POSLUMA Digital Patient Brochure

Detailed information about POSLUMA PET Imaging

POSLUMA PET imaging helps shed light on prostate cancer

A precise way to image prostate cancer

Not an actual patient

Please see full Important Safety Information throughout and the enclosed Prescribing Information. Please see full Important Safety Information on back cover and the enclosed Prescribing Information.

When you’re first diagnosed A closer look at prostate cancer If you’ve been newly diagnosed with prostate cancer, your doctor is going to take steps to develop a treatment plan that’s right for you. Your treatment plan will detail the goals, expected length, and any other important considerations of the treatment selected by you and your doctor.

288,300 Approximately

new cases of prostate cancer are expected to be diagnosed in the United States in 2023.

Prostate cancer is the second leading cause of cancer-related death in men in the United States, but survival rates are improving as detection and treatment technology continues to advance.

3.1 million prostate cancer survivors in the United States.

Early detection

Treatment

SELECT IMPORTANT SAFETY INFORMATION • Risk of Image Misinterpretation in Patients with Suspected Prostate Cancer Recurrence: The interpretation of POSLUMA PET may differ depending on imaging readers, particularly in the prostate/prostate bed region. Because of the associated risk of false positive interpretation, consider multidisciplinary consultation and histopathological confirmation when clinical decision-making hinges on flotufolastat F18 uptake only in the prostate/prostate bed region or only on uptake interpreted as borderline.

If prostate cancer returns Up to 40% to 50% of men diagnosed and treated for prostate cancer will have a recurrence within 10 years . Recurrent prostate cancer means that your disease has come back after treatment. Even after you’ve been treated for prostate cancer, your doctor will continue to monitor for recurrence. If they suspect that your prostate cancer has returned, there are different ways they might investigate— one of those ways is through imaging .

It’s vital to know where prostate cancer is located in your body so that you and your doctor can choose the most appropriate treatment plan. Imaging with POSLUMA can help your doctor locate prostate cancer with confidence.

Please see full Important Safety Information throughout and the enclosed Prescribing Information.

The importance of imaging

Imaging is a process that creates pictures of areas inside the body. It has many applications, one of them being cancer detection. While multiple types of imaging scans can help provide important information about prostate cancer, they all have pros and cons. What is imaging?

Common imaging scan overview

Prostate cancer detection

In bones

In soft tissue

When it’s very small

When PSA levels are low †

PET

MRI

N/A

Bone scan

= yes

N/A = not applicable

= yes, with limitations

= no

*While PET scans have limitations in detecting microscopic metastases, they do detect smaller metastases than CT scans or MRIs. † PSA <2 ng/mL.

CT=computed tomography; MRI=magnetic resonance imaging; PET=positron emission tomography; PSA=prostate-specific antigen.

Understanding the information provided by different imaging scans can help you advocate for yourself, so you can talk to your doctor about which ones may be right for you .

Please see full Important Safety Information throughout and the enclosed Prescribing Information.

Why choose a PET scan?

PET scans are often chosen to help develop an informed treatment plan for prostate cancer because they provide important information.

First, an imaging agent–like POSLUMA–is injected into the body. Then, it binds to a target, such as cancer cells, to light it up. This can be seen on images from a PET scan, showing the location of the disease. Keep in mind that like all imaging agents, POSLUMA may not detect all prostate cancer. How do PET scans work?

How POSLUMA works

The surface of most prostate cancer cells has elevated levels of a protein called prostate-specific membrane antigen, or PSMA . As an advanced diagnostic imaging agent, POSLUMA is highly specific to PSMA and attaches to it, highlighting prostate cancer where it’s located.

As with all diagnostic imaging tests, it’s possible that physicians may interpret POSLUMA PET scan results incorrectly. This means that a negative POSLUMA PET scan does not confirm or rule out the presence of prostate cancer.

PET=positron emission tomography. SELECT IMPORTANT SAFETY INFORMATION

• P OSLUMA use contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Advise patients to hydrate before and after administration and to void frequently after administration. Ensure safe

handling to minimize radiation exposure to the patient and health care providers.

What to expect with a POSLUMA PET scan After your scan During your scan Before your scan

H2O

MIN ~20

Continue to hydrate and urinate frequently for the first few hours

Fasting is not necessary, so you can stick to your normal diet

The scan itself will take about 20 minutes

H2O

You’ll review and discuss the results at your next doctor’s visit. Please note that it’s possible for physicians to interpret the results of an imaging scan incorrectly

You may be asked to change body positions, but generally you will be on your back with your arms above your head

Hydrate well. Make sure to urinate immediately before your scan

60 MIN

POSLUMA will be injected ahead of time, about 60 minutes before your scan

POSLUMA was not associated with any serious adverse reactions in the clinical trials.

SELECT IMPORTANT SAFETY INFORMATION • The adverse reactions reported in ≥0.4% of patients in clinical studies were diarrhea, blood pressure increase and injection site pain. • Drug Interactions: androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of flotufolastat F 18 in prostate cancer. The effect of these therapies on performance of POSLUMA PET has not been established.

Ask your doctor about POSLUMA

Discussion points for you and your doctor

I’d like to know if a PET scan is an option for me I want to know more about the safety of imaging scans I’d like to talk about what the different treatment options are depending on what’s found on the scan I’ve had a POSLUMA PET scan previously, and now that my prostate cancer has recurred, should I have another?

Stating your preferences for your treatment plan

I’m interested in a personalized treatment plan I’m interested in treating my prostate cancer aggressively Being healthy for as long as possible is very important to me Avoiding hormone therapy for as long as possible is very important to me

Having a POSLUMA PET scan can provide you and your doctor with important information about your initial prostate cancer diagnosis or suspected recurrence.

Please see full Important Safety Information throughout and the enclosed Prescribing Information.

Talk to your doctor about scheduling a POSLUMA PET scan

Your scheduled POSLUMA PET scan Date: ______________________ Time: _________________________ Imaging center: _ _________________________________________ Address: _________________________________________________ __________________________________________________________ Phone number: ___________________________________________

Follow-up visit

Date: _______________________ Time: _ _____________________

INDICATION POSLUMA ® (flotufolastat F 18) injection is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer • with suspected metastasis who are candidates for initial definitive therapy • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level IMPORTANT SAFETY INFORMATION • Image interpretation errors can occur with POSLUMA PET. A negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. The performance of POSLUMA for imaging metastatic pelvic lymph nodes in patients prior to initial definitive therapy seems to be affected by serum PSA levels and risk grouping. The performance of POSLUMA for imaging patients with biochemical evidence of recurrence of prostate cancer seems to be affected by serum PSA levels. Flotufolastat F 18 uptake is not specific for prostate cancer and may occur in other types of cancer, in non-malignant processes, and in normal tissues. Clinical correlation, which may include histopathological evaluation, is recommended. • R isk of Image Misinterpretation in Patients with Suspected Prostate Cancer Recurrence: The interpretation of POSLUMA PET may differ depending on imaging readers, particularly in the prostate/prostate bed region. Because of the associated risk of false positive interpretation, consider multidisciplinary consultation and histopathological confirmation when clinical decision-making hinges on flotufolastat F18 uptake only in the prostate/prostate bed region or only on uptake interpreted as borderline. • P OSLUMA use contributes to a patient’s overall long-term cumulative radiation exposure. Long- term cumulative radiation exposure is associated with an increased risk for cancer. Advise patients to hydrate before and after administration and to void frequently after administration. Ensure safe handling to minimize radiation exposure to the patient and health care providers. • T he adverse reactions reported in ≥0.4% of patients in clinical studies were diarrhea, blood pressure increase and injection site pain. • D rug Interactions: androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of flotufolastat F 18 in prostate cancer. The effect of these therapies on performance of POSLUMA PET has not been established.

To report suspected adverse reactions to POSLUMA, call 1-844-POSLUMA (1-844-767-5862) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Full POSLUMA prescribing information is available at www.posluma.com/prescribing-information.pdf

BEDPRC23-0047A 06/23

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use POSLUMA ® safely and effectively. See full prescribing information for POSLUMA. POSLUMA (flotufolastat F 18) injection, for intravenous use Initial U.S. Approval: 2023 ----------------------------- INDICATIONS AND USAGE -------------------------- POSLUMA is a radioactive diagnostic agent indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer: • with suspected metastasis who are candidates for initial definitive therapy • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level. (1) ------------------------- DOSAGE AND ADMINISTRATION -------------------- • Recommended amount of radioactivity of POSLUMA is 296 MBq (8 mCi) administered as an intravenous bolus injection. (2.2) • Initiate imaging approximately 60 minutes after administration. Scanning should start from mid-thigh and proceed to base of skull. (2.4) • See full prescribing information for additional preparation, handling, administration, imaging, and radiation dosimetry information. (2.3, 2.4) ---------------------- DOSAGE FORMS AND STRENGTHS --------------------- Injection: 296 MBq/mL to 5,846 MBq/mL (8 mCi/mL to 158 mCi/mL) as flotufolastat F 18 gallium in approximately 25 mL at end of synthesis in a multiple-dose vial. (3)

----------------------------- CONTRAINDICATIONS -------------------------------- None. (4) ------------------------ WARNINGS AND PRECAUTIONS ----------------------- • Risk of Image Misinterpretation: Image interpretation errors can occur with POSLUMA imaging. Interpretation of POSLUMA PET may differ depending on imaging readers in patients with suspected recurrence of prostate cancer. Consider multidisciplinary consultation and histopathological confirmation. (5.1, 14.2) • Radiation risk: POSLUMA contributes to a patient’s long-term cumulative radiation exposure. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure. (2.1, 5.2) ------------------------------- ADVERSE REACTIONS ------------------------------ The most common adverse reactions (≥0.4%) are diarrhea, blood pressure increase, and injection site pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Blue Earth Diagnostics Ltd at 1-844-POSLUMA (1-844-767-5862) or FDA at 1-800- FDA-1088 or www.fda.gov/medwatch . See 17 for PATIENT COUNSELING INFORMATION Revised: 5/2023

FULL PRESCRIBING INFORMATION: CONTENTS* HIGHLIGHTS OF PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Radiation Safety - Drug Handling 2.2

8.5

Geriatric Use

10 OVERDOSAGE 11 DESCRIPTION

11.1 Chemical Characteristics 11.2 Physical Characteristics 11.3 External Radiation 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY

Recommended Dose and Administration Instructions

2.3 2.4 2.5 2.6

Patient Preparation Image Acquisition

Image Display and Interpretation

Radiation Dosimetry 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Image Misinterpretation 5.2 Radiation Risks 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Imaging Prior to Initial Definitive Therapy of Prostate Cancer 14.2 Imaging for Suspected Recurrence of Prostate Cancer 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.

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FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE POSLUMA is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer • with suspected metastasis who are candidates for initial definitive therapy. • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level. 2 DOSAGE AND ADMINISTRATION 2.1 Radiation Safety - Drug Handling Handle POSLUMA with safety measures to minimize radiation exposure [ see Warnings and Precautions (5.2)] . Use waterproof gloves, effective radiation shielding, including syringe shields, and other appropriate safety measures when handling and administering POSLUMA. Radiopharmaceuticals should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. 2.2 Recommended Dose and Administration Instructions Recommended Dose The recommended amount of radioactivity to be administered in adults is 296 MBq (8 mCi) as an intravenous bolus injection. Preparation and Administration Instructions • Inspect POSLUMA visually for particulate matter and discoloration before administration. Do not use the drug if the solution contains particulate matter or is discolored. • Use aseptic technique and radiation shielding when withdrawing and administering POSLUMA. • Calculate the necessary volume to administer based on calibration time and required dose. • The recommended maximum volume of undiluted POSLUMA is 5 mL. • POSLUMA may be diluted with 0.9% Sodium Chloride Injection, USP. • Assay the dose in a dose calibrator before administration. Post Administration Instructions • After the POSLUMA injection, administer an intravenous flush of sterile 0.9% Sodium Chloride Injection, USP to ensure full delivery of the dose. • Dispose of any unused drug in a safe manner in compliance with applicable regulations.

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2.3 Patient Preparation Instruct patients to drink water prior to administration of POSLUMA to ensure adequate hydration and to continue drinking and voiding frequently for the first few hours following administration to reduce radiation exposure. 2.4 Image Acquisition

• Patients should void immediately prior to imaging. • Position the patient supine with arms above the head.

• Begin image acquisition approximately 60 minutes after POSLUMA injection. • Image acquisition should start from mid-thigh and proceed to the base of the skull. • Scan duration is approximately 20 minutes depending on the number of bed positions and acquisition time per bed position (typically 3 minutes). Adapt imaging technique according to the equipment used and patient characteristics in order to obtain the best image quality possible. 2.5 Image Display and Interpretation POSLUMA binds to PSMA. PET images obtained using POSLUMA indicate the presence of PSMA in tissues [see Clinical Pharmacology ( 12.1)] . Lesions should be considered suspicious if uptake is greater than physiologic uptake in that tissue or greater than adjacent background if no physiologic uptake is expected. Tumors that do not express PSMA will not be visualized. Increased uptake in tumors is not specific for prostate cancer [see Warnings and Precautions (5.1)]. 2.6 Radiation Dosimetry Estimated absorbed radiation doses for adult patients following intravenous injection of POSLUMA are shown in Table 1. The effective radiation dose resulting from the administration of the recommended activity of 296 MBq of POSLUMA is 4.1 mSv. The radiation absorbed doses to the critical organs of adrenal glands, kidneys, and submandibular glands for the recommended activity of 296 MBq are 54.3 mGy, 51 mGy, and 43.8 mGy, respectively. When PET/CT is performed, exposure to radiation will increase by an amount dependent on the settings used in the CT acquisition. Table 1: Estimated Radiation Absorbed Doses in Organs/Tissues in Adults who Received POSLUMA Organ/Tissue Absorbed Dose per Unit Administered Activity (mGy/MBq) Mean Adrenal glands 0.184 Brain 0.002 Breasts 0.004 Gallbladder wall 0.017 Lower large intestine wall 0.007 Upper large intestine wall 0.01 Heart wall 0.02 Kidneys 0.172 Lacrimal glands 0.08 * Liver 0.062 Lungs 0.01

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Muscle

0.006 0.012 0.005 0.028 0.114 * 0.01 0.002 0.012 0.083 0.012 0.065 * 0.148 * 0.005

Osteogenic cells

Ovaries Pancreas

Parotid glands Red bone marrow

Skin

Small intestine

Spleen

Stomach wall Sublingual glands

Submandibular glands

Testes

Thymus gland

0.01 0.01

Thyroid

Urinary bladder wall

0.006 **

Uterus

0.011

Effective dose (mSv/MBq) 0.014 ** * The absorbed dose value reflects self-irradiation only; no dose contribution from other regions to the glands is added. ** A 1-hour bladder voiding interval is assumed.

3 DOSAGE FORMS AND STRENGTHS Injection: 296 MBq/mL to 5,846 MBq/mL (8 mCi/mL to 158 mCi/mL) as flotufolastat F 18 gallium in approximately 25 mL at end of synthesis supplied as a clear, colorless solution in a multiple-dose vial.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Risk of Image Misinterpretation

Image interpretation errors can occur with POSLUMA PET. A negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. The performance of POSLUMA for imaging metastatic pelvic lymph nodes in patients prior to initial definitive therapy seems to be affected by serum PSA levels and risk grouping [See Clinical Studies (14.1)] . The performance of POSLUMA for imaging patients with biochemical evidence of recurrence of prostate cancer seems to be affected by serum PSA levels [See Clinical Studies (14.2)] . Flotufolastat F 18 uptake is not specific for prostate cancer and may occur in other types of cancer, in non-malignant processes, and in normal tissues. Clinical correlation, which may include histopathological evaluation, is recommended. Risk of Image Misinterpretation in Patients with Suspected Prostate Cancer Recurrence The interpretation of POSLUMA PET may differ depending on imaging readers, particularly in the prostate/prostate bed region [see Clinical Studies (14.2)]. Because of the associated risk of false positive

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interpretation, consider multidisciplinary consultation and histopathological confirmation when clinical decision-making hinges on flotufolastat F18 uptake only in the prostate/prostate bed region or only on uptake interpreted as borderline. 5.2 Radiation Risks POSLUMA use contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Advise patients to hydrate before and after administration and to void frequently after administration. Ensure safe handling to minimize radiation exposure to the patient and health care providers [see Dosage and Administration (2.1, 2.2)] . Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of POSLUMA was evaluated in 747 patients with prostate cancer [see Clinical Studies (14.1,14.2)] . All patients received a single administration of POSLUMA with an administered radioactivity (mean ± SD) of 307 ± 23 MBq (8.3 ± 0.6 mCi). The mean age of patients was 67 years (range: 43 to 86 years); distribution by race was 78 % White, 12 % Black or African American, 2 % other, and 7% un reported; and distribution by ethnicity was 5 % Hispanic /Latino, 87% non -Hispanic/Latino, and 8 % unrepo rted. The adverse reactions reported in ≥ 0 .4% of patients are shown in Table 2. Table 2: Adverse Reactions in ≥ 0.4% of Patients with Prostate Cancer Receiving POSLUMA Adverse Reaction POSLUMA N = 747 n (%) Diarrhea 5 (0.7%) Blood pressure increase 4 (0.5 %) Injection site pain 3 (0.4%) 6 ADVERSE REACTIONS 6.1

7 DRUG INTERACTIONS Androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such as androgen receptor antagonists, can result in changes in uptake of flotufolastat F 18 in prostate cancer. The effect of these therapies on performance of POSLUMA PET has not been established.

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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary

POSLUMA is not indicated for use in females. There are no available data on the use of POSLUMA in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with flotufolastat F 18. Radioactive drugs, including POSLUMA, have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. 8.2 Lactation Risk Summary POSLUMA is not indicated for use in females. There are no data on the presence of flotufolastat F 18 in human milk, the effect on the breastfed infant, or the effect on milk production. 8.4 Pediatric Use The safety and effectiveness of POSLUMA have not been established in pediatric patients. 8.5 Geriatric Use Among the total number of patients receiving POSLUMA in clinical studies of prostate cancer, 463 ( 62%) were 65 years of age and older, while 118 (16 %) were 75 years of age and older [see Clinical Studies (14.1,14.2)] . No overall differences in safety or effectiveness were observed between these patients and younger adult patients. 10 OVERDOSAGE In the event of an overdose of POSLUMA, maintain hydration of the patient and frequent voiding to minimize radiation exposure. A diuretic might also be considered. If possible, an estimate of the radiation effective dose administered to the patient should be made. Chemical Characteristics POSLUMA (flotufolastat F 18) injection is a radioactive diagnostic agent for intravenous use. The active ingredient of POSLUMA is flotufolastat F 18 gallium, of which the molecular structure includes a DOTAGA complex with nonradioactive gallium. Radioactive fluorine-18 is covalently bound to silicon. Chemically, flotufolastat F 18 gallium is gallate(6-), [(4 S ,8 S ,13 R ,27 R ,30 R ,35 S )-35-[4,10-bis[(carboxy- k O )methyl]-7-(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl-k N 1 ,k N 4 ,k N 7 ,k N 10 ]-30-[[[4-[bis(1,1- dimethylethyl)fluoro- 18 F -silyl]benzoyl]amino]methyl]-1,36-dihydroxy-1,6,11,18,21,29,32,36-octaoxo- 5,7,12,17,22,28,31-heptaazahexatriacontane-4,8,13,27-tetracarboxylato(9-)]-, hydrogen (1:6). The molecular weight is 1537.3 g/mol and the structural formula is: 11 DESCRIPTION 11.1

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POSLUMA is a sterile, non-pyrogenic, clear, colorless, and isotonic solution. Each mL contains up to 20 mcg of flotufolastat gallium, up to 5,846 MBq (158 mCi) as flotufolastat F 18 gallium at end of synthesis, and the following inactive ingredients: not more than 10 % ( v/v) alcohol, 1.9 mg anhydrous citric acid, 7.2 mg sodium chloride, and 0.75 mg sodium hydroxide to adjust pH between 4 and 6. POSLUMA contains no preservative. 11.2 Physical Characteristics POSLUMA contains fluorine-18 (F 18) which is a cyclotron produced radionuclide that decays by positron emission (β+ decay, 96.7%) and orbital electron capture (3.3%) to stable oxygen -18 with a physical half-life of 109.8 minutes (Table 3). The principal photons useful for diagnostic imaging are the coincident pair of 511 keV gamma photons, resulting from the interaction of the emitted positron with an electron (Table 4). Table 3: Physical Decay Chart for Fluorine-18 Minutes Fraction Remaining 0 1 15 0.909 30 0.826 60 0.683 110 0.5 220 0.25

Table 4:

Principal Radiation Produced from Decay of Fluorine-18 Energy (keV)

Abundance (%)

Positron Gamma

249.8

96.7 193.5

511

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11.3 External Radiation The point source air-kerma coefficient for F 18 is 3.75 × 10 -17 Gy m 2 /(Bq s). The first half-value thickness of lead (Pb) for F 18 gamma rays is approximately 6 mm. The relative reduction of radiation emitted by F 18 that results from various thicknesses of lead shielding is shown in Table 5. The use of 8 cm of Pb will decrease the radiation transmission (i.e., exposure) by a factor of about 10,000. Table 5: Radiation Attenuation of 511 keV Gamma Rays by Lead Shielding Shield Thickness cm of Lead (Pb) Coefficient of Attenuation 0.6 0.5 2 0.1 4 0.01 6 0.001 8 0.0001

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of action

Flotufolastat F 18 binds to PSMA (IC50 = 4.4 nM) expressed on cells, including prostate cancer cells, and is internalized. Prostate cancer cells usually overexpress PSMA. Fluorine- 18 is a ß+ emitting radionuclide that can be detected using positron emission tomography. 12.2 Pharmacodynamics The relationship between flotufolastat F 18 plasma concentrations and image interpretation has not been fully characterized. 12.3 Pharmacokinetics Distribution Following intravenous administration, flotufolastat F 18 distributes to liver (15.8% of administered activ ity), heart blood pool (7.4%), and kidneys (3.2%) and is cleared from the blood.

Elimination Metabolism Flotufolastat F 18 does not undergo metabolism up to 50 minutes post injection. Excretion

Elimination is by urinary excretion. Appr oximately 7% of the administered activity was excreted in the urine in the first 2 hours post- injection with approximately 15% excreted by 4.5 hours post -injection.

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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies to assess the carcinogenicity or mutagenic potential of flotufolastat have not been conducted. However, flotufolastat F 18 has the potential to be mutagenic because of the F 18 radionuclide. No studies in animals have been performed to evaluate potential impairment of fertility in males or females. Imaging Prior to Initial Definitive Therapy of Prostate Cancer The safety and efficacy of POSLUMA were evaluated in LIGHTHOUSE (NCT04186819), a prospective, multicenter, open-label, single-arm study in patients with prostate cancer who were candidates for initial definitive therapy. The study enrolled 356 patients diagnosed with unfavorable intermediate-risk (32%) or high-/very high- risk prostate cancer ( 68% ) who were candidates for radical prostatectomy and pelvic lymph node dissection (PLND). Unfavorable intermediate-risk was defined as having any ≥ 2 intermediate risk factors [T2b-T2c, Gleason score 7, PSA 10-20], Gleason pattern 4+3=7, or ≥ 50% of bio psy cores positive for prostate cancer. High or very high-risk was defined as having T3 or T4 disease, Gleason score ≥8, primary Gleason pattern 5, and/or PSA >20. 14 CLINICAL STUDIES 14.1 All patients received a single dose of POSLUMA with an administered radioactivity (mean ± SD) of 307 ± 23 MBq (8.3 ± 0.62 mCi), followed by PET/CT scan from mid-thigh to base of the skull. Three central readers blinded to clinical information independently interpreted each scan for lesions considered positive for prostate cancer in pelvic lymph nodes, categorized by subregion and left and right laterality [see Dosage and Administration (2.5 ) ] . Positive lesions in the prostate gland, lymph nodes outside the pelvis, soft tissue/parenchyma, and bones were also recorded. A total of 296 patients ( 83%) u nderwent standard-of-care prostatectomy and template PLND and had sufficient histopathology data for evaluation of the pelvic lymph nodes. The mean age was 65 years (range 46 to 82 years); distribution by race was 82 % White, 8% Black or African American, 0.3 % o ther, and 10 % unreported; and distribution by ethnicity was 5 % Hispanic/Latino, 86% non -Hispanic/Latino, and 9 % unreported. The median serum PSA was 8.4 ng/mL. The total Gleason score was 7 for 45 %, 8 for 26%, and 9 for 25% of the patients, with the remainder of the patients having Gleason scores of 6 or 10. Approximately 24 % of patients had pelvic lymph node metastases based on histopathology. POSLUMA performance was evaluated against histopathology after matching by hemipelvis. Table 6 shows the results, such that at least one true positive hemipelvis region defined a true positive patient. Table 6: Patient-Level, Hemipelvis Region-Matched Performance of POSLUMA PET for Detection of Pelvic Lymph Node Metastasis (N1) in LIGHTHOUSE N=296 Reader 1 Reader 2 Reader 3 True Positive 21 19 16

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False Positive True Negative False Negative Sensitivity, (%) [95% CI] Specificity, (%) [ 95% CI ]

210

212

219

3 0% [20, 42] 93 % [89, 96] 57 % [40, 73] 81% [76, 86]

27% [17, 39] 94 % [90, 97] 58 % [39, 75] 81 % [75, 85]

23 % [14, 35] 97 % [94, 99] 70 % [47, 87] 80 % [75, 85]

Positive Predictive Value , (%) [95% CI] Negative Predictive Value , (%) [95% CI]

CI= confidence interval In exploratory analyses, there were numerical trends towards higher sensitivity among patients with PSA greater than or equal to the median value (8.4 ng/mL) and among patients with high-risk or very high-risk categorization. POSLUMA-positive lesions outside of the prostate gland and pelvic lymph nodes (M1) were also evaluated. As a percentage of the 352 patients with an evaluable POSLUMA scan and of the 61 patients with at least one POSLUMA positive M1 lesion, 10 % ( 95% CI: 7 % to 13 %) and 56% ( 95% CI: 42% to 68%) , respectively, had at least one matching positive M1 lesion between the POSLUMA majority read and a reference standard consisting of other imaging evaluated by a separate consensus panel or histopathology. 14.2 Imaging for Suspected Recurrence of Prostate Cancer The safety and efficacy of POSLUMA were evaluated in SPOTLIGHT (NCT04186845), a prospective, multicenter, open-label, single-arm study in patients with biochemical evidence of recurrent prostate cancer. The study enrolled 391 patients with suspected recurrence defined by either serum PSA of at least 0.2 ng/mL after radical prostatectomy (with confirmatory PSA level also at least 0.2 ng/mL) or by an increase in serum PSA of at least 2 ng/mL above the nadir after other therapies. All patients received a single dose of POSLUMA with an administered radioactivity (mean ± SD) of 306 ± 22 MBq (8.27 ±0.61 mCi), followed by PET/CT scan from mid-thigh to base of the skull. Three central readers blinded to clinical information independently interpreted each scan by region for the presence and location of lesions considered positive for prostate cancer [see Dosage and Administration (2.5)] . The regions interpreted were grouped into three for primary analysis: prostate/prostate bed; pelvic lymph nodes; and other (including extra-pelvic lymph nodes, bone, and soft tissue/parenchyma). A total of 389 patients had an evaluable POSLUMA PET scan. The mean age was 68 years (range: 43 to 86 years); distribution by r ace was 75% White, 16% Black or African American, 4 % other, and 5% unreported; and distribution by ethnici ty 5% w as Hispanic/Lati no, 87% non - Hispanic/Latino, and 8% unreported. The median baseline serum PSA level was 1.1 ng/mL with 60 % of patients having a baseline PSA <2.0 ng/mL. Prior treatment included radical prostatectomy in 79 % of the patients. POSLUMA-positive interpretations were compared to a reference standard of either histopathology or other imaging (CT, MRI, Technetium 99m bone scan, or fluciclovine F 18 PET) obtained within 90 days

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Reference ID: 5180081

of the POSLUMA scan using a lesion-to-lesion co-localization method and separate consensus panel. Reference standard information for negative interpretations was not collected. At least one POSLUMA-positive lesion was detected by at least one reader in 366 patients (94%) . Reference standard information consisted of imaging only (n=297) or histopathology (n=69). As a percentage of patients with an evaluable scan, 51 % ( 9 5% CI: 46 % to 56 % ) for reader 1, 48% ( 95 % CI: 43 % to 53 % ) for reader 2, and 49% (95% CI: 44 % to 54 % ) for reader 3 had at least one matching positive region between the POSLUMA scan and the reference standard. Of all POSLUMA-positive regions, 46% (9 5% CI: 42% to 50%) for reader 1, 60% (95% CI: 55% to 66 % ) for reader 2, and 53% (95% CI: 48% to 58%) for reader 3 were categorized as positive by the reference standard. Table 7 shows patient-level results from the majority read stratified by serum PSA level. Percent PET positivity was calculated as the percentage of patients with POSLUMA-positive lesions out of all patients with an evaluable PET scan. Percent PET positivity includes true and false positives and is not a measure of diagnostic performance. Table 7: Patient-Level POSLUMA PET Results and Percent PET Positivity Stratified by Serum PSA Level in SPOTLIGHT by Majority Read (N=389)

PET Positive Patients

Percent PET Positivity [95% CI]

PSA (ng/mL)

PET Negative Patients

Histopathology

Imaging only a

Total

NPA

64 % [54,72] 76 % [64,86] 93 % [82, 99] 97 % [94, 99] 83 % [79, 86]

< 0.5

121

≥ 0.5 and < 1

≥ 1 and < 2

≥ 2

156

152

Total

389

322

153

101

PSA = prostate-specific antigen, PA = positive agreement, NPA = no positive agreement, CI = confidence interval a Imaging comprised of one or more of the following: CT, MRI, 99m Tc Bone Scan, fluciclovine F 18 PET

Variable Interpretation in Patients with Suspected Prostate Cancer Recurrence POSLUMA reader agreement was evaluated for the three central readers and 389 patients. Inter-reader Fleiss κ was 0. 41 (95% CI: 0.39-0.43). The three readers agreed on the presence or absence of positive lesions across all five evaluated regions in 118 patients (30 % unanimity) [see Warning and Precautions (5.1)]. Given the level of inter-reader agreement observed overall, POSLUMA reader agreement was further evaluated by regional subgroup . The Fleiss κ for was 0.40 ( 95% CI: 0.3 3-0.46) in the prostate/prostate bed, 0.73 (9 5% CI: 0.67-0.78) in the pelvic lymph nodes, and 0.62 (95% CI: 0. 58-0.65) across the other regions.

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Reference ID: 5180081

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied

POSLUMA injection is supplied as a clear, colorless solution in a multiple-dose glass vial (NDC 69932- 002-50) containing 296 MBq/mL to 5,846 MBq/mL (8 mCi/mL to 158 mCi/mL) as flotufolastat F 18 gallium in approximately 25 mL at end of synthesis. Storage and Handling Store POSLUMA at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Store POSLUMA in the original container in radiation shielding. The expiration date and time are provided on the container label. Use POSLUMA within 10 hours from end of synthesis. Dispose of unused POSLUMA in compliance with applicable regulations. This preparation is approved for use by persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.

17 PATIENT COUNSELING INFORMATION Adequate Hydration

Instruct patients to drink a sufficient amount of water to ensure adequate hydration before their PET study and urge them to drink and urinate as often as possible during the first hours following the administration of POSLUMA, in order to reduce radiation exposure [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

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Reference ID: 5180081

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