Axumin

What is Axumin and how is it used?

Axumin is a prescription medicine used as a diagnostic imaging tool in Positron Emission Tomography scans (PET) for suspected Prostate Cancer. Axumin may be used alone or with other medications.

Axumin belongs to a class of drugs called Diagnostic Imaging Agents.

It is not known if Axumin is safe and effective in children.

What are the possible side effects of Axumin?

Axumin may cause serious side effects including:

• hives,
• difficulty breathing,
• swelling of your face, lips, tongue, or throat,
• chest pain or pressure,
• cough,
• trouble swallowing,
• dizziness,
• fast heartbeat,
• itching,
• skin rash, and
• unusual tiredness or weakness

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Axumin include:

• injection site pain and redness, and
• changes in taste

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Axumin. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DESCRIPTION

Chemical Characteristics

Axumin contains the fluorine 18 (F 18) labeled synthetic amino acid analog fluciclovine. Fluciclovine F 18 is a radioactive diagnostic agent used with PET imaging. Chemically, fluciclovine F 18 is (1r, 3r)-1- amino-3[¹⁸F]fluorocyclobutane-1-carboxylic acid. The molecular weight is 132.1 and the structural formula is:

Axumin is a sterile, non-pyrogenic, clear, colorless, hyperosmolal (approximately 500 - 540 mOsm/kg) injection for intravenous use. Each milliliter contains up to 2 micrograms of fluciclovine, 335 to 8200 MBq (9 to 221 mCi) fluciclovine F 18 at calibration time and date, and 20 mg trisodium citrate in water for injection. The solution also contains hydrochloric acid, sodium hydroxide and has a pH between 4 and 6.

Physical Characteristics

Fluorine 18 (F 18) is a cyclotron produced radionuclide that decays by positron emission (ß+ decay, 96.7%) and orbital electron capture (3.3%) to stable oxygen 18 with a physical half-life of 109.7 minutes. The positron can undergo annihilation with an electron to produce two gamma rays; the energy of each gamma ray is 511 keV (Table 2).

Table 2: Principal Radiation Produced from Decay of Fluorine 18 Radiation

	Energy (keV)	Abundance (%)
Positron	249.8	96.7
Gamma	511.0	193.5

External Radiation

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 of Pb will decrease the radiation transmission (i.e., exposure) by a factor of about 10,000.

Table 3: 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

INDICATIONS

Axumin is indicated for positron emission tomography (PET) in men with suspected prostate cancer recurrence based on elevated blood prostate specific antigen (PSA) levels following prior treatment.

DOSAGE AND ADMINISTRATION

Radiation Safety -Drug Handling

Axumin is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure during administration [see WARNINGS AND PRECAUTIONS]. Use waterproof gloves and effective shielding, including syringe shields, when handling and administering Axumin.

Recommended Dose And Administration Instructions

The recommended dose is 370 MBq (10 mCi) administered as an intravenous bolus injection.

• Inspect Axumin 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 Axumin.
• Calculate the necessary volume to administer based on calibration time and date, using a suitably calibrated instrument. The recommended maximum volume of injection of undiluted Axumin is 5mL.
• Axumin may be diluted with 0.9% Sodium Chloride Injection, USP.
• After the Axumin 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.

Patient Preparation Prior To PET Imaging

• Advise the patient to avoid any significant exercise for at least one day prior to PET imaging.
• Advise patients not to eat or drink for at least 4 hours (other than sips of water for taking medications) prior to administration of Axumin.
• Advise patients to void approximately 30 minutes to 60 minutes prior to administration of Axumin and then refrain from voiding until after the scan has been completed

Image Acquisition Guidelines

Position the patient supine with arms above the head. Begin PET scanning 3 minutes to 5 minutes after completion of the Axumin injection. It is recommended that image acquisition should start from mid-thigh and proceed to the base of the skull. Typical total scan time is between 20 minutes to 30 minutes.

Image Display And Interpretation

Localization of prostate cancer recurrence in sites typical for prostate cancer recurrence is based on fluciclovine F 18 uptake in comparison with tissue background. For small lesions (less than 1cm in diameter) focal uptake greater than blood pool should be considered suspicious for prostate cancer recurrence. For larger lesions, uptake equal to or greater than bone marrow is considered suspicious for prostate cancer recurrence.

Radiation Dosimetry

The radiation absorbed doses estimated for adult patients following intravenous injection of Axumin are shown in Table 1. Values were calculated from human biodistribution data using OLINDA/EXM (Organ Level Internal Dose Assessment/Exponential Modeling) software.

The (radiation absorbed) effective dose resulting from the administration of the recommended activity of 370 MBq of Axumin is 8 mSv. For an administered activity of 370 MBq (10 mCi), the highest-magnitude radiation doses are delivered to the pancreas, cardiac wall, and uterine wall: 38 mGy, 19 mGy, and 17 mGy, respectively. If a CT scan is simultaneously performed as part of the PET procedure, exposure to ionizing radiation will increase in an amount dependent on the settings used in the CT acquisition.

Table 1: Estimated Radiation Absorbed Doses in Various Organs/Tissues in Adults who Received Axumin

Organ/Tissue	Mean Absorbed Dose per Unit Administered Activity (microGy/MBq)
Adrenal glands	16
Brain	9
Breasts	14
Gallbladder wall	17
Lower large intestine wall	12
Small intestine wall	13
Stomach wall	14
Upper large intestine wall	13
Heart wall	52
Kidneys	14
Liver	33
Lungs	34
Muscle	11
Ovaries	13
Pancreas	102
Red bone marrow	25
Osteogenic cells	23
Skin	8
Spleen	24
Testes	17
Thymus gland	12
Thyroid	10
Urinary bladder wall	25
Uterus	45
Total body	13
Effective dose	22 (microSv/MBq)

HOW SUPPLIED

Dosage Forms And Strengths

Injection: supplied as a clear, colorless solution in a 30 mL or 50 mL multiple-dose vial containing 335 MBq/mL to 8,200 MBq/mL (9 mCi/mL to 221 mCi/mL) fluciclovine F 18 at calibration time and date.

Axumin is supplied as a clear, colorless injection in a 30 mL or 50 mL multiple-dose glass vial containing approximately 26 mL solution of 335 MBq/mL to 8,200 MBq/mL (9 mCi/mL to 221 mCi/mL) fluciclovine F 18 at calibration time and date.

30 mL sterile multiple-dose vial: NDC 69932-001-30
50 mL sterile multiple-dose vial: NDC 69932-001-50

Storage And Handling

Store Axumin at controlled room temperature (USP) 20°C to 25°C (68°F to 77°F). Axumin does not contain a preservative. Store Axumin within the original container in radiation shielding. Do not use Axumin more than 10 hours after end of synthesis and dispose of in accordance with institutional guidelines.

This preparation is approved for use by persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.

Marketed by Blue Earth Diagnostics Ltd. Oxford, UK OX4 4GA. Revised: May 2021

SIDE EFFECTS

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 clinical trial database for Axumin includes data from 877 subjects including 797 males diagnosed with prostate cancer. Most patients received a single administration of Axumin, a small number of subjects (n = 50) received up to five administrations of the drug. The mean administered activity was 370 MBq (range, 163 MBq to 485 MBq).

Adverse reactions were reported in ≤1% of subjects during clinical studies with Axumin. The most common adverse reactions were injection site pain, injection site erythema and dysgeusia.

DRUG INTERACTIONS

No Information Provided

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk For Image Misinterpretation

Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. The performance of Axumin seems to be affected by PSA levels [See Clinical Studies]. Fluciclovine F 18 uptake is not specific for prostate cancer and may occur with other types of cancer and benign prostatic hypertrophy in primary prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended.

Hypersensitivity Reactions

Hypersensitivity reactions including anaphylaxis may occur in patients who receive Axumin. Emergency resuscitation equipment and personnel should be immediately available.

Radiation Risks

Axumin 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. Ensure safe handling to minimize radiation exposure to the patient and health care providers [see DOSAGE AND ADMINISTRATION].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No long term studies in animals have been performed to evaluate the carcinogenic potential of fluciclovine.

Mutagenesis

Fluciclovine was not mutagenic in vitro in reverse mutation assay in bacterial cells and in chromosome aberration test in cultured mammalian cells, and was negative in an in vivo clastogenicity assay in rats after intravenous injection of doses up to 43 mcg/kg. However, fluciclovine F 18 has the potential to be mutagenic because of the F 18 radioisotope.

Impairment Of Fertility

No studies in animals have been performed to evaluate potential impairment of fertility in males or females.

Use In Specific Populations

Pregnancy

Risk Summary

Axumin is not indicated for use in females and there is no information on the risk of adverse development outcomes in pregnant women or animals with the use of fluciclovine F 18.

Lactation

Risk Summary

Axumin is not indicated for use in females and there is no information of the presence of fluciclovine F 18 in human milk.

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

Geriatric Use

Of the total number of patients in clinical studies of Axumin, the average age was 66 years with a range of 21 to 90 years. No overall differences in safety or effectiveness were observed between older subjects and younger subjects.

OVERDOSE

In case of overdose of Axumin, encourage patients to maintain hydration and to void frequently to minimize radiation exposure.

CONTRAINDICATIONS

None

CLINICAL PHARMACOLOGY

Mechanism Of Action

Fluciclovine F 18 is a synthetic amino acid transported across mammalian cell membranes by amino acid transporters, such as LAT-1 and ASCT2, which are upregulated in prostate cancer cells. Fluciclovine F 18 is taken up to a greater extent in prostate cancer cells compared with surrounding normal tissues.

Pharmacodynamics

Following intravenous administration, the tumor-to-normal tissue contrast is highest between 4 and 10 minutes after injection, with a 61% reduction in mean tumor uptake at 90 minutes after injection.

Pharmacokinetics

Distribution

Following intravenous administration, fluciclovine F 18 distributes to the liver (14% of administered activity), pancreas (3%), lung (7%), red bone marrow (12%) and myocardium (4%). With increasing time, fluciclovine F 18 distributes to skeletal muscle.

Excretion

Across the first four hours post-injection, 3% of administered radioactivity was excreted in the urine.

Across the first 24 hours post-injection, 5% of administered radioactivity was excreted in the urine.

Clinical Studies

The safety and efficacy of Axumin were evaluated in two studies (Study 1 and Study 2) in men with suspected recurrence of prostate cancer based on rising PSA levels following radical prostatectomy and/or radiotherapy.

Study 1 evaluated 105 Axumin scans in comparison to histopathology obtained by biopsy of the prostate bed and biopsies of lesions suspicious by imaging. PET/CT imaging generally included the abdomen and pelvic regions. The Axumin images were originally read by on-site readers. The images were subsequently read by three blinded independent readers. Table 4 shows the performance of Axumin in the detection of recurrence in each patient scan and, specifically, within the prostatic bed and extra-prostatic regions, respectively. The results of the independent read were generally consistent with one another and confirmed the results of the on-site reads.

Table 4: Performance of Axumin in Patients with Biochemically Suspected Recurrent Prostate Cancer, at the Patient Level and at the Prostate Bed and Extraprostatic Region Levels

	Reader 1	Reader 2	Reader 3
Patient	N = 104	N = 105	N = 99
True Positive	75	72	63
False Positive	24	23	13
True Negative	5	7	15
False Negative	0	3	8
Prostate Bed	N = 98	N = 97	N = 96
True Positive	58	56	47
False Positive	29	26	15
True Negative	10	12	24
False Negative	1	3	10
Extraprostatic	N = 28	N = 28	N = 25
True Positive	25	26	22
False Positive	2	2	2
True Negative	0	0	0
False Negative	1	0	1
N = number of patient scans evaluated

The detection rate of Axumin seems to be affected by PSA levels [see WARNINGS AND PRECAUTIONS]. In general, patients with negative scans had lower PSA values than those with positive scans. The detection rate (number with positive scans/total scanned) for patients with a PSA value of less than or equal to 1.78 ng/mL (1st PSA quartile) was 15/25, of which 11 were histologically confirmed as positive. In the remaining three PSA quartiles, the detection rate was 71/74, of which 58 were histologically confirmed. Among the 25 patients in the first PSA quartile, there were 4 false positive scans and 1 false negative scan. For the 74 patients with PSA levels greater than1.78 ng/mL, there were 13 false positive scans and no false negative scans.

Study 2 evaluated the concordance between 96 Axumin and C11 choline scans in patients with median PSA value of 1.44 ng/mL (interquartile range = 0.78 ng/mL to 2.8 ng/mL). The C 11 choline scans were read by on-site readers. The Axumin scans were read by the same three blinded independent readers used for Study 1. The agreement values between the Axumin and C11 choline reads were 61%, 67% and 77%, respectively.

PATIENT INFORMATION

• Instruct patients to avoid significant exercise for at least a day before the PET scan.
• Instruct patients not to eat or drink for at least 4 hours before the PET scan (other than sips of water for taking medications).
• Instruct patients to try to urinate approximately 30 minutes to 60 minutes prior to planned start time of the PET scan and to avoid further urination until after the scan has been completed.