PIFLUFOLASTAT F-18: 191 Adverse Event Reports & Safety Profile

11 DESCRIPTION

11.1 Chemical Characteristics PYLARIFY contains fluorine 18 (F 18), radiolabeled prostate-specific membrane antigen inhibitor imaging agent. Chemically piflufolastat F 18 is 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}ureido)-pentanedioic acid. The molecular weight is 441.4 and the structural formula is: The chiral purity of the unlabeled piflufolastat F 18 precursor is greater than 99% (S,S). PYLARIFY is a sterile, non-pyrogenic, clear, colorless solution for intravenous injection. Each milliliter contains 37 to 2,960 MBq (1 to 80 mCi) piflufolastat F 18 with ≤0.01 µg/mCi of piflufolastat at calibration time and date, and ≤ 78.9 mg ethanol in 0.9% sodium chloride injection USP. The pH of the solution is 4.5 to 7.0. PYLARIFY has a radiochemical purity of at least 95% up to 10 hours following end of synthesis, and specific activity of at least 1000 mCi/µmol at the time of administration.

Chemical

Structure

11.2 Physical Characteristics PYLARIFY is radiolabeled with fluorine 18 (F 18), a cyclotron produced radionuclide that decays by positron emission to stable oxygen 18 with a half-life of 109.8 minutes. 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 3).

Table

3.

Principal Radiation

Produced from Decay of Fluorine 18 Radiation Energy (keV) Abundance (%)

Positron

249.8

96.9 Gamma 511 193.5

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 4. The use of 8 cm Pb decreases the radiation transmission (i.e. exposure) by a factor of about 10,000.

Table

4.

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

AND USAGE PYLARIFY 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. PYLARIFY 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 )

AND ADMINISTRATION Recommended dose is 333 MBq (9 mCi) with an acceptable range of 296 MBq to 370 MBq (8 mCi to 10 mCi), administered as a bolus intravenous injection. ( 2.2 ) Initiate imaging approximately 60 minutes after PYLARIFY administration. The patient should void immediately prior to initiation of imaging. Image acquisition should start from mid-thigh and proceed to the skull vertex. ( 2.3 , 2.4 ) See full prescribing information for additional preparation, handling, administration, imaging, and radiation dosimetry information. ( 2 )

2.1 Radiation Safety – Drug Handling PYLARIFY is a radioactive drug. Only authorized persons qualified by training and experience should receive, use, and administer PYLARIFY. Handle PYLARIFY with appropriate safety measures to minimize radiation exposure during administration <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . Use waterproof gloves and effective radiation shielding, including syringe shields, when preparing and handling PYLARIFY.

2.2 Recommended Dosage and Administration Instructions Recommended Dose The recommended amount of radioactivity to be administered for PET imaging is 333 MBq (9 mCi) with an acceptable range of 296 MBq to 370 MBq (8 mCi to 10 mCi) administered as a single bolus intravenous injection. Preparation and Administration Use aseptic technique and radiation shielding when preparing and administering PYLARIFY. Visually inspect the radiopharmaceutical solution. Do not use if it contains particulate matter or if it is discolored (PYLARIFY is a clear, colorless solution). Calculate the necessary volume to administer based on calibration time and required dose. PYLARIFY may be diluted with 0.9% Sodium Chloride Injection, USP. Assay the dose in a suitable dose calibrator prior to administration.

Post Administration Instructions

Follow the PYLARIFY injection with an intravenous flush of 0.9% Sodium Chloride Injection USP. Dispose of any unused PYLARIFY in compliance with applicable regulations.

2.3 Patient Preparation Instruct patients to drink water to ensure adequate hydration prior to administration of PYLARIFY and to continue drinking and voiding frequently for the first few hours following administration to reduce radiation exposure <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

2.4 Image Acquisition The recommended start time for image acquisition is 60 minutes after PYLARIFY injection. Starting image acquisition more than 90 minutes after injection may adversely impact imaging performance. Patients should void immediately prior to image acquisition. Position the patient supine with arms above the head. Image acquisition should start from mid-thigh and proceed to the skull vertex. Scan duration is 12 minutes to 40 minutes depending on the number of bed positions (typically 6 to 8) and acquisition time per bed position (typically 2 minutes to 5 minutes).

2.5 Image Display and Interpretation PYLARIFY binds to prostate-specific membrane antigen (PSMA). Based on the intensity of the signals, PET images obtained using PYLARIFY indicate the presence of PSMA in tissues. 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 Radiation absorbed dose estimates are shown in Table 1 for organs and tissues of adult male patients from intravenous administration of PYLARIFY. The radiation effective dose resulting from administration of 370 MBq (10 mCi) of PYLARIFY to an adult weighing 70 kg is estimated to be 4.3 mSv. The radiation doses for this administered dose to the critical organs, which are the kidneys, liver, and spleen, are 45.5 mGy, 13.7 mGy, and 10 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 PYLARIFY Organ/Tissue Mean Absorbed dose per Unit Administered Activity (mGy/MBq)

Mean Standard Deviation

Adrenal glands 0.0131

0.0013 Brain 0.0021

0.0003 Breasts 0.0058

0.0007 Gallbladder wall 0.0141

0.0012 Lower large intestine wall 0.0073

0.001 Small intestine 0.0089

0.0009 Stomach wall 0.0092

0.0008 Upper large intestine wall 0.0091

0.0009 Heart wall 0.0171

0.0022 Kidneys 0.123

0.0434 Liver 0.037

0.0058 Lungs 0.0102

0.0016 Muscle 0.0069

0.0008 Pancreas 0.0124

0.0011 Red bone marrow 0.0071

0.0007 Osteogenic cells 0.0099

0.0012 Skin 0.0052

0.0006 Spleen 0.0271

0.0115 Testes 0.0059

0.0008 Thymus gland 0.007

0.0008 Thyroid 0.0062

0.0009 Urinary bladder wall 0.0072

0.001 Effective dose 0.0116 (mSv/MBq) 0.0022 (mSv/MBq)

None. None. ( 4 )

REACTIONS The most common reported adverse reactions are headache, dysgeusia, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Progenics Pharmaceuticals, Inc. at 1-800-362-2668 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 PYLARIFY was evaluated in 593 patients, each receiving one dose of PYLARIFY. The average injected activity was 340 ± 26 MBq (9.2 ± 0.7 mCi). The adverse reactions reported in &gt;0.5% of patients within the studies are shown in Table 2. In addition, a hypersensitivity reaction was reported in one patient (0.2%) with a history of allergic reaction.

Table

2.

Adverse

Reactions with a Frequency >0.5% in Patients Who Received PYLARIFY (n = 593)

Adverse

Reaction n (%)

Headache

13 (2%)

Dysgeusia

10 (2%)

Fatigue

7 (1%)

AND PRECAUTIONS Risk of Image Misinterpretation : PYLARIFY uptake can be seen in a variety of tumor types as well as in non-malignant processes and normal tissues. Image interpretation errors can occur with PYLARIFY imaging. ( 5.1 )

Hypersensitivity

Reactions : Monitor patients for hypersensitivity reactions, particularly patients with a history of allergy to other drugs and foods. ( 5.2 )

Radiation

Risk : Ensure safe drug handling to protect patients and health care workers from unintentional radiation exposure. ( 5.3 )

5.1 Risk of Image Misinterpretation Imaging interpretation errors can occur with PYLARIFY imaging. 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 PYLARIFY for imaging of patients with biochemical evidence of recurrence of prostate cancer seems to be affected by serum PSA levels [ see Clinical Studies (14) ]. The performance of PYLARIFY for imaging of metastatic pelvic lymph nodes prior to initial definitive therapy seems to be affected by risk factors such as Gleason score and tumor stage [ see Clinical Studies (14) ]. PYLARIFY uptake is not specific for prostate cancer and may occur with other types of cancer as well as non-malignant processes and in normal tissues. Clinical correlation, which may include histopathological evaluation of the suspected prostate cancer site, is recommended.

5.2 Hypersensitivity Reactions Monitor patients for hypersensitivity reactions, particularly patients with a history of allergy to other drugs and foods. Reactions may not be immediate. Always have trained staff and resuscitation equipment available.

5.3 Radiation Risks Diagnostic radiopharmaceuticals, including PYLARIFY, expose patients to radiation <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> . Radiation exposure is associated with a dose-dependent increased risk of cancer. Ensure safe handling and preparation procedures to protect patients and health care workers from unintentional radiation exposure. Advise patients to hydrate before and after administration and to void frequently after administration <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

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