NDC 24417-681 Ga-68-dotatoc

Edotreotide Gallium Ga-68

NDC Product Code 24417-681

NDC 24417-681-30

Package Description: 14 mL in 1 VIAL, MULTI-DOSE

NDC Product Information

Ga-68-dotatoc with NDC 24417-681 is a a human prescription drug product labeled by Uihc � P E T Imaging Center. The generic name of Ga-68-dotatoc is edotreotide gallium ga-68. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Uihc � P E T Imaging Center

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Ga-68-dotatoc Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • EDOTREOTIDE GALLIUM GA-68 4 mCi/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ALCOHOL (UNII: 3K9958V90M)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Uihc � P E T Imaging Center
Labeler Code: 24417
FDA Application Number: NDA210828 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 09-01-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Ga-68-dotatoc Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Ga 68 DOTATOC Injection is indicated for use with positron emission tomography (PET) for the localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients.

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.

Other

Recommended DosageIn 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.

  • AdministrationUse 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.

  • Somatostatin AnalogsSomatostatin analogs bind to the same somatostatin receptors as Ga 68 DOTATOCDiscontinue 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)].

Patient HydrationInstruct 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)].

Clinical Trial ExperienceBecause 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: nauseaThe following adverse reactions occurred at a rate of a < 1%Skin and Subcutaneous Tissue Disorders: pruritusVascular Disorders: flushing

Risk SummaryThere 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.

Risk SummaryThere 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.

Clinical ConsiderationsTo decrease exposure to the breastfed infant, advise a lactating woman to interrupt breastfeeding and pump and discard breast milk for 8 hours after Ga 68 DOTATOC Injection administration.

DistributionGa 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.

EliminationRadiotracer elimination is exclusively via urine. Approximately 16% of the injected dose is excreted in urine in the first two to four hours post-injection.

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 readerN = 177NET status as identified by readerReferencePositiveNegativeN: number of patients, CI: confidence interval,Reader 1Positive1215Negative1239   Agreement (%)Percent reader agreement with reference; (95% CI)Exact method91 (85, 95)89 (75, 96)Reader 2Positive1206Negative1338   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.

Radiation RiskAdvise 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)].

LactationAdvise 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)].

Manufactured and Distributed by:UIHC – P E T Imaging Center0911Z JPP200 Hawkins DriveIowa City, IA 52242

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 DOTATOCSiteAbsorbed Dose (mGy/MBq)Urinary bladder wall0.119 ± 0.058Spleen0.108 ± 0.065Kidney0.082 ± 0.020Adrenal gland0.077 ± 0.028Liver0.041 ± 0.014Red marrow0.016 ± 0.003Gallbladder wall0.015 ± 0.001Total body0.014 ± 0.002Lungs0.007 ± 0.001Effective dose (mSv/MBq)0.021 ± 0.003The 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 InjectionAgeModel Weight (kg)Effective Dose per Injection Activity (mSv/MBq)Adult73.70.01915 years56.80.02610 years33.20.0415 years19.80.0661 year9.70.13Newborn3.60.36

3 Dosage Forms And Strengths

Injection: Gallium Ga 68 DOTATOC Injection is a clear, colorless solution in a 30 mL multiple-dose vial containing 18.5 MBq/mL to 148 MBq/mL (0.5 mCi/mL to 4 mCi/mL) of Ga 68 DOTATOC Injection at calibration date and time.

4 Contraindications

None

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)].

5.2 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)].

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)].

8.4 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

In the event of a radiation overdose, reduce the absorbed dose to the patient by increasing the elimination of the radionuclide from the body by reinforced hydration, frequent bladder voiding, and diuretics, if needed. If possible, perform an estimate of the radioactive dose given to the patient.

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 DOTATOCGallium-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), and3% 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% DisintegrationMean Energy (MeV)beta+88%0.8360beta+1.1%0.3526gamma178%0.5110gamma3%1.0770X-ray2.8%0.0086X-ray1.4%0.0086Table 4: Physical Decay Chart for Gallium Ga-68MinutesFraction Remaining01.000150.858300.736600.541900.3981200.2931800.1583600.025

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) ShieldingShield Thickness(Pb) mmCoefficient of Attenuation60.5120.25170.1340.01510.001

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.

12.2 Pharmacodynamics

The relationship between Ga 68 DOTATOC plasma concentrations and successful imaging was not explored in clinical trials.

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.

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).

Storage And Handling

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.

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