Netspot Dosage

2.1 Radiation Safety

Drug Handling
After radiolabeling, handle the gallium Ga 68 dotatate injection with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.1)]. Use waterproof gloves, effective radiation shielding and appropriate safety measures when preparing and handling gallium Ga 68 dotatate injection.

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.

Patient Preparation
Instruct patients to drink a sufficient amount of water to ensure adequate hydration prior to administration of gallium Ga 68 dotatate injection. Drink and void frequently during the first hours following administration to reduce radiation exposure.

2.2 Recommended Dosage and Administration Instructions

In adults and pediatric patients, the recommended amount of radioactivity to be administered for PET imaging is 2 MBq/kg (0.054 mCi/kg) of body weight up to 200 MBq (5.4 mCi) by intravenous injection (bolus).

Verify the injected radioactivity by measuring the radioactivity of the syringe containing the gallium Ga 68 dotatate injection with a dose calibrator before administration to the patient [see Dosage and Administration (2.4)]. Ensure that the injected radioactivity is within ± 10% of the recommended activity.

2.3 Drug Preparation

The NETSPOT kit is supplied as 2 vials [see Dosage Forms and Strengths (3)] which allows for direct preparation of gallium Ga 68 dotatate injection with the eluate from one of the following generators (see below for specific instructions for use with each generator):

• Eckert & Ziegler GalliaPharm germanium-68/gallium-68 (68Ge/68Ga) generator
• IRE ELiT Galli Eo germanium-68/gallium-68 (68Ge/68Ga) generator

The 68Ge/68Ga generators are not supplied with the NETSPOT kit.

Components of the kit:

• Vial 1 (reaction vial with lyophilized powder) contains: 40 mcg dotatate, 5 mcg 1,10-phenanthroline; 6 mcg gentisic acid; 20 mg mannitol.
• Vial 2 (buffer vial) contains: 60 mg formic acid; 56.5 mg sodium hydroxide and water for injection.

Ancillary supplies (not included in the kit):

• ​Ancillary supplies needed (not supplied in kit): 1 mL sterile plastic syringe, 5 mL sterile plastic syringe, non-metallic or silicone coated sterile needles (size 21 to 23G), 0.2 micron sterile vented filter.

Prepare gallium Ga 68 dotatate injection according to the following aseptic procedure:

a. Use suitable shielding to reduce radiation exposure.

b. Wear waterproof gloves.

c. Test periodically (weekly) the gallium-68 chloride eluate for germanium-68 breakthrough by suitable method. Germanium-68 breakthrough and other gamma emitting radionuclides should be ≤ 0.001%.

d. Set the temperature of the shielded dry bath to 95°C (203°F) and wait for the temperature to reach the set point and stabilize.

e. Prepare syringes for elution and radiolabeling steps per Table 1 below.

f. Use non-metallic or silicone coated needles to minimize trace metal impurity levels. Radiolabeling of carrier molecules with gallium-68 chloride is very sensitive to the presence of trace metal impurities.

g. Use 1 mL low dead space plastic syringe to precisely measure the adequate volume of reaction buffer to be added during preparation. Do not use glass syringe.

h. Prior to piercing vial septums, flip the cap off and swab the top of the vial closure with alcohol to disinfect the surface, and allow the stopper to dry.

Table 1. Solutions for Generator Elution and Radiolabeling Reaction

Solutions for use with Eckert & Ziegler GalliaPharm generator
Syringe	Solution	Purpose
5 mL sterile plastic syringe	5 mL of 0.1 N sterile HCl supplied by the generator manufacturer	For elution of the generator
1 mL sterile plastic syringe	Vial 2 buffer Calculate the volume (in mL) by multiplying the volume of HCl used for the elution of the generator in mL by its molarity: Reaction buffer volume in mL = HCl volume in mL x HCl molarity (5 mL x 0.1 N = 0.5 mL of reaction buffer).	For radiolabeling reaction
Solutions for use with IRE Galli Eo generator
5 mL sterile plastic syringe	3.9 mL sterile water for injection	For preliminary dilution of Vial 1
1 mL sterile plastic syringe	Vial 2 buffer Calculate the volume (in mL) by multiplying the volume of HCl used for the elution of the generator in mL by its molarity: Reaction buffer volume in mL = HCl volume in mL x HCl molarity (1.1 mL x 0.1 N = 0.11 mL of reaction buffer).	For radiolabeling reaction

i. Pierce the Vial 1 septum with a sterile needle connected to a 0.2 micron sterile vented filter (not supplied) to maintain atmospheric pressure within the vial during the radiolabeling process.

j. Follow the generator specific radiolabeling procedures below. Then continue with the incubation step k.

Radiolabeling with Eckert & Ziegler GalliaPharm generator

• ​Connect the male luer of the outlet line of the GalliaPharm generator to a sterile needle (size 21G to 23G).
• Connect Vial 1 directly to the outlet line of the GalliaPharm generator by pushing the needle through the rubber septum and place the vial in a lead shield container.
• Elute the generator directly into the Vial 1 according to the instructions for use of the GalliaPharm generator that are supplied by Eckert & Ziegler, in order to reconstitute the lyophilized powder with 5 mL of eluate. Perform the elution manually or by means of a pump.
• ​At the end of the elution, disconnect the generator from Vial 1 by removing the needle from the rubber septum, and immediately (do not delay buffer addition more than 10 min) add the kit reaction buffer in the 1 mL sterile syringe (size 21G to 23G; the amount of reaction buffer was determined in Table 1).
• Withdraw the syringe and the 0.2 micron sterile air venting filter.

Radiolabeling with IRE Galli Eo generator

• ​Set the Galli Eo generator for the elution according to manufacturer instructions. Connect a sterile needle (size 21G to 23G) to the outlet tube of the generator, turn the button by 90° to loading position then wait 10 seconds before turning the button back to the initial position.
• Reconstitute Vial 1 with 3.9 mL of sterile water for injection as prepared in Table 1.
• Add the 0.1 mL reaction buffer to Vial 1 as prepared in Table 1.
• Connect Vial 1 to the outlet line of the Galli Eo generator by pushing the needle through the rubber septum.
• Connect one end of the two male luer ends of a sterile extension line to the 0.2 micron sterile vent filter inserted into Vial 1.
• Assemble a sterile needle on the second male luer end of the sterile extension line and connect it to a sterile evacuated vial (17 mL minimum volume) by pushing the needle through the rubber septum. The generator elution will start.
• Wait for the elution to be completed (minimum 3 minutes, according to the Galli Eo generator manufacturer instructions for use).
• At the end of the elution, first withdraw the needle from the evacuated vial in order to establish atmospheric pressure into Vial 1, then disconnect Vial 1 from the generator by removing the needle from the rubber septum and remove the 0.2 micron sterile vent filter from Vial 1.

Incubation

k. Using a tong, move Vial 1 to the heating hole of the dry bath, and leave the vial at 95°C (203°F), not to exceed 98°C (208°F), for at least 7 minutes (do not exceed 10 minutes heating) without agitation or stirring.

l. After 7 minutes, remove the vial from the dry bath, place it in an appropriate lead shield and let it cool down to room temperature for approximately 10 minutes.

m. Assay the whole vial containing the gallium Ga 68 dotatate injection for total radioactivity concentration using a dose calibrator and record the result.

n. Perform the quality controls according to the recommended methods in order to check the compliance with the specifications [see Dosage and Administration (2.5)].

o. Prior to use, visually inspect the solution behind a shielded screen for radioprotection purposes. Only use solutions that are clear without visible particles.

p. Keep the vial containing the gallium Ga 68 dotatate injection upright in a radio-protective shield container at a temperature below 25°C (77°F) until use.

​q. After addition of gallium-68 chloride to the reaction vial, use gallium Ga 68 dotatate injection within 4 hours. After radiolabeling, do not perform further dilutions.

Figure 1. Radiolabeling Procedure for Eckert & Ziegler GalliaPharm Generator​

Figure 2. Radiolabeling Procedure for IRE Galli Eo Generator​

2.4 Administration

Prior to use, visually inspect the prepared gallium Ga 68 dotatate injection behind a lead glass shield for radioprotection purposes. Only use solutions that are clear without visible particles. Using a single-dose syringe fitted with a sterile needle (size 21G to 23G) and protective shielding, aseptically withdraw the prepared gallium Ga 68 dotatate injection prior to administration. Measure the total radioactivity in the syringe by a dose calibrator immediately prior to administration. The dose calibrator must be calibrated with National Institute of Standards and Technology (NIST) traceable standards.

Accidental extravasation may cause local irritation due to the acidic pH of the gallium Ga 68 dotatate injection. In case of extravasation, the injection must be stopped, the site of injection must be changed and the affected area should be irrigated with 0.9% Sodium Chloride Injection, USP.

Handle and dispose radioactive material in accordance with applicable regulations.

2.5 Specifications and Quality Control

Perform the quality controls in Table 2 behind a lead glass shield for radioprotection purposes.

Table 2. Specifications of Gallium Ga 68 Dotatate Injection

Test	Acceptance criteria	Method
Appearance	Colorless and particulate free	Visual inspection
pH	3.2 to 3.8	pH-indicator strips
Labeling efficiency	Gallium Ga 68 dotatate ≥ 95% and other gallium-68 species ≤ 5%	Thin layer chromatography (ITLC, see details below)

Determine labeling efficiency of gallium Ga 68 dotatate injection applying one of the following recommended methods:

Obtain the following materials:

• ITLC SA or ITLC SG
• Ammonium acetate 1M: Methanol (1:1 V/V)
• Developing tank
• Radiometric TLC scanner

ITLC methods 1 and 2 (longer development length)

Perform the following:

1. Pour ammonium acetate 1M: Methanol (1:1 V/V) solution to a depth of 3 mm to 4 mm in the developing tank, cover the tank, and allow it to equilibrate.
2. Apply a drop of the gallium Ga 68 dotatate injection on a pencil line 1 cm from the bottom of the ITLC strip.
3. Place the ITLC strip in the developing tank and allow it to develop for a distance of 10 cm from the point of application (i.e., to the top pencil mark).
4. Scan the ITLC with a radiometric TLC scanner.
5. Calculate radiochemical purity (RCP) by integration of the peaks on the chromatogram. Do not use the reconstituted product if the RCP is less than 95%.
6. The retention factor (Rf) specifications are as follows for ITLC SA or ITLC SG:
   ITLC SA: Non-complexed gallium-68 species, Rf = 0 to 0.1; gallium Ga 68 dotatate, Rf = 0.6 to 0.8
   ITLC SG: Non-complexed gallium-68 species, Rf = 0 to 0.1; gallium Ga 68 dotatate, Rf = 0.8 to 1

ITLC method 3 (shorter development length)

Perform the following:

a) Pour ammonium acetate 1M: Methanol (1:1 V/V) solution to a depth of 3 mm to 4 mm in the developing tank, cover the tank, and allow it to equilibrate.

b) Apply a drop of the gallium Ga 68 dotatate injection on a pencil line 1 cm from the bottom of an ITLC SG strip.

c) Place the ITLC SG strip in the developing tank and allow it to develop for a distance of 6 cm from the point of application (i.e., to 7 cm from the bottom of the ITLC strip).

d) Scan the ITLC SG with a radiometric TLC scanner.

e) Calculate radiochemical purity (RCP) by integration of the peaks on the chromatogram. Do not use the reconstituted product if the RCP is less than 95%.

f) The retention factor (Rf) specifications are as follows:
Non-complexed gallium-68 species, Rf = 0 to 0.1; gallium Ga 68 dotatate, Rf = 0.8 to 1

2.6 Image Acquisition

For gallium Ga 68 dotatate PET imaging, the acquisition must include a whole body acquisition from skull to mid-thigh. Images can be acquired 40 minutes to 90 minutes after the intravenous administration of the gallium Ga 68 dotatate. Adapt imaging acquisition delay and duration according to the equipment used, and the patient and tumor characteristics, in order to obtain the best image quality possible.

2.7 Image Interpretation

Gallium Ga 68 dotatate binds to somatostatin receptors. Based upon the intensity of the signals, PET images obtained using gallium Ga 68 dotatate indicate the presence and density of somatostatin receptors in tissues. Tumors that do not bear somatostatin receptors will not be visualized. Increased uptake in tumors is not specific for NET [see Warnings and Precautions (5.3)].

2.8 Radiation Dosimetry

Estimated radiation absorbed doses per injection activity for organs and tissues of adult patients following an intravenous bolus of gallium Ga 68 dotatate are shown in Table 3. Estimated radiation effective doses per injection activity for adult and pediatric patients following an intravenous bolus of gallium Ga 68 dotatate are shown in Table 4.

Gallium-68 decays with a half-life of 68 minutes to stable zinc-68:

• 89% through positron emission with a mean energy of 836 keV followed by photonic annihilation radiations of 511 keV (178%),
• 10% through orbital electron capture (X-ray or Auger emissions), and
• 3% through 13 gamma transitions from 5 exited levels.

The radiation effective dose resulting from the administration of 150 MBq (4.05 mCi) [within the range of the recommended gallium Ga 68 dotatate injection dose] to an adult weighing 75 kg, is about 3.15 mSv. For an administered activity of 150 MBq (4.05 mCi) the typical radiation absorbed dose to the critical organs, which are the urinary bladder wall, the spleen, the kidneys and the adrenals, are about 15 mGy, 16 mGy, 14 mGy and 13 mGy, respectively. Because the spleen has one of the highest physiological uptakes, higher uptake and radiation dose to other organs or pathologic tissues may occur in patients with spleen disorders (e.g., splenectomy and/or splenosis) [see Warnings and Precautions (5.3)].

Physical data
Gamma constant: 0.67 mrem/hr per mCi at 1 meter [1.8E-4 mSv/hr per MBq at 1 meter]
Specific Activity: 4.1E7 Ci/g [1.51E18 Bq/g] max

Table 3. Estimated Radiation Absorbed Dose per Injection Activity in Selected Organs and Tissues of Adults from Intravenous Administration of Gallium Ga 68 Dotatate Injection

Organ/Tissue	Absorbed dose per administered activity (mGy/MBq)
	Mean	SD
Adrenals	0.086	0.052
Brain	0.01	0.002
Breasts	0.01	0.002
Gallbladder wall	0.016	0.002
Lower large intestine wall	0.015	0.002
Small intestine	0.025	0.004
Stomach wall	0.013	0.002
Upper large intestine wall	0.021	0.003
Heart wall	0.018	0.003
Kidneys	0.093	0.016
Liver	0.05	0.015
Lungs	0.006	0.001
Muscle	0.012	0.002
Ovaries	0.016	0.001
Pancreas	0.015	0.002
Red marrow	0.015	0.003
Osteogenic cells	0.021	0.005
Skin	0.01	0.002
Spleen	0.109	0.058
Testes	0.01	0.001
Thymus	0.012	0.002
Thyroid	0.011	0.002
Urinary bladder wall	0.098	0.048
Uterus	0.015	0.002
Total body	0.014	0.002
Effective dose per injection activity	mSv/MBq
	0.021	0.003

Table 4. Estimated Radiation Effective Dose per Injection Activity after a Gallium Ga 68 Dotatate Injection Dose

Age	Effective dose per injection activity (mSv/MBq)
Adult	0.021
15 years	0.025
10 years	0.04
5 years	0.064
1 year	0.13
Newborn	0.35

Table 4 indicates how effective dose per injection activity scales with body habitus in computational models of adult and pediatric patients.