic angiogram should be performed to label. The useful life of the SIR-Spheres Diarrhea 6 3 1 0 establish arterial anatomy of the liver. microspheres ends 24 hours after the time of TOTAL 222 320 23 23 calibration. The particle size has been validated • A nuclear medicine break through scan before shipment, as 32.5 μ ± 2.5 μ. Less than 10% (Intrahepatic Technetium MAA Scan) to determine The data are from a clinical trial with 34 patients on will be < 30 μ and > 35 μ. the percent lung shunting. If a port has been chemotherapy only, and 36 patients on inserted, this test can be performed through the chemotherapy plus SIR-Spheres microspheres. port. 11 Appendices

Potential Serious Adverse Events Due to High • Serologic tests of liver function should be I. General Information Radiation performed to determine the extent of liver function II. Dose Preparation Procedure damage. III. Calculation of Individual Dose Acute pancreatitis: causes immediate severe IV. Radiation Dosimetry abdominal pain. Verify by SPECT imaging of the Appropriate imaging studies are recommended to V. Technique for Performing the Intra hepatic abdomen (Yttrium-90 Bremsstrahlung image) and determine the extent of disease. These may include Technetium MAA Scan test for serum amylase. chest x-ray, CT scan of chest and abdomen, abdominal ultrasound and a bone scan. VI. Correction for Decay Radiation Pneumonitis: causes excessive non- productive cough. Verify by X-ray evidence of pneumonitis. 9 Radiation Safety Appendix I: General Information Restricted to Accredited Facilities Acute Gastritis: causes abdominal pain. Verify by The preparation and implant procedure must be standard methods to diagnosis gastric ulceration. regarded as being a potentially serious radiation SIR-Spheres microspheres may only be dispatched to a duly licensed or accredited facility capable of Acute cholecystitis: causes significant upper hazard to the staff and a serious contamination handling therapeutic medical isotopes. hazard. Regulatory and local radiation usage abdominal pain and may require cholecystectomy for guidelines should be followed concerning resolution. Verify by appropriate imaging studies. Restricted to Trained and Licensed Physicians implantation and post-implantation care. Radioembolization induced liver disease This device is licensed by the Agency for distribution

(REILD): REILD is a rare complication following to persons licensed pursuant to 105 CMR 120.589 or The following are sample measured SIRT. REILD is characterized by a well-defined under equivalent licenses of the Nuclear Regulatory thermoluminescent dosimetry (TLD) exposures to constellation of temporal, clinical, biochemical and Commission, an Agreement State, or a licensing personnel. histopathologic findings. It typically manifests State. Only doctors qualified and licensed under Title approximately 4 to 8 weeks post-SIRT and is Table 4 – Exposure Dose per Patient for Implant 10 Code of Federal Regulations Part 35 (Nuclear characterized clinically by jaundice and ascites in the Preparation (Technologist) Regulatory Commission) and trained under the absence of tumor progression or bile duct Sirtex TEC training program may order and implant Lens of the obstruction. Trunk Hands Eye SIR-Spheres microspheres. mSv (mrem) mSv (mrem) The typical biochemical picture of REILD is an mSv (mrem) elevated bilirubin (> 3 mg/dL) in almost all cases, Deep Dose 0.027 (2.7) 0.026 (2.6) 0.35 (35) Appendix II: Dose Preparation Procedure elevated alkaline phosphatase (ALP) and gamma- (10 mm) • Unpack SIR-Spheres microspheres, leaving glutamyl transpeptidase (GGT) in most cases, Shallow Dose 0.003 (0.3) 0.004 (0.4) shipping vial in lead pot. accompanied by virtually no change in the (0.07mm) • Place on the bench top in a lead or acrylic transaminases (AST and ALT). In the event that a Assuming handling of a 3 GBq device and dose preparation liver biopsy is performed, the typical histological time of 30 minutes. TLDs were worn near the pelvis, on the shielded box if available. appearance is of sinusoidal obstruction that may shirt’s lapel, and on the working finger. • Remove the center of aluminum seal from sterile resemble veno-occlusive disease. V-vial with forceps, and clean the septum with an REILD may occur in both non-cirrhotic and cirrhotic Table 5 – Exposure Dose per Patient for Implant alcohol swab. Procedure (Physician) patients. • Place the V-vial in an empty lead pot (10 cm x Lens of the Prophylactic treatment with methyl-prednisolone and Trunk Hands 6 cm) for stability and shielding. Eye mSv (mrem) mSv (mrem) ursodeoxycholic acid starting on the day of SIRT and mSv (mrem) • Insert a short 25 gauge needle through the continued for two months may reduce the incidence Shallow Dose septum of the V-vial until it just pierces the septum 0.038 (3.8) 0.12 (12) 0.32 (32) of REILD. (0.07mm) to create a vent In the treatment of REILD, low molecular weight Deep Dose • Remove the SIR-Spheres microspheres shipping 0.004 (0.4) 0.054 (5.4) heparin may also be considered but both (10 mm) vial from the lead pot and shake vigorously to corticosteroids and heparin may only be useful if Assuming average patient dose of approximately 2 GBq and disperse the SIR-Spheres microspheres. commenced very early in the course of the disease. dose injection time of 20 minutes. • Using a dose calibrator, determine the activity in See also Section 4.2. the shipping vial and return it to the lead pot.

Post-Implant Exposure • Remove partially the aluminum seal of the SIR- 8 Patient Selection and Pre- Exposure data from patients implanted with an Spheres microspheres shipping vial, clean with average of 2.1 GBq at approximately 5-6 hours post alcohol swab. treatment Testing implantation at the following distances from the • Insert a 25 gauge needle through the septum of Patients are indicated for treatment with SIR- patient’s abdomen: the shipping vial to create a vent, ensuring the Spheres microspheres when the metastatic Distance Exposure needle is well clear of the contents in the shipping colorectal cancer in the liver is considered non- 0.25 m 18.8 Sv/hr vial. resectable. In any of the following circumstances, patients would generally be considered non- 0.5 m 9.2 Sv/hr • Use a shielded 5 ml syringe with a 21 gauge resectable: 1.0 m 1.5 Sv/hr hypodermic needle at least 50 mm long to puncture the septum of the SIR-Spheres • Multiple liver metastases together with 2.0 m 0.4 Sv/hr microspheres shipping vial, and quickly draw back involvement of both lobes. 4.0 m <0.1 Sv/hr and forth several times in order to mix the SIR- (1 mSv = 100 mrem) Spheres microspheres thoroughly.

SSL-US-13 Date of Issue: February 2017 (CR2189) Page 2 of 3 • Quickly withdraw the pre calculated patient • Draw ROI around the whole liver and the whole the liver. The patient received 2 GBq of SIR-Spheres radiation dose, and transfer into the vented V-vial lung and get the total counts for the lung and the microspheres. In such a case, the calculated in the other lead pot. Withdraw the required liver radiation dose to the tumor is 294 Gy and the dose amount quickly before the contents of the shipping • Calculate the % shunt using following formula: to the liver tissue is 58.5 Gy. vial start to settle. 퐿푢푛푔 퐶표푢푛푡푠 % 푆ℎ푢푛푡 = ( ) × 100 The radiation dose for other organs would be • Verify the patient dose in the V-vial by re- 퐿𝑖푣푒푟 퐶표푢푛푡푠 + 퐿푢푛푔 퐶표푢푛푡푠 measuring the activity in the shipping vial with minimal or negligible, except for the organs adjacent dose calibrator, and correct, if necessary. to the liver, such as the stomach, large intestine, gall In order to optimize the risk/benefit for patients bladder, and the lung. The radiation dose may • Put the V-vial, containing the confirmed patient receiving SIR-Spheres microspheres, limiting the increase significantly, when there is shunting of the dose into the dedicated acrylic shield. radiation exposure to the lungs to ≤ 30 Gy is arterial blood to the lung, stomach, or small intestine.

required. The calculation of estimated radiation The patient dose is now ready for transport to the exposure to the lungs is given by the following Appendix V: Technique for Performing the SIR-Spheres microspheres implantation room. formulae: Intra-Hepatic Technetium MAA Scan Appendix III: Calculation of Individual Activity that may potentially reach the lung: Purpose: To assess arterial perfusion of the liver Dose 퐴푙푢푛푔 (퐺퐵푞) = 퐴푡표푡푎푙 × 퐿⁄100 and the fraction of radiopharmaceutical tracer that The recommended method for calculating the Where: will pass through the liver and lodge in the lungs. individual patient dose is the Body Surface Area Alung = lung activity (GBq) Agent: Technetium-99 labeled MAA (BSA) method. Atotal = total prescribed activity (GBq) (Macro-Aggregated Albumin) L = lung shunt (%) The safety profile of the prescribed activity equations Dose: 150 MBq (4 mCi) that enable accurate lobar treatment with SIR- The resulting lung dose, given that a given amount Equipment: Any large FOV gamma camera Spheres microspheres is well established. The BSA of activity shunts from the liver to the lung: method can take into account the volume of a single Administration: The patient needs to have a 49670 × 퐴푙푢푛푔 treated lobe, as well as that of the entire liver. 퐷 (퐺푦) = surgically implanted port or trans-femoral catheter 푙푢푛푔 푀 푙푢푛푔 placed in the hepatic artery. The Technetium-99 In this respect, the approach of lobar treatment Where: labeled MAA is injected into the port or catheter. versus whole liver treatment with SIR-Spheres Dlung = lung dose (Gy) Imaging: The patient is positioned supine under the microspheres is based on the presence of visible Alung = lung activity (GBq) gamma camera and the following images recorded: tumors on pre-treatment CT or MR imaging. If liver Mlung = mass of the lung (g) tumors are only visible in one lobe, then SIR- • Anterior and posterior images of abdomen and Spheres microspheres should be administered to Example of prescribed activity calculation for thorax - collect 700k –1000k cts for abdomen and that lobe only, thus sparing the contralateral lobe right lobe treatment same time for thorax. from unnecessary internal radiation. Total liver volume = 1,800 mL • Right lateral abdomen – same time acquisition as Total right lobe volume including tumor = 1,200 mL for anterior Use of dosimetry formulas Tumor volume in the right lobe = 300 mL Analysis: Draw ROI around whole of liver and whole BSA must first be determined and is calculated from BSA = 2.0 m2 the following equation (Equation 1): of lung fields. Calculate Gmean for liver region and Liver-lung shunt = 20% lung region. Calculate Lung/Liver ratio using the 퐵푆퐴 (푚2) = 0.20247 × ℎ푒𝑖푔ℎ푡(푚)0.725 Lung Mass = 1000 g 0.425 following formula: × 푤푒𝑖푔ℎ푡(푘푔) 푃푟푒푠푐푟𝑖푏푒푑 푎푐푡𝑖푣𝑖푡푦 푓표푟 푡ℎ푒 푟𝑖푔ℎ푡 푙표푏푒 (퐺퐵푞) % lung shunting = (counts of total lung / counts of 300 1,200 total lung plus counts of liver) x 100 = [2.0 − 0.2 + { }] × [ ] = ퟏ. ퟑퟕ 푮푩풒 Prescribed activity calculation for whole liver / 1,200 1,800 bilobar treatment Appendix VI: Correction for Decay Prescribed activity of SIR-Spheres microspheres (GBq) In this example, given the lung shunt = 20%, The physical half-life of yttrium-90 is 64.1 hours. 푉푡푢푚표푟 pulmonary radiation exposure is taken into = (퐵푆퐴 − 0.2) + ( ) Radioactive decay factors should be applied at the 푉푡푢푚표푟 + 푉푛표푟푚푎푙 푙푖푣푒푟 consideration: time of patient dose preparation, in order to calculate Where: 퐴푙푢푛푔 (퐺퐵푞) = 1.37 퐺퐵푞 × 20⁄100 = ퟎ. ퟐퟕퟒ 푮푩풒 the true value of radioactivity present. Vtumor is the total volume of tumor in the liver

Table 6 – Decay Factors of SIR-Spheres microspheres Vnormal liver is the volume of the non-tumor liver tissue Given that 0.274 GBq shunts from the liver to the lung, the resulting lung dose is: Hours Decay Factor Prescribed activity calculation for lobar or super- 0.5 0.995 selective treatment 49670 × 0.274 퐷푙푢푛푔 (퐺푦) = = ퟏퟑ. ퟔퟏ 푮풚 In patients who receive lobar or segmental treatment 1000 푔 1 0.989 2 0.979 with SIR-Spheres microspheres the prescribed activity must be reduced in accordance with the size A pulmonary radiation exposure of 13.61 Gy is less 3 0.968 of the portion of the liver being treated. than the 30 Gy established limit, therefore no 4 0.956 푇푢푚표푟 푣표푙푢푚푒퐿 reduction in prescribed activity would be required. 5 0.947 퐴푐푡𝑖푣𝑖푡푦퐿 (퐺퐵푞) = [퐵푆퐴 − 0.2 + { }] 푇표푡푎푙 푣표푙푢푚푒퐿 6 0.937 푇표푡푎푙 푣표푙푢푚푒퐿 Note: SIR-Spheres microspheres are 7 0.927 × [ ] contraindicated in patients with greater than 20% 푇표푡푎푙 푙𝑖푣푒푟 푣표푙푢푚푒 8 0.917 Where: lung shunting of the hepatic artery blood flow determined by Technetium MAA scan. 9 0.907 ActivityL is the prescribed activity for the lobe 10 0.898 Tumor volumeL is the volume of tumor present in the 11 0.888 lobe Appendix IV: Radiation Dosimetry 12 0.878 Total volumeL is the total volume of the lobe The radiation dosimetry of the SIR-Spheres including the tumor in the lobe microspheres can be a complex and difficult task 24 0.772 Total liver volume is the total volume of the liver due to the non-uniform distribution of the particles in 36 0.678 including the tumor the normal liver and the tumors. In general, 1 GBq 48 0.595 BSA is the Body Surface Area as per Equation 1 (27 mCi) of yttrium-90/kg of tissue provides 50 Gy of 72 0.459 radiation dose.2 However, because of the Lung Shunt Calculation Procedure Caution: The time of the initial calibration must be converted non-uniform distribution of the dose between the to the user’s local time. • Inject 4 mCi (150 MBq) of 99mTc MAA into the tumor and the normal liver tissue, a proportionally hepatic artery via a catheter larger amount of radiation will be delivered to the • Use a large FOV gamma camera, and obtain tumor tissue, and less amount to the liver. anterior and posterior images of the chest and abdomen (with 700 k to 1 million counts on For example, a patient has a liver weighing 1500 g, abdomen, and the same count on the chest) and has two tumor nodules, a 4 cm size tumor in the right lobe, and a 3 cm size nodule in the left lobe. • Take right lateral abdomen, using same count The post-injection images suggest that there is 5:1 density ratio for unit volume between the tumor and

2 Russell, Carden, Herron: ‘Dosimetry Calculations of Yttrium-90 used in the treatment of .’ Endocurietherapy/Hypertherm Oncol. 1988;4:171-186

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