Label: GA-68-DOTATOC- edotreotide gallium ga-68 injection, solution
- NDC Code(s): 24417-681-30
- Packager: UIHC – P E T Imaging Center
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: New Drug Application
Updated December 8, 2021
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Ga 68 DOTATOC INJECTION safely and effectively. See full prescribing information for Ga 68 DOTATOC INJECTION.
Ga 68 DOTATOC Injection, for intravenous use
Initial U.S. Approval: 2019
RECENT MAJOR CHANGES
Warnings and Precautions (5.2) 12/2021
INDICATIONS AND USAGE
Ga 68 DOTATOC Injection is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients. (1)
DOSAGE AND ADMINISTRATION
- Recommended dose for adults is 148 MBq (4 mCi) as a bolus intravenous injection (2.2)
- Recommended dose for pediatric patients is 1.59 MBq/kg (0.043 mCi/kg) with a range of 11.1 MBq (0.3 mCi) to 111 MBq (3 mCi), as a bolus intravenous injection (2.2)
- Initiate imaging 55 to 90 minutes after drug administration (2.4)
- See full prescribing information for additional preparation, administration, imaging and radiation dosimetry information (2)
DOSAGE FORMS AND STRENGTHS
Injection: 18.5 MBq/mL to 148 MBq/mL (0.5 mCi/mL to 4 mCi/mL) of Ga 68 DOTATOC Injection in a multiple-dose glass vial (3)
WARNINGS AND PRECAUTIONS
- Radiation Risk: 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 (2.1, 2.3, 5.1)
- Hypersensitivity Reactions: Most reported reactions were rash and pruritus and reversible either spontaneously or with routine symptomatic management. (5.2)
- Risk for Image Misinterpretation: Uptake of Ga 68 DOTATOC injection can be seen in a variety of tumor types that contain somatostatin receptors, and in other pathologic conditions, and as a normal physiologic variant (e.g. uncinate process of the pancreas) (5.3)
Reported adverse reactions include: Nausea, pruritis, and flushing.
To report SUSPECTED ADVERSE REACTIONS, contact the UIHC – P E T Imaging Center at 1-319-356-1092 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch (6)
Somatostatin Analogs: Somatostatin analogs competitively bind to the same somatostatin receptors as Ga 68 DOTATOC Injection and may affect imaging –Discontinue short-acting somatostatin analogs 24 hours before imaging with Ga 68 DOTATOC and image just prior to dosing with long-acting somatostatin analogs (2.3, 7)
USE IN SPECIFIC POPULATIONS
Lactation: Breast milk should be pumped and discarded for 8 hours after administration (8.2)
See 17 for PATIENT COUNSELING INFORMATION.
Table of Contents
FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Radiation Safety – Drug Handling
Handle Ga 68 DOTATOC 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 Ga 68 DOTATOC 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.
2.2 Recommended Dosage and Administration Instructions
In adults, the recommended amount of radioactivity to be administered for PET imaging is 4 mCi (148 MBq) with a range of 3 mCi to 5 mCi (111 MBq to 185 MBq) administered as an intravenous injection with an injection rate of approximately 10 seconds per mL.
In pediatric patients, the recommended amount of radioactivity to be administered for PET imaging is 0.043 mCi/kg of body weight (1.59 MBq/kg) with a range of 0.3 mCi (11.1 MBq) to 3 mCi (111 MBq) as an intravenous injection with an injection rate of approximately 10 seconds per mL.
- Use Ga 68 DOTATOC Injection within 3 hours of calibration time.
- Use aseptic technique and radiation shielding when withdrawing and administering Ga 68 DOTATOC Injection.
- Inspect Ga 68 DOTATOC Injection visually for particulate matter and discoloration before administration. Do not use the drug if the solution contains particulate matter or is discolored.
- Calculate the necessary volume to administer based on measured activity, volume, calibration time, and date.
- Measure the patient dose immediately prior to administration in a dose calibrator.
- After injection of Ga 68 DOTATOC Injection, administer an intravenous flush of sodium chloride injection, 0.9% to ensure full delivery of the dose.
- Dispose of any unused drug in a safe manner in compliance with applicable regulations.
2.3 Use with Somatostatin Analogs and Patient Hydration
Somatostatin analogs bind to the same somatostatin receptors as Ga 68 DOTATOC
- Discontinue short-acting somatostatin analogs 24 hours before imaging with Ga 68 DOTATOC Injection.
- Image patients with Ga 68 DOTATOC Injection just prior to dosing with long-acting analogs of somatostatin [see Drug Interactions (7)].
Instruct patients to drink water to ensure adequate hydration prior to administration of Ga 68 DOTATOC Injection and to continue to drink and void frequently during the first hours following administration to reduce radiation exposure [see Warnings and Precautions (5.1)].
2.4 Image Acquisition
For Ga 68 DOTATOC PET imaging, a whole-body acquisition from the skull vertex to mid-thigh is recommended. Image acquisition can begin at 60 minutes (range 55 to 90 minutes) after the intravenous administration of the Ga 68 DOTATOC Injection. Adapt Ga 68 DOTATOC Injection uptake time and scan duration according to the equipment used, and the patient and tumor characteristics, to obtain the optimal image quality.
2.5 Image Interpretation
Ga 68 DOTATOC binds to somatostatin receptors. Based upon the intensity of the signals, PET images obtained using Ga 68 DOTATOC Injection indicate the presence and density of somatostatin receptors in tissues, .Uptake can also be seen in a variety of non-NET tumors that contain somatostatin receptors or as a normal physiologic variant [see Warnings and Precautions (5.2)]. NET tumors that do not bear somatostatin receptors will not be visualized.
2.6 Radiation Dosimetry
Estimated radiation absorbed doses per injected activity for organs and tissues of adult patients following an intravenous bolus of Ga 68 DOTATOC Injection are shown in Table 1. Estimated radiation effective doses per injected activity for adult and pediatric patients following an intravenous bolus administration of Ga 68 DOTATOC Injection are shown in Table 2.
Table 1: Estimated Radiation Absorbed Dose per Injected Activity in Selected Organs with Ga 68 DOTATOC Site Absorbed Dose (mGy/MBq) Urinary bladder wall 0.119 ± 0.058 Spleen 0.108 ± 0.065 Kidney 0.082 ± 0.020 Adrenal gland 0.077 ± 0.028 Liver 0.041 ± 0.014 Red marrow 0.016 ± 0.003 Gallbladder wall 0.015 ± 0.001 Total body 0.014 ± 0.002 Lungs 0.007 ± 0.001 Effective dose (mSv/MBq) 0.021 ± 0.003
The effective radiation dose resulting from the administration of 148 MBq (4 mCi) to an adult weighing 75 kg, is about 3.11 mSv. For an administered activity of 148 MBq (4 mCi) the typical radiation dose to the critical organs, which are the urinary bladder wall, the spleen and the kidneys/adrenals, are about 18 mSv, 16 mSv and 12 mSv, 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 splenectomy.
Table 2: Estimated Radiation Effective Dose per Injected Activity after a Ga-68 DOTATOC Injection Age Model Weight (kg) Effective Dose per Injection Activity (mSv/MBq) Adult 73.7 0.019 15 years 56.8 0.026 10 years 33.2 0.041 5 years 19.8 0.066 1 year 9.7 0.13 Newborn 3.6 0.36
- 3 DOSAGE FORMS AND STRENGTHS
- 4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Radiation Risk
Ga 68 DOTATOC Injection contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an 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 [see Dosage and Administration (2.1, 2.3)].
5.3 Risk for Image Misinterpretation
The uptake of Ga 68 DOTATOC Injection reflects the level of somatostatin receptor density in NETs, however, uptake can also be seen in a variety of other tumors that also express somatostatin receptors. Increased uptake might also be seen in other non-cancerous pathologic conditions that express somatostatin receptors including thyroid disease or in subacute inflammation, or might occur as a normal physiologic variant (e.g. uncinate process of the pancreas) [see Dosage and Administration (2.5)].
A negative scan after the administration of Ga 68 DOTATOC Injection in patients who do not have a history of NET disease does not rule out disease [see Clinical Studies (14)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Hypersensitivity reactions
6.1 Clinical Trial 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 Ga-68 DOTATOC injection was evaluated in 334 patients in clinical trials of patients receiving a single dose of Ga-68 DOTATOC injection for imaging known or suspected NET.
The following adverse reactions occurred at a rate of < 2%:
Gastrointestinal Disorders: nausea
The following adverse reactions occurred at a rate of a < 1%
Skin and Subcutaneous Tissue Disorders: pruritus
Vascular Disorders: flushing
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of other somatostatin receptor imaging agents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug.
7 DRUG INTERACTIONS
Non-radioactive somatostatin analogs bind to the same somatostatin receptors as Ga 68 DOTATOC Injection. Image patients with Ga 68 DOTATOC Injection just prior to dosing with long-acting analogs of somatostatin. Short-acting analogs of somatostatin can be used up to 24 hours before imaging with Ga 68 DOTATOC Injection [see Dosage and Administration (2.3)].
8 USE IN SPECIFIC POPULATIONS
There are no available data on the use of Ga 68 DOTATOC Injection in pregnant women to identify a risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with Ga 68 DOTATOC. However, all radiopharmaceuticals, including Ga 68 DOTATOC Injection have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering Ga 68 DOTATOC Injection administration to a pregnant woman, inform the patient of the potential for adverse pregnancy outcomes based on the radiation dose from Ga 68 DOTATOC Injection and the gestational timing of exposure.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.
There is no information on the presence of Ga 68 DOTATOC in human milk, the effect on the breastfed infant, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ga 68 DOTATOC Injection and any potential adverse effects on the breastfed child from Ga 68 DOTATOC Injection or from the underlying maternal condition.
8.4 Pediatric Use
The safety and efficacy of Ga 68 DOTATOC Injection have been established in pediatric patients with neuroendocrine tumors. Efficacy is based on data from 14 patients in Study A and B demonstrating the ability of Ga 68 DOTATOC to image NETs [see Clinical Studies (14)]. The safety profile of Ga 68 DOTATOC Injection is similar in adult and pediatric patients with somatostatin receptor positive tumors. The recommended Ga 68 DOTATOC injected dose in pediatric patients is weight based [see Dosage and Administration (2.2)].
8.5 Geriatric Use
Clinical studies of Ga 68 DOTATOC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- 10 OVERDOSAGE
11.1 Chemical Characteristics
Ga 68 DOTATOC Injection is a radioactive diagnostic agent for intravenous administration. It contains 3.6 mcg/mL (DOTA-0-Phe1-Tyr3) octreotide, 18.5 MBq/mL to 148 MBq/mL (0.5 mCi to 4 mCi/mL) of Ga 68 DOTATOC at calibration time, and ethanol (10% v/v) in sodium chloride (9 mg/mL) solution (approximately 14 mL volume). Ga 68 DOTATOC Injection is a sterile, pyrogen free, clear, colorless, buffered solution, with a pH between 4 to 8.
Ga 68 DOTATOC, also known as Gallium-68 (DOTA0-Phe1-Tyr3) octreotide, is a cyclic 8 amino acid peptide with a covalently bound chelator (DOTA). The peptide has the amino acid sequence: H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH, and contains one disulfide bond. Ga 68 DOTATOC has a molecular weight of 1489.65 g/mol and its chemical structure is shown in Figure 1.
Figure 1: Chemical Structure of Ga 68 DOTATOC
Gallium-68 labeled 2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(2R,3R)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid.
11.2 Physical Characteristics
Table 3 and Table 4 display the principal radiation emission data and physical decay of Ga 68.
Gallium-68 (Ga 68) decays with a half-life of 68 minutes to stable Zn 68:
- 89% through positron emission with a mean energy of 836 keV followed by emission of two 511 keV annihilation photons (178%),
- 10% through orbital electron capture (with associated X-ray or Auger emissions), and
- 3% through 13 gamma transitions from 5 excited levels of the daughter Zn 68 nucleus. The most probable prompt gamma emission is a 1088 keV gamma with a 3.2% per decay probability.
Table 3: Principal Radiation Emission Data (>1%) Radiation/Emission % Disintegration Mean Energy (MeV) beta+ 88% 0.8360 beta+ 1.1% 0.3526 gamma 178% 0.5110 gamma 3% 1.0770 X-ray 2.8% 0.0086 X-ray 1.4% 0.0086 Table 4: Physical Decay Chart for Gallium Ga-68 Minutes Fraction Remaining 0 1.000 15 0.858 30 0.736 60 0.541 90 0.398 120 0.293 180 0.158 360 0.025
11.3 External Radiation
Gamma constant: 1.8 × 10-4 mSv/hr per MBq at 1 meter [0.67 mrem/hr per mCi at 1 meter] Table 5 displays the radiation attenuation by lead shielding of Ga 68.
Table 5: Radiation Attenuation of 511 keV Photons by Lead (Pb) Shielding Shield Thickness
Coefficient of Attenuation 6 0.5 12 0.25 17 0.1 34 0.01 51 0.001
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ga 68 DOTATOC binds to somatostatin receptors, with highest affinity (Ki = 2.5± 0.5 nanomolar) for subtype 2 receptors (sstr2). Ga 68 DOTATOC binds to cells that express somatostatin receptors including malignant neuroendocrine cells, which overexpress sstr2 receptors. Gallium 68 is a β+ emitting radionuclide with associated 511 keV annihilation photons that allow positron emission tomography (PET) imaging.
The relationship between Ga 68 DOTATOC plasma concentrations and successful imaging was not explored in clinical trials.
Ga 68 DOTATOC distributes to all sstr2-expressing organs such as pituitary, thyroid, spleen, adrenals, kidney, pancreas, prostate, liver, and salivary glands. Uptake in the lung and lymph nodes are lower as compared to other sstr-2 expressing organs.
14 CLINICAL STUDIES
The safety and efficacy of Ga-68 DOTATOC Injection were established in two single-center, open-label studies (Study A and Study B) in which 282 patients with known or suspected SSTR-positive NETs received a single dose of Ga-68 DOTATOC. A total of 238 of the 282 patients (84%) had a history of neoplasm at the time of Ga-68 DOTATOC imaging. Among the 282 patients, 59% were female and 95% white; the mean age was 54 years (range from 4 to 82 years).
The Ga-68 DOTATOC images were rated by two independent readers blinded to clinical information as either positive or negative for NET within each patient. The imaging results were compared to a composite reference consisting of histopathology and imaging (MR, CT, or In-111 pentetreotide imaging) acquired within 1 year of the Ga-68 DOTATOC imaging, as well as chromogranin A and pancreastatin levels. The proportion of patients positive for NET per composite reference who were identified as positive by the Ga-68 DOTATOC image was used to quantify positive percent agreement. The proportion of patients without NET per composite reference who were identified as negative by the Ga-68 DOTATOC image was used to quantify negative percent agreement.
Study A (NCT: 01619865) included 220 subjects with known or suspected SSTR positive tumors referred for diagnosis or evaluation of disease extension before or after treatment. A total of 178 of the 220 patients (81%) had a history of neoplasm at the time of Ga-68 DOTATOC imaging. In 177 of the 220 patients, sufficient data to establish NET status per composite reference was available for efficacy evaluation. Table 6 shows the performance of Ga-68 DOTATOC in the detection of NETs for Study A.
Table 6: Study A. Performance of Ga-68 DOTATOC in the detection of NET by reader N = 177 NET status as identified by reader Reference Positive Negative N: number of patients, CI: confidence interval, Reader 1 Positive 121 5 Negative 12 39 Agreement (%)* (95% CI)† 91 (85, 95) 89 (75, 96) Reader 2 Positive 120 6 Negative 13 38 Agreement (%)* (95% CI)† 90 (84, 95) 86 (73, 95)
Study B (NCT: 01869725) included 62 patients with histologically positive NET or other SSTR positive tumor referred for evaluation of disease before or after treatment. In 59 of the 62 patients, sufficient data to establish NET status per composite reference was available for efficacy evaluation. The estimated positive and negative percent agreements were 92% and 75% for reader 1 and 90% and 75% for reader 2, respectively.
16 HOW SUPPLIED/STORAGE AND HANDLING
Ga 68 DOTATOC Injection is supplied in a multiple-dose, capped 30 mL glass vial containing 18.5 MBq/mL to 148 MBq/mL (0.5 mCi/mL to 4 mCi/mL) of Ga 68 DOTATOC at calibration time in approximately 14 mL of solution (NDC 24417-681-30).
Store Ga 68 DOTATOC Injection upright in a lead shielded container at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Receipt, transfer, handling, possession or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regulatory Commission, Agreement States or Licensing States as appropriate. Store and dispose of Ga 68 DOTATOC Injection in accordance with the regulations and a general license, or its equivalent, of an Agreement State or a Licensing State.
17 PATIENT COUNSELING INFORMATION
Advise patients to drink water to ensure adequate hydration prior to their PET study and recommend they drink and urinate as often as possible during the first hours following the administration of Ga 68 DOTATOC Injection, in order to reduce radiation exposure [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
Advise a lactating woman to interrupt breastfeeding and pump and discard breast milk for 8 hours after Ga 68 DOTATOC Injection administration in order to minimize radiation exposure to a breastfed infant [see Use in Specific Populations (8.2)].
- SPL UNCLASSIFIED SECTION
PRINCIPAL DISPLAY PANEL - 14 mL Vial Label
DOTATOC Ga 68 INJECTION
Diagnostic - For intravenous Use Only
Contains: 18.5 MBq/mL to 148 MBq/mL (0.5 mCi/mL to 4 mCi/mL) of no-carrier
added Ga-68 DOTATOC @ end of synthesis; 9 mg/mL of sodium chloride
UIHC-PET Imaging Center
200 Hawkins Drive
Iowa City, IA 52242
TOTAL ACTIVITY: mCi
TOTAL VOLUME: mL
RADIOACTIVE CONCENTRATION: mCi/mL @ EOS TIME
Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F–86°F);
Store upright in a lead shielded container. Expires 3 hours from end of synthesis.
See full prescribing information for dosage and administration information.
Do not use if cloudy or if contains particulate matter.
CAUTION: RADIOACTIVE MATERIAL
INGREDIENTS AND APPEARANCE
edotreotide gallium ga-68 injection, solution
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:24417-681 Route of Administration INTRAVENOUS Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EDOTREOTIDE GALLIUM GA-68 (UNII: Y68179SY2L) (EDOTREOTIDE GALLIUM GA-68 - UNII:Y68179SY2L) EDOTREOTIDE GALLIUM GA-68 4 mCi in 1 mL Inactive Ingredients Ingredient Name Strength ALCOHOL (UNII: 3K9958V90M) sodium chloride (UNII: 451W47IQ8X) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:24417-681-30 14 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product 09/01/2019 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA210828 09/01/2019 Labeler - UIHC – P E T Imaging Center (063513265)