DailyMed Label: Detectnet

DailyMed Label: Detectnet

2021

DailyMed Prescription

Detectnet

copper Cu 64 Dotatate

CURIUM US LLC

NDC: 69945-064

NDC: 69945-064

NDC: 69945-064

NDC: 69945-064

NDC: 69945-064

Detectnet contains copper Cu 64 dotatate, which is a radioactive diagnostic drug for use with PET imaging. Chemically, copper Cu 64 dotatate is described as copper (Cu 64)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10- tetraazacyclododec-1-yl) acetyl]-Dphenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L- threoninyl-L-cysteinyl-L-threonine-cyclic (2-7) disulfide. The molecular weight is 1497.2 Daltons and the following is the structural formula: Detectnet is a sterile, clear, colorless to yellow solution for intravenous use. Each 10 mL single-dose vial contains 148 MBq (4 mCi) of copper Cu 64 dotatate at calibration date and time in 4 mL solution volume. Additionally, each mL of the solution contains 40 mg ascorbic acid, 0.05 ml of dehydrated alcohol, USP (ethanol) in sterile water for injection, USP. The pH is adjusted with sodium hydroxide, hydrochloric acid and is between 5.5 to 7.5. chemical structure Table 2 and Table 3 display the principal radiation emission data and physical decay of copper Cu 64. Copper Cu 64 decays with a half-life t 1/2 =12.7 hours: 17.6% by positron emission to Ni 64 followed by emission of two 511 keV annihilation photons, 38.5% by beta decay to Zn 64, 43.8% by electron capture to Ni 64, and 0.475% by gamma radiation/internal conversion. Table 2. Principal radiation emission data (>1%) of copper Cu 64  Radiation/Emission  % Disintegration  Mean Energy (keV)   Positron (β + )  17.6  278 Beta (β - )  38.5  190.7  Gamma (γ)  35.7 0.48  511 1346 Table 3. Physical decay chart of copper Cu 64 Hours Fraction Remaining Hours Fraction Remaining  0  1.00  18  0.374  1  0.947 24 (1 day)   0.270  3  0.849  36 (1.5 days)  0.140  6  0.721  48 (2 days)  0.073  9  0.612  72 (3 days)  0.020  12  0.520  96 (4 days)  0.005 Gamma constant: 3.6 X 10 -5 mSv/hr per MBq at 1 meter (0.133 mrem/hr per mCi at 1 meter) Table 4 displays the radiation attenuation by lead shielding of copper Cu 64. Table 4. Radiation attenuation of copper Cu 64 by lead shielding  Shield Thickness cm of Lead (Pb)  Coefficient of Attenuation  0.51  0.5  1.60  0.1  3.45  0.01  6.83  0.001

Detectnet is indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult patients. Detectnet is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult patients. ( 1 )

Recommended dose is 148 MBq (4 mCi) administered as an intravenous bolus injection. ( 2.2 ) Begin acquiring images 45 to 90 minutes after drug administration. ( 2.4 ) See full prescribing information for additional preparation, administration, imaging and dosimetry information. ( 2 ) Handle Detectnet 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 Detectnet. 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. Recommended Dosage In adults, the recommended amount of radioactivity to be administered for PET imaging is 148 MBq (4 mCi) administered as an intravenous injection over a period of approximately 1 minute. Administration Use Detectnet within 2 hours after calibration time. Use aseptic technique and radiation shielding when withdrawing and administering Detectnet. Inspect Detectnet 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. Use a dose calibrator to measure the patient dose immediately prior to administration of Detectnet. After injection of Detectnet, administer an intravenous flush of 0.9% sodium chloride injection, USP. Dispose of any unused drug in a safe manner in compliance with applicable regulations. Somatostatin Analogs Image patients just prior to dosing with somatostatin analogs. For patients on long-acting somatostatin analogs, a wash-out period of 28 days is recommended prior to imaging. For patients on short-acting somatostatin analogs, a washout period of 2 days is recommended prior to imaging  [see Drug Interactions ( 7.1 )] . Patient Hydration Instruct patients to drink water to ensure adequate hydration prior to administration of Detectnet and to continue to drink and void frequently during the first hours following administration to reduce radiation exposure [see Warnings and Precautions ( 5.1 )] . Pregnancy Status Assessment of pregnancy status is recommended in females of reproductive potential before administering Detectnet. For Detectnet PET imaging, a whole-body acquisition from the skull vertex to mid-thigh is recommended. Image acquisition can begin between 45 to 90 minutes after the intravenous administration of Detectnet. Adapt Detectnet uptake time and scan duration according to the equipment used and the patient and tumor characteristics, to obtain the optimal image quality. Copper Cu 64 dotatate binds to somatostatin receptors. Based upon the intensity of the signals, PET images obtained using copper Cu 64 dotatate 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. Estimated radiation absorbed doses per injected activity for organs and tissues of adult patients following an intravenous administration of copper Cu 64 dotatate injection are shown in Table 1. Table 1. Estimated radiation absorbed dose per injected activity in selected organs with copper Cu 64 dotatate injection Target Organ Mean Mean of 5 patients. absorbed dose (mGy/MBq)  Adrenals  0.137  Brain  0.013  Breasts  0.013  Gallbladder wall  0.040  Lower large intestine wall  0.043  Small intestine  0.066  Stomach wall  0.019  Upper large intestine wall  0.022  Heart wall  0.019  Kidneys  0.139  Liver  0.161  Lungs  0.017  Muscle  0.019  Ovaries  0.019  Pancreas  0.093  Red marrow  0.027  Osteogenic cells   0.034   Skin  0.012  Spleen  0.115  Testes  0.014  Thymus  0.015  Thyroid  0.014  Urinary bladder wall  0.037  Uterus  0.019  Total body  0.025  Effective dose (mSv/MBq)  0.032 The effective radiation dose resulting from the administration of 148 MBq (4 mCi) to an adult is about 4.7 mSv. For an administered activity of 148 MBq (4 mCi) the typical radiation dose to the critical organs, which are the liver, the kidneys/adrenals, and the spleen, are about 24 mGy, 21 mGy and 17 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 splenectomy.

Injection; sterile, clear, colorless to yellow solution in a single-dose vial containing 148 MBq (4 mCi) (37 MBq (1 mCi) per 1 mL) of copper Cu 64 dotatate at calibration date and time. Injection: 148 MBq (4 mCi) (37 MBq (1 mCi) per 1 mL) of copper Cu 64 dotatate in a single-dose vial. ( 3 )

None. None ( 4 ).

Radiation Risk: Ensure safe handling and preparation procedures to protect patients and health care workers from unintentional radiation exposure ( 5.1 ). Advise patients to hydrate before and after administration and to void frequently after administration. ( 2.3 ) 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 Detectnet can be seen in a variety of tumor types other than NETs, in other pathologic conditions, and as a normal physiologic variant (e.g., uncinate process of the pancreas). ( 5.3 ) Diagnostic radiopharmaceuticals, including Detectnet, contribute 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 )] . Hypersensitivity reactions following administration of somatostatin receptor imaging agents predominantly consisted of cutaneous reactions such as rash and pruritus. Reactions reversed either spontaneously or with routine symptomatic management. Less frequently hypersensitivity reactions included angioedema or cases with features of anaphylaxis. The uptake of copper Cu 64 dotatate 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 Detectnet in patients who do not have a history of NET disease does not rule out disease [see Clinical Studies ( 14 )] .

The following clinically significant adverse reactions are described elsewhere in the labeling:

Somatostatin Analogs: Somatostatin analogs competitively bind to the same somatostatin receptors as copper Cu 64 dotatate and may affect imaging. Image patients just prior to dosing with somatostatin analogs. For patients on long-acting somatostatin analogs, a wash-out period of 28 days is recommended prior to imaging. For patients on short-acting somatostatin analogs, a washout period of 2 days is recommended prior to imaging. ( 2.3 , 7.1 ) Non-radioactive somatostatin analogs and copper Cu 64 dotatate competitively bind to somatostatin receptors (SSTR2). Image patients just prior to dosing with somatostatin analogs. For patients on long-acting somatostatin analogs, a wash-out period of 28 days is recommended prior to imaging. For patients on short-acting somatostatin analogs, a washout period of 2 days is recommended prior to imaging  [see Dosage and Administration ( 2.3 )].

Lactation: Advise patients to interrupt breastfeeding for 12 hours after Detectnet administration ( 8.2 ). Risk Summary All radiopharmaceuticals, including Detectnet have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. Advise a pregnant woman of the potential risks of fetal exposure to radiation from administration of Detectnet. There are no data on Detectnet use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No animal reproduction studies have been conducted with copper Cu 64 dotatate injection. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Risk Summary There are no data on the presence of copper Cu 64 dotatate in human milk, the effect on the breastfed infant, or the effect on milk production. Lactation studies have not been conducted in animals. Advise a lactating woman to interrupt breastfeeding for 12 hours after Detectnet administration in order to minimize radiation exposure to a breastfed infant. The safety and effectiveness of Detectnet have not been established in pediatric patients. Clinical studies of Detectnet 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.

How Supplied Detectnet (NDC 69945-064-01) is supplied as a sterile, clear, colorless to yellow solution in a 10 mL single-dose vial containing 148 MBq (4 mCi) (37 MBq (1 mCi) per mL) of copper Cu 64 dotatate at calibration date and time. The sealed vial is contained in a shielded (lead) container for radiation protection. The product is shipped in a Type A package. Discard unused portion from the single-patient use vial. Storage and Handling Store Detectnet in an upright position within the lead shielding to protect handlers from exposure to radiation. Store Detectnet at controlled room temperature 20 ° C to 25 ° C (68 ° F to 77 ° F). Do not use and discard Detectnet 2 hours after the calibration date and time. This radiopharmaceutical is for distribution and use by persons under license by the U.S. Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State. Store and dispose of Detectnet in compliance with the appropriate regulations of the government agency authorized to license the use of this radionuclide.

Copper Cu 64 dotatate binds to somatostatin receptors with highest affinity for subtype 2 receptors (SSTR2). It binds to cells that express somatostatin receptors including malignant neuroendocrine cells, which overexpress SSTR2 receptors. Copper Cu 64 is a positron (β+) emitting radionuclide with an emission yield that allows positron emission tomography (PET) imaging. The relationship between copper Cu 64 dotatate plasma concentrations and successful imaging was not explored in clinical trials. Distribution After 1 to 3 hours of a single dose administration of copper Cu 64 dotatate injection, the maximum radioactivity is observed in adrenal glands, kidney, pituitary glands, spleen, and liver. Elimination Metabolism The metabolism of copper Cu 64 dotatate is unknown. Excretion Following a single intravenous dose (4.15 ± 0.13 mCi) of Detectnet (n = 6), between 16% to 40% radioactivity of the injected dose was recovered in urine over a 6-hour collection time. Specific Populations The effect of hepatic impairment or renal impairment on copper Cu 64 dotatate pharmacokinetics has not been studied.

Carcinogenicity and mutagenicity studies have not been conducted with copper Cu 64 dotatate injection; however, radiation is a carcinogen and mutagen. No animal studies were conducted to determine the effects of copper Cu 64 dotatate on fertility or embryology.

The efficacy of Detectnet was established in two single-center, open-label studies. Study 1 prospectively evaluated a total of 63 subjects, including 42 patients with known or suspected NET based on histology, conventional imaging, or clinical evaluations and 21 healthy volunteers. Of the 42 patients, 37 (88%) had a history of NETs at the time of Detectnet imaging. Among the total study population of 63 subjects, 28 (44%) were men and 35 (56%) were women with most subjects being white (86%). The mean age of the subjects was 54 years (range 25 to 82 years). Detectnet images from each subject were interpreted as either positive or negative for NET by three independent readers who were blinded to clinical information and other imaging results. PET imaging results were compared to a composite reference standard consisting of a single oncologist’s blinded assessment of subject diagnosis based on available histopathology results, reports of conventional imaging (MRI, contrast CT, bone scintigraphy, F 18 fludeoxyglucose PET/CT, F 18 sodium fluoride PET/CT, In 111 pentetreotide SPECT/CT, Ga 68 dotatate PET/CT) performed within 8 weeks prior to Detectnet imaging, and clinical and laboratory data including chromogranin A and serotonin levels. The proportion of subjects positive for disease per composite reference who were identified as positive by Detectnet imaging was used to quantify positive percent agreement. The proportion of subjects without disease per composite reference who were identified as negative by Detectnet imaging was used to quantify negative percent agreement. Table 5 shows the performance of Detectnet in the detection of NET for Study 1. Table 5: Performance of Detectnet in the detection of NET by reader in Study 1 n: number of patients, CI: confidence interval, *Reader 1 interpreted one of the 63 PET scans as “not evaluable”, **Wilson score interval with continuity correction NET status as identified by reader Reference Positive Negative Reader 1 (n=62)* Positive 30 1 Negative 3 28 Percent Reader Agreement (95% CI)** 91 (75, 98) 97 (80, 99) Reader 2 (n=63) Positive 30 6 Negative 3 24 Percent Reader Agreement (95% CI)** 91 (75, 98) 80 (61, 92) Reader 3 (n=63) Positive 30 3 Negative 3 27 Percent Reader Agreement (95% CI)** 91 (75, 98) 90 (72, 97) Study 2 showed similar performance through retrospective analysis of published data collected in 112 patients (63 males, 49 females; mean age 62 years, range 30 to 84 years) with a known history of NET.

Detect net TM                                          Sterile (copper Cu 64 dotatate injection)         NDC 69945-064-01 148 MBq (4 mCi) per 4 mL at calibration (37 MBq (1 mCi) per 1 mL) For Intravenous Use Only Single-Dose Vial - Discard Unused Portion. Cal. time: 1700 CT      Exp. time: 1900 CT Cal. date:                     Exp. date: Lot #: Vial label