Cerianna™

Limitations of Use

Tissue biopsy should be used to confirm recurrence of breast cancer and to verify ER status by pathology. CERIANNA is not useful for imaging other receptors, such as human epidermal growth factor receptor 2 (HER2) and the progesterone receptor (PR).

CERIANNA is supplied in a 50 mL multiple-dose glass vial (NDC 72874-001-01) containing a clear, colorless injection solution at a strength of 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) fluoroestradiol F 18 at the end of synthesis. Each vial contains multiple doses and is enclosed in a shield container to minimize external radiation exposure.

The safety and effectiveness of CERIANNA in pediatric patients have not been established.

Clinical studies of fluoroestradiol F 18 injection did not reveal any difference in pharmacokinetics or biodistribution in patients aged 65 and over.

The effectiveness of CERIANNA for detecting ER-positive non-primary breast cancer lesions was evaluated based on published study reports of fluoroestradiol F 18. Study 1 (NCT01986569) enrolled 90 women (median age 55 years, 39% premenopausal) with histologically confirmed invasive breast cancer. The patients had first known or suspected recurrence of treated breast cancer or stage IV metastatic breast cancer. Recent biopsy of lesions outside of bone and areas with high physiologic fluoroestradiol F 18 uptake was also required [see Dosage and Administration (2.5)]. Patients concurrently using estrogen receptor modulators or fulvestrant discontinued them 60 days prior to fluoroestradiol F 18 administration. Concurrent use of aromatase inhibitors was permitted. Three image readers were blinded to all clinical information, except for the location of the largest biopsied lesion, for which pathologists independently provided an Allred score (0 to 8). The image readers scored the intensity of FES uptake on a three-point scale relative to normal biodistribution as either "decreased," "equivocal," or "increased" (1 to 3).

Image reader performance for distinguishing between ER-positive and ER-negative fluoroestradiol F 18 uptake was compared to biopsy in 85 patients. Of the 47 patients with positive biopsy (Allred score ≥ 3), 36 were positive on imaging (majority reader score = 3). Ten of 11 patients with false negative imaging had Allred scores between 3 and 6 [see Warnings and Precautions (5.1)]. Of the 38 patients with negative biopsy, all 38 were negative on imaging.

Study 2 (NCT00602043) in 13 patients showed similar results.

None.

Diagnostic radiopharmaceuticals, including CERIANNA, expose patients to radiation [see Dosage and Administration (2.6)]. Radiation exposure is associated with a dose-dependent increased risk of cancer. Ensure safe drug handling and patient preparation procedures to protect patients and health care providers from unintentional radiation exposure [see Dosage and Administration (2.1) and (2.3)].

Reported adverse reactions include: injection-site pain and dysgeusia (6)

To report SUSPECTED ADVERSE REACTIONS, contact GE HealthCare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drugs that bind to the estrogen receptor (ER) may compete with the binding of fluoroestradiol F 18 and may reduce the detection of ER-positive lesions with CERIANNA.

Before administering CERIANNA, discontinue drugs that bind to the ER, such as SERMs and SERDs, for at least 5 biological half-lives (e.g., elacestrant for 11 days, tamoxifen for 8 weeks, and fulvestrant for 28 weeks) [see Dosage and Administration (2.3)].

The relationship between fluoroestradiol F18 plasma concentrations and image interpretation has not been studied. Fluoroestradiol F18 uptake measured by PET in human tumors is directly proportional to tumor ER expression measured by in vitro assays.

Position the patient supine with arms above the head, if possible. The recommended start time for image acquisition is 80 minutes after the intravenous administration of CERIANNA. Scan duration adapted from the range of 20 minutes to 30 minutes and imaging start times adapted within the range of 20 minutes to 80 minutes may be customized according to the equipment used and patient and tumor characteristics for optimal image quality.

CERIANNA is indicated for use with positron emission tomography (PET) imaging for the detection of estrogen receptor (ER)-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer.

The point source air-kerma coefficient for F 18 is 3.75 × 10^-17 Gy m² / (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 3. The use of 8 cm Pb decreases the radiation transmission (i.e., exposure) by a factor of about 10,000.

Radiation absorbed dose estimates are shown in Table 1 for organs and tissues of adults from intravenous administration of CERIANNA. The radiation effective dose resulting from administration of 222 MBq (6 mCi) of CERIANNA to an adult weighing 70 kg is estimated to be 4.9 mSv. Critical organs include the liver, gallbladder, and uterus. When PET/CT is performed, exposure to radiation will increase by an amount dependent on the settings used for the CT acquisition.

Fluoroestradiol F 18 binds ER. The following binding affinity: Kd = 0.13 ± 0.02 nM, Bmax = 1901 ± 89 fmol/mg, and IC₅₀ = 0.085 nM, was determined in an ER-positive human breast cancer cell line (MCF-7).

Uptake of fluoroestradiol F 18 depends on ER density and function in tumors and physiologic tissue, including in liver, ovary, and uterus. Detection of ER-positive tumors should be based on comparison with tissue background outside of organs with high physiologic uptake and regions with high activity due to hepatobiliary and urinary excretion.

• Risk of Misdiagnosis. Do not use CERIANNA in lieu of biopsy when biopsy is indicated in patients with recurrent or metastatic breast cancer. Pathology or clinical characteristics that suggest a patient may benefit from systemic hormone therapy should take precedence over a discordant negative CERIANNA scan. (5.1)
• Radiation Risks. Ensure safe drug handling and patient preparation procedures to protect patients and health care providers from unintentional radiation exposure. (2.1, 2.3, 5.2)

• Recommended dose is 222 MBq (6 mCi), with a range of 111 MBq to 222 MBq (3 mCi to 6 mCi), administered as an intravenous injection over 1 to 2 minutes. (2.2)
• Recommended imaging start time is 80 minutes (range 20 minutes to 80 minutes) after drug administration. (2.4)
• See full prescribing information for additional preparation, administration, imaging, and radiation dosimetry information. (2)

Injection: clear, colorless solution in a multiple-dose vial containing 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) of fluoroestradiol F 18 at end of synthesis.

CERIANNA contains fluoroestradiol fluorine 18 (F 18), a synthetic estrogen analog. Chemically, fluoroestradiol F 18 is [18F]16α-fluoro-3,17β-diol-estratriene-1,3,5(10). The molecular weight is 289.37, and the structural formula is:

CERIANNA is a sterile, clear, colorless solution for intravenous injection, with an osmolarity of 340 mOsm. Its pH ranges between 5.5 to 8.0. The composition of the final product in 40 mL solution is fluoroestradiol no more than 5 mcg, fluoroestradiol F 18 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL), sodium ascorbate 0.44% w/v in sodium chloride 0.9% w/v, and ethanol no more than 3.2% w/v.

CERIANNA is radiolabeled with 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 2).

• Lactation: Interrupt breastfeeding. Advise a lactating woman to avoid breastfeeding for 4 hours after CERIANNA administration. (8.2)

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 CERIANNA was evaluated from published clinical studies of 1,207 patients with breast cancer receiving at least one fluoroestradiol F 18 administration. The following adverse reactions occurred at a rate < 1%:

• General disorders: injection-site pain
• Neurological and gastrointestinal disorders: dysgeusia

CERIANNA is a radioactive drug. Only authorized persons qualified by training and experience should receive, use, and administer CERIANNA. Handle CERIANNA with appropriate safety measures to minimize radiation exposure during administration [see Warnings and Precautions (5.2)]. Use waterproof gloves and effective radiation shielding, including syringe shields, when preparing and handling CERIANNA.

CERIANNA™ (fluoroestradiol F 18) Injection

148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) @ End of Synthesis

For Intravenous Use Only

Multiple-Dose Vial

Rx ONLY

Date of manufacture:

Expiration date & time:__________; ______hr:min

Lot# _______________________________________

Volume: ________ mL

Store at 20°C to 25°C (68°F to 77°F)

Store upright in a shielded container

Do not use if cloudy or if it contains particulate matter

Contains: 148 MBq/mL to 3,700 MBq/mL

(4 mCi/mL to 100 mCi/mL) of no-carrier added

fluoroestradiol F 18 @ EOS;

sodium ascorbate 0.44% w/v in sodium chloride 0.9% w/v

and ethanol no more than 3.2% w/v

Usual dosage: See prescribing information

CAUTION: RADIOACTIVE

MATERIAL

Dist.by: GE Healthcare, Inc., Arlington Heights, IL 60004 USA

GE is a trademark of General Electric Company used under

trademark license.

100112-0B

NDC 72874-001-01

Multiple-Dose Vial

CERIANNA™ (fluoroestradiol F 18) Injection

148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) @ EOS*

For Intravenous Use Only

Sterile, Non-pyrogenic

Diagnostic

Date/time of calibration: _____________; ________hr:min

Expiration date & time: _____________; ________hr:min

Volume: _______________________ mL

Lot # ________________________

Concentration: ___________mCi/mL

at time of calibration

Total Activity: ____________mCi at

time of calibration

Contains: 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100

mCi/mL) of no-carrier added fluoroestradiol F 18 @ EOS*;

sodium ascorbate 0.44% w/v in sodium chloride 0.9% w/v

and ethanol no more than 3.2% w/v

Usual dosage: See prescribing information

Do not use if cloudy or if it contains particulate matter

*EOS = End of Synthesis

CAUTION: RADIOACTIVE MATERIAL

Expires 12 hours after EOS*

Store at 20°C to 25°C (68°F to 77°F)

Store upright in a shielded container

Aseptically withdraw and handle doses

[18F] Half-Life = 109.8 minutes

Calculate correct dosage from date

and time of calibration

Dist. by: GE Healthcare, Inc.

Arlington Heights, IL 60004 USA

GE is a trademark of General Electric

Company used under trademark license.

100113-0B

Rx ONLY

Limitations of Use

Tissue biopsy should be used to confirm recurrence of breast cancer and to verify ER status by pathology. CERIANNA is not useful for imaging other receptors, such as human epidermal growth factor receptor 2 (HER2) and the progesterone receptor (PR).

CERIANNA is supplied in a 50 mL multiple-dose glass vial (NDC 72874-001-01) containing a clear, colorless injection solution at a strength of 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) fluoroestradiol F 18 at the end of synthesis. Each vial contains multiple doses and is enclosed in a shield container to minimize external radiation exposure.

The safety and effectiveness of CERIANNA in pediatric patients have not been established.

Clinical studies of fluoroestradiol F 18 injection did not reveal any difference in pharmacokinetics or biodistribution in patients aged 65 and over.

The effectiveness of CERIANNA for detecting ER-positive non-primary breast cancer lesions was evaluated based on published study reports of fluoroestradiol F 18. Study 1 (NCT01986569) enrolled 90 women (median age 55 years, 39% premenopausal) with histologically confirmed invasive breast cancer. The patients had first known or suspected recurrence of treated breast cancer or stage IV metastatic breast cancer. Recent biopsy of lesions outside of bone and areas with high physiologic fluoroestradiol F 18 uptake was also required [see Dosage and Administration (2.5)]. Patients concurrently using estrogen receptor modulators or fulvestrant discontinued them 60 days prior to fluoroestradiol F 18 administration. Concurrent use of aromatase inhibitors was permitted. Three image readers were blinded to all clinical information, except for the location of the largest biopsied lesion, for which pathologists independently provided an Allred score (0 to 8). The image readers scored the intensity of FES uptake on a three-point scale relative to normal biodistribution as either "decreased," "equivocal," or "increased" (1 to 3).

Image reader performance for distinguishing between ER-positive and ER-negative fluoroestradiol F 18 uptake was compared to biopsy in 85 patients. Of the 47 patients with positive biopsy (Allred score ≥ 3), 36 were positive on imaging (majority reader score = 3). Ten of 11 patients with false negative imaging had Allred scores between 3 and 6 [see Warnings and Precautions (5.1)]. Of the 38 patients with negative biopsy, all 38 were negative on imaging.

Study 2 (NCT00602043) in 13 patients showed similar results.

None.

Diagnostic radiopharmaceuticals, including CERIANNA, expose patients to radiation [see Dosage and Administration (2.6)]. Radiation exposure is associated with a dose-dependent increased risk of cancer. Ensure safe drug handling and patient preparation procedures to protect patients and health care providers from unintentional radiation exposure [see Dosage and Administration (2.1) and (2.3)].

Reported adverse reactions include: injection-site pain and dysgeusia (6)

To report SUSPECTED ADVERSE REACTIONS, contact GE HealthCare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drugs that bind to the estrogen receptor (ER) may compete with the binding of fluoroestradiol F 18 and may reduce the detection of ER-positive lesions with CERIANNA.

Before administering CERIANNA, discontinue drugs that bind to the ER, such as SERMs and SERDs, for at least 5 biological half-lives (e.g., elacestrant for 11 days, tamoxifen for 8 weeks, and fulvestrant for 28 weeks) [see Dosage and Administration (2.3)].

The relationship between fluoroestradiol F18 plasma concentrations and image interpretation has not been studied. Fluoroestradiol F18 uptake measured by PET in human tumors is directly proportional to tumor ER expression measured by in vitro assays.

Position the patient supine with arms above the head, if possible. The recommended start time for image acquisition is 80 minutes after the intravenous administration of CERIANNA. Scan duration adapted from the range of 20 minutes to 30 minutes and imaging start times adapted within the range of 20 minutes to 80 minutes may be customized according to the equipment used and patient and tumor characteristics for optimal image quality.

CERIANNA is indicated for use with positron emission tomography (PET) imaging for the detection of estrogen receptor (ER)-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer.

The point source air-kerma coefficient for F 18 is 3.75 × 10^-17 Gy m² / (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 3. The use of 8 cm Pb decreases the radiation transmission (i.e., exposure) by a factor of about 10,000.

Radiation absorbed dose estimates are shown in Table 1 for organs and tissues of adults from intravenous administration of CERIANNA. The radiation effective dose resulting from administration of 222 MBq (6 mCi) of CERIANNA to an adult weighing 70 kg is estimated to be 4.9 mSv. Critical organs include the liver, gallbladder, and uterus. When PET/CT is performed, exposure to radiation will increase by an amount dependent on the settings used for the CT acquisition.

Fluoroestradiol F 18 binds ER. The following binding affinity: Kd = 0.13 ± 0.02 nM, Bmax = 1901 ± 89 fmol/mg, and IC₅₀ = 0.085 nM, was determined in an ER-positive human breast cancer cell line (MCF-7).

Uptake of fluoroestradiol F 18 depends on ER density and function in tumors and physiologic tissue, including in liver, ovary, and uterus. Detection of ER-positive tumors should be based on comparison with tissue background outside of organs with high physiologic uptake and regions with high activity due to hepatobiliary and urinary excretion.

• Risk of Misdiagnosis. Do not use CERIANNA in lieu of biopsy when biopsy is indicated in patients with recurrent or metastatic breast cancer. Pathology or clinical characteristics that suggest a patient may benefit from systemic hormone therapy should take precedence over a discordant negative CERIANNA scan. (5.1)
• Radiation Risks. Ensure safe drug handling and patient preparation procedures to protect patients and health care providers from unintentional radiation exposure. (2.1, 2.3, 5.2)

• Recommended dose is 222 MBq (6 mCi), with a range of 111 MBq to 222 MBq (3 mCi to 6 mCi), administered as an intravenous injection over 1 to 2 minutes. (2.2)
• Recommended imaging start time is 80 minutes (range 20 minutes to 80 minutes) after drug administration. (2.4)
• See full prescribing information for additional preparation, administration, imaging, and radiation dosimetry information. (2)

Injection: clear, colorless solution in a multiple-dose vial containing 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) of fluoroestradiol F 18 at end of synthesis.

CERIANNA contains fluoroestradiol fluorine 18 (F 18), a synthetic estrogen analog. Chemically, fluoroestradiol F 18 is [18F]16α-fluoro-3,17β-diol-estratriene-1,3,5(10). The molecular weight is 289.37, and the structural formula is:

CERIANNA is a sterile, clear, colorless solution for intravenous injection, with an osmolarity of 340 mOsm. Its pH ranges between 5.5 to 8.0. The composition of the final product in 40 mL solution is fluoroestradiol no more than 5 mcg, fluoroestradiol F 18 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL), sodium ascorbate 0.44% w/v in sodium chloride 0.9% w/v, and ethanol no more than 3.2% w/v.

CERIANNA is radiolabeled with 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 2).

• Lactation: Interrupt breastfeeding. Advise a lactating woman to avoid breastfeeding for 4 hours after CERIANNA administration. (8.2)

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 CERIANNA was evaluated from published clinical studies of 1,207 patients with breast cancer receiving at least one fluoroestradiol F 18 administration. The following adverse reactions occurred at a rate < 1%:

• General disorders: injection-site pain
• Neurological and gastrointestinal disorders: dysgeusia

CERIANNA is a radioactive drug. Only authorized persons qualified by training and experience should receive, use, and administer CERIANNA. Handle CERIANNA with appropriate safety measures to minimize radiation exposure during administration [see Warnings and Precautions (5.2)]. Use waterproof gloves and effective radiation shielding, including syringe shields, when preparing and handling CERIANNA.

CERIANNA™ (fluoroestradiol F 18) Injection

148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) @ End of Synthesis

For Intravenous Use Only

Multiple-Dose Vial

Rx ONLY

Date of manufacture:

Expiration date & time:__________; ______hr:min

Lot# _______________________________________

Volume: ________ mL

Store at 20°C to 25°C (68°F to 77°F)

Store upright in a shielded container

Do not use if cloudy or if it contains particulate matter

Contains: 148 MBq/mL to 3,700 MBq/mL

(4 mCi/mL to 100 mCi/mL) of no-carrier added

fluoroestradiol F 18 @ EOS;

sodium ascorbate 0.44% w/v in sodium chloride 0.9% w/v

and ethanol no more than 3.2% w/v

Usual dosage: See prescribing information

CAUTION: RADIOACTIVE

MATERIAL

Dist.by: GE Healthcare, Inc., Arlington Heights, IL 60004 USA

GE is a trademark of General Electric Company used under

trademark license.

100112-0B

NDC 72874-001-01

Multiple-Dose Vial

CERIANNA™ (fluoroestradiol F 18) Injection

148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) @ EOS*

For Intravenous Use Only

Sterile, Non-pyrogenic

Diagnostic

Date/time of calibration: _____________; ________hr:min

Expiration date & time: _____________; ________hr:min

Volume: _______________________ mL

Lot # ________________________

Concentration: ___________mCi/mL

at time of calibration

Total Activity: ____________mCi at

time of calibration

Contains: 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100

mCi/mL) of no-carrier added fluoroestradiol F 18 @ EOS*;

sodium ascorbate 0.44% w/v in sodium chloride 0.9% w/v

and ethanol no more than 3.2% w/v

Usual dosage: See prescribing information

Do not use if cloudy or if it contains particulate matter

*EOS = End of Synthesis

CAUTION: RADIOACTIVE MATERIAL

Expires 12 hours after EOS*

Store at 20°C to 25°C (68°F to 77°F)

Store upright in a shielded container

Aseptically withdraw and handle doses

[18F] Half-Life = 109.8 minutes

Calculate correct dosage from date

and time of calibration

Dist. by: GE Healthcare, Inc.

Arlington Heights, IL 60004 USA

GE is a trademark of General Electric

Company used under trademark license.

100113-0B

Rx ONLY