2.1 Radiation Safety - Drug Handling

Choline C 11 Injection is a radioactive drug and should be handled with appropriate safety measures to

minimize radiation exposure during administration. Use waterproof gloves and effective shielding when

handling Choline C 11 Injection. Radiopharmaceuticals, including Choline C 11 Injection, should only be used

by or under the control of physicians who are qualified by specific training and experience in the safe use and

handling of radioactive materials, 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

The recommended dose is 370 – 740 MBq (10 – 20 mCi) administered as a bolus intravenous injection. The

radioactivity dose (370 – 740 MBq, 10 – 20 mCi) is chosen based on patient body dimensions and the

characteristics of the image acquisition system

• Inspect Choline C 11 Injection visually for particulate matter and discoloration before administration. Do not use the drug if the solution contains particulate matter or is discolored.
• Aseptically withdraw Choline C 11 Injection from its container and administer the drug as a bolus through a peripheral venous catheter.
• Dispose of any unused drug in a safe manner, in compliance with applicable regulations.

2.3 Patient Preparation

Prior to administration of Choline C 11 Injection:

• Fasting for at least six hours is recommended to minimize the potential for dietary choline interference with radioactivity uptake in tissue.
• Ensure that the patient is well hydrated and encourage voiding when imaging is completed.

2.4 Radiation Dosimetry

The estimated radiation absorbed doses for adults from intravenous injection of Choline C 11 Injection are shown in Table 1.  These estimates are calculated from data in Tolvanen 1 and using OLINDA/EXM (Organ Level Internal Dose Assessment/Exponential Modeling) software from Vanderbilt University. 2

aGastrointestinal

bAssumed radiation weighting factor, w r, (formerly defined as quality factor, Q) of 1 for conversion of

absorbed dose (Gray or rad) to dose equivalent (Sieverts or rem) for C 11. To obtain radiation absorbed dose in

rad/mCi from the above table, multiply the dose in μGy/MBq by 0.0037, (e.g.,3.59 μGy/MBq x 0.0037 =

0.0133 rad/mCi).

cRadiation tissue weighting factors, wT, used in the calculation of effective dose are from 1990

Recommendations of the International Commission on Radiological Protection, ICRP Publication 60 (1991). To

obtain radiation absorbed dose in rem/mCi from above table, multiply the dose in μGy/MBq by 0.0037, (e.g.,

4.35 μGy/MBq x 0.0037 = 0.0161 rem/mCi).

The effective dose resulting from a 740 MBq (20 mCi) dosage of Choline C 11 Injection is 3.22 mSv in

an adult, (740 x 4.35 = 3219 μSv = 3.22 mSv). The use of a CT scan to calculate attenuation correction

for reconstruction of 11C-choline images (as done in PET/CT imaging) will add radiation exposure.

Based upon current scanning techniques, an effective dose of 5.8 mSv would be added from CT

scanning. The actual radiation dose is operator, scanner, and patient dependent. The total radiation

exposure from 11C-choline administration and subsequent scan on a PET/CT scanner is estimated to be

9.0 mSv (3.2 mSv + 5.8 mSv).

2.5 Imaging Guidelines

• Initiate image acquisition immediately after administration of Choline C 11 Injection. Imaging is typically performed from the base of the pelvis to the base of the skull.
• Acquire static emission images 0 to 15 minutes from the time of injection.
• Localized uptake of 11 C-choline in a site suspicious for prostate cancer recurrence (a positive image) is determined by comparison of the anatomical relationship of concentrated radioactivity to the neighboring tissue background, exclusive of the radioactivity physiologically accumulated within the pancreas, liver, spleen, kidney and colon.

5.1 Imaging Errors

Imaging errors have been reported with 11C-choline PET and PET/CT 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

cancer.   11C-choline uptake is not specific for prostate cancer and may occur with other types of cancer (such as

lung carcinoma and brain tumors). Clinical correlation, including histopathological evaluation of the suspected

recurrence site, is essential to proper use of the PET imaging information.

• Blood PSA levels < 2 ng/mL have been associated with poor performance of 11C-choline PET imaging (higher numbers of false positive and false negative results) [ see Clinical Studies (14)].
• Tissue inflammation as well as prostatic hyperplasia have been associated with false positive 11C-choline PET images.
• Concomitant colchicine or androgen-deprivation therapeutic drugs (such as luteinizing hormone-releasing analogs and anti-androgen drugs) may interfere with 11C-choline PET imaging. One published report of 18F-methylcholine PET imaging indicated that discontinuation of colchicine for two weeks resolved the colchicine effect. The impact of discontinuation of androgen-deprivation therapy upon 11C-choline PET imaging has not been established [ see Drug Interactions (7)].

5.2 Allergic Reactions

As with any injectable drug product, allergic reactions and anaphylaxis may occur. Emergency resuscitation equipment and personnel should be immediately available.

5.3 Radiation Risks

Choline C 11 Injection contributes to a patient’s overall long-term cumulative radiation exposure. Long- term cumulative radiation exposure is associated with an increased risk for cancer. Safe handling should be ensured to minimize radiation exposure to the patient and health care workers [ see Dosage and Administration (2.1)] .

8.1 Pregnancy

Pregnancy Category C.

There are no adequate and well controlled studies with Choline C 11 Injection in pregnant women and the fetal radiation dose from a 11C-choline PET imaging study is unknown. It is not known whether Choline C 11 Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Animal reproduction studies have not been conducted with 11C-choline.

All radiopharmaceuticals, including Choline C 11 Injection, have a potential to cause fetal harm. The likelihood of fetal harm depends on the stage of fetal development and the magnitude of the radiopharmaceutical dose. Assess pregnancy status before administering Choline C 11 Injection to a female of child bearing potential. Choline C 11 Injection should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

Choline C 11 Injection is not indicated for use in women. It is not known whether Choline C 11 Injection is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for radiation exposure to nursing infants from Choline C 11 Injection, nursing mothers should use alternative infant nutrition sources (e.g., stored breast milk or infant formula) and pump and discard breast milk for 8 hours (>10 half-lives of radioactive decay for 11C isotope) after administration of the drug or avoid use of the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Choline C 11 Injection have not been established in pediatric patients.

11.1 Chemical Characteristics

Choline C 11 Injection is a positron emitting radiopharmaceutical that is used for diagnostic purposes in conjunction with PET imaging. The active ingredient, 11C-choline, has the molecular formula of  C4 11CH 14NOCl with a molecular weight of 138.63 g and has the following chemical structure:

Choline C 11 Injection is provided as a ready to use sterile, pyrogen-free, clear and colorless solution.  Each milliliter contains 148 MBq to 3,700 MBq (4 mCi - 100 mCi) of 11C-choline at EOS calibration time in aqueous 0.9% sodium chloride solution.  The pH of the solution is between 4.5 and 8.0. 

11.2 Physical Characteristics

Carbon 11 is a cyclotron-produced radionuclide that decays to Boron 11 by positron emission and has a physical half-life of 20.4 minutes (Table 2).

Table 2: Principal Radiation Emission Data for 11C

*Produced by positron annihilation

The specific gamma ray constant (point source air kerma coefficient) for 11C-choline is 5.8 R/mCi-hr at 1 cm. Selected coefficients of attenuation are listed in Table 3 as a function of lead shield thickness. For example, the use of 39 mm thickness of lead will attenuate the external radiation by a factor of about 1,000.

Table 3:  Radiation Attenuation of 511 keV Photons by lead(Pb) shielding

Table 4 lists fractions remaining at selected time intervals from the calibration time. This information may be used to correct for physical decay of the radionuclide.

Table 4: Physical Decay Chart for 11C

*Calibration time

12.1  Mechanism of Action

Choline C 11 Injection is a radiolabeled analog of choline, a precursor molecule essential for the  biosynthesis of cell membrane phospholipids. Choline is involved in synthesis of the structural components of cell membranes, as well as modulation of trans-membrane signaling. Increased phospholipid synthesis (i.e., increased uptake of choline) has been associated with cell proliferation and the transformation process that occurs in tumor cells.

12.2  Pharmacodynamics

In a study of men with prostatic hyperplasia or primary prostate cancer, PET imaging showed 11C- choline  radioactivity accumulated rapidly within the prostate; uptake appeared to peak by five minutes following injection of the drug and activity was retained over the subsequent 30 minute scanning period. Little uptake was observed in the bladder and rectum.

12.3  Pharmacokinetics

Distribution:  11C-choline distributes mainly to the pancreas, kidneys, liver, spleen and colon [ see Dosage and Administration (2.4)].  Based upon the relatively low urinary excretion of radioactivity, renal distribution is predominantly to the organ itself, rather than via formation of urine.

Metabolism: Following intravenous administration, 11C-choline undergoes metabolism resulting in the  detection of 11C-betaine as the major metabolite in blood. In a study of patients with prostate cancer or brain disorders, the fractional activities of 11C-choline and 11C-betaine in human arterial plasma appeared to reach a plateau within 25 minutes, with 11C-betaine representing 82% ± 9% of the total 11C detected at that time point. A small amount of unmetabolized 11C-choline was detected within the blood at the final sampling time point (40 minutes).

Elimination: Urinary excretion of 11C-choline was < 2% of the injected radioactivity at 1.5 hours after  injection of the drug. The rate of 11C-choline excretion in urine was 0.014 mL/min.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies have not been performed to evaluate the carcinogenic potential of Choline C 11  Injection. The mutagenic potential of Choline C 11 Injection has not been adequately evaluated; however, any radiopharmaceutical, including Choline C 11 Injection, has the potential to be mutagenic. The effect of Choline C 11 Injection on fertility has not been evaluated.

16.1 How Supplied

Choline C 11 Injection is packaged in a glass vial containing between 148 MBq to 3,700 MBq (4 mCi to 100 mCi) of 11C-choline at EOS calibration time in aqueous 0.9% sodium chloride solution (approximately 10 mL volume).

16.2 Storage and Handling

Store Choline C 11 Injection at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) (see USP Controlled Room Temperature). Use the solution within 90 minutes of EOS calibration.

FINAL PRODUCT VIAL LABEL