Lutetium Lu 177 dotatate is a radiolabeled somatostatin analog indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults. Premedicate with antiemetics as well as an amino acid solution. Because lutetium Lu 177 dotatate is a radiopharmaceutical, appropriate safety measures should be undertaken to minimize radiation exposure.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-Lutetium Lu 177 dotatate is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure. Store in original packaging to protect from ionizing radiation (lead shielding).
-Use waterproof gloves and effective radiation shielding when handling lutetium Lu 177 dotatate.
-Lutetium Lu 177 dotatate 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 radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.
Emetic Risk
-Moderate
-Administer antiemetics before initiating the recommended amino acid solution infusion 30 minutes prior to each lutetium Lu 177 dotatate dose.
Route-Specific Administration
Injectable Administration
Intravenous Administration
-Do not inject lutetium Lu 177 dotatate directly into any other intravenous solution.
-Premedicate against hypersensitivity reactions in those patients with a history of grade 1 or 2 hypersensitivity reactions to lutetium Lu 177; do not rechallenge patients with a history of grade 3 or 4 hypersensitivity reactions.
-Administer antiemetics before the start of the recommended amino acid solution infusion.
-Initiate a sterile IV amino acid solution infusion 30 minutes before the start of a lutetium Lu 177 dotatate infusion, using either a three-way valve with the same venous access as lutetium Lu 177 dotatate, or through a separate venous access in the patient's other arm. Continue the amino acid infusion during and for at least 3 hours after completion of the lutetium Lu 177 dotatate infusion.
-Lutetium Lu 177 dotatate may be infused using the gravity method, peristaltic pump method, or syringe pump method; do not administer as an IV bolus.
-Use the peristaltic pump method or the syringe method when administering a reduced dose of lutetium Lu 177 dotatate due to an adverse reaction. When using the gravity method for a reduced dose, adjust the lutetium Lu 177 dotatate dose before administration to avoid delivery of an incorrect volume.
Amino Acid Solution Specifications:
-L-lysine HCl content: between 18 and 25 g (equivalent to 14.4 to 20 g L-lysine).
-L-arginine HCl content: between 18 and 25 g (equivalent to 14.9 to 20.7 g L-arginine).
-Volume: 1 to 2 L.
-Osmolality: less than 1,200 mOsmol/kg.
Preparation:
-Use aseptic technique and radiation shielding during handling and administration of lutetium Lu 177 dotatate. Use tongs when handling vial to minimize radiation exposure.
-Inspect the product visually for particulate matter and discoloration prior to administration under a shielded screen. Discard vial if particulates or discoloration are present.
-Confirm the amount of radioactivity of lutetium Lu 177 dotatate to be delivered to the patient with an appropriate dose calibrator prior to (and after) each administration. The shelf-life is 72 hours from the date and time of calibration.
Intravenous infusion, gravity method:
-Infuse lutetium Lu 177 dotatate directly from the original container.
-Insert a 2.5 cm, 20 gauge needle (short needle) into the lutetium Lu 177 dotatate vial; ensure the needle does not touch the lutetium Lu 177 dotatate solution in th vial. Do not connect this short needle directly to the patient.
-Via catheter, connect the lutetium Lu 177 dotatate vial to 500 mL 0.9% Sodium Chloride Injection (used to transport the lutetium Lu 177 dotatate solution during the infusion). Do not allow the 0.9% Sodium Chloride Injection to flow into the lutetium Lu 177 dotatate vial prior to the initiation of the infusion, and do not inject lutetium Lu 177 dotatate directly into the 0.9% Sodium Chloride Injection solution.
-Insert a second needle that is 9 cm, 18 gauge (long needle) into the lutetium Lu 177 dotatate vial. This long needle should touch and be secured to the bottom of the lutetium Lu 177 dotatate vial during the entire infusion. Connect the long needle to the patient by an IV catheter that is prefilled with 0.9% sterile sodium chloride.
-Use a clamp or infusion pump to regulate the flow of the 0.9% Sodium Chloride Injection solution via the short needle into the lutetium Lu 177 dotatate vial at 50 mL/hour to 100 mL/hour for 5 to 10 minutes; then increase the rate to 200 mL/hour to 300 mL/hour for an additional 25 to 30 minutes (the 0.9% Sodium Chloride Injection solution entering the vial through the short needle will carry the lutetium Lu 177 dotatate from the vial to the patient via the catheter connected to the long needle over a total duration of 30 to 40 minutes).
-During the infusion, ensure that the level of 0.9% Sodium Chloride Injection in the lutetium Lu 177 dotatate vial remains constant.
-Disconnect the vial from the long needle line and clamp the saline line once the level of radioactivity is stable for at least 5 minutes.
-Flush the IV catheter with 25 mL of 0.9% Sodium Chloride Injection.
-Confirm the amount of radioactivity of lutetium Lu 177 dotatate delivered to the patient with an appropriate dose calibrator after each administration.
-Dispose of any unused medicinal product or waste material in accordance with local and federal laws.
Intravenous infusion, peristaltic pump method:
-Infuse lutetium Lu 177 dotatate directly from the original container.
-Insert a filtered 2.5 cm, 20 gauge needle (short venting needle) into the lutetium Lu 177 dotatate vial; ensure the needle does not touch the lutetium Lu 177 dotatate solution in th vial. Do not connect this short needle directly to the patient or to the peristaltic pump.
-Insert a second needle that is 9 cm, 18 gauge (long needle) into the lutetium Lu 177 dotatate vial. This long needle should touch and be secured to the bottom of the lutetium Lu 177 dotatate vial during the entire infusion. Connect the long needle and a 0.9% Sodium Chloride Injection solution to a 3-way stopcock valve using appropriate tubing.
-Connect the output of the 3-way stopcock valve to tubing installed on the input side of the peristaltic pump according to manufacturer's instructions.
-Prime the line by opening the 3-way stopcock valve and pumping the lutetium Lu 177 dotatate solution through the tubing until it reaches the exit of the valve.
-Prime the IV catheter that will be connected to the patient by opening the 3-way stopcock valve to the 0.9% Sodium Chloride Injection solution and pumping this solution until it reaches the exit of the valve.
-Connect the primed IV catheter to the patient and set the 3-way stopcock valve so that the lutetium Lu 177 dotatate solution is in line with the peristaltic pump.
-Infuse an appropriate volume of lutetium Lu 177 dotatate solution over a 30- to 40-minute period to deliver the desired radioactivity.
-Stop the peristaltic pump and change the position of the 3-way stopcock valve so that the pump is in line with the 0.9% Sodium Chloride Injection solution.
-Restart the peristaltic pump and infuse an IV flush of 25 mL of 0.9% Sodium Chloride Injection solution through the IV catheter to the patient.
-Confirm the amount of radioactivity of lutetium Lu 177 dotatate delivered to the patient with an appropriate dose calibrator after each administration.
-Dispose of any unused medicinal product or waste material in accordance with local and federal laws.
Intravenous infusion, syringe pump method:
-Using a disposable syringe fitted with a syringe shield and a sterile 9 cm, 18 gauge disposable needle (long needle), withdraw an appropriate volume of lutetium Lu 177 dotatate solution to deliver the desired radioactivity. A filtered 2.5 cm, 20 gauge needle (short venting needle) can be used to reduce the resistance from the pressurized vial to aid in withdrawal. Ensure the short needle does not touch the lutetium Lu 177 dotatate solution in the vial.
-Fit the syringe into the shielded pump, including a 3-way stopcock valve between the syringe and an IV catheter pre-filled with 0.9% Sodium Chloride Injection.
-Infuse an appropriate volume of lutetium Lu 177 dotatate solution over a 30- to 40-minute period to deliver the desired radioactivity.
-Stop the syringe pump and change the position of the 3-way stopcock valve to flush the syringe with 25 mL of 0.9% Sodium Chloride Injection solution.
-Restart the syringe pump.
-After the flush of the syringe has been completed, flush the IV catheter to the patient with 25 mL of 0.9% Sodium Chloride Injection solution.
-Confirm the amount of radioactivity of lutetium Lu 177 dotatate delivered to the patient with an appropriate dose calibrator after each administration.
-Dispose of any unused medicinal product or waste material in accordance with local and federal laws.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, myelosuppression was reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone, including lymphopenia (all grade, 90% vs. 39%; grade 3 or 4, 44% vs. 4%), anemia (all grade, 81% vs. 54%; grade 3 or 4, 0% vs. 1%), leukopenia (all grade, 55% vs. 20%; grade 3 or 4, 2% vs. 0%), and neutropenia (all grade, 26% vs. 11%; grade 3 or 4, 3% vs. 0%). Thrombocytopenia was reported in 53% (grade 3 or 4, 1%) of patients treated with lutetium Lu 177 dotatate compared with 17% (grade 3 or 4, 0%) in the octreotide monotherapy group, with the nadir occurring at a median of 5.1 weeks after the first dose of lutetium Lu 177 dotatate; the median time to recovery of 2 months. Of the patients who developed thrombocytopenia, 68% had platelet recovery to normal or baseline levels; of those that did not (n = 19), 1 patient recovered to grade 3, 9 patients to grade 2, and 5 patients recovered to grade 1.
New primary malignancy has been reported with lutetium Lu 177 dotatate treatment. In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors with a median follow-up time of 76 months, 2.3% of patients receiving lutetium Lu 177 dotatate plus long-acting octreotide developed myelodysplastic syndrome (MDS) compared with no patients treated with high-dose octreotide alone. In a subset of patients from separate single-center, single-arm trial, MDS occurred in 2% of patients treated with lutetium Lu 177 dotatate after a median time to onset of 29 months (range, 9 months to 45 months); acute leukemia was reported in 0.5% of patients after a median time of 55 months (range, 32 months to 125 months).
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, an increased serum creatinine was reported in 85% (grade 3 or 4, 1%) of patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with 73% (grade 3 or 4, 0%) of patients who received long-acting octreotide alone. Renal failure (unspecified) occurred in 12% (grade 3 or 4, 3%) of patients in the lutetium Lu 177 dotatate arm compared with 3% (grade 3 or 4, 1%) of those in the octreotide monotherapy arm, including decreased glomerular filtration rate, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, and renal impairment. Renal failure was reported in less than 1% of patients treated with lutetium Lu 177 dotatate between 3 to 36 months after treatment in a single-center, single arm trial; two of these patients (n = 8) had underlying renal impairment or risk factors for renal failure (e.g., diabetes or hypertension) and required dialysis.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, elevated hepatic enzymes were reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone, including increased GGT (all grade, 66% vs. 67%; grade 3 or 4, 20% vs. 16%), increased alkaline phosphatase (all grade, 65% vs. 54%; grade 3 or 4, 5% vs. 9%), increased AST (all grade, 50% vs. 35%; grade 3 or 4, 5% vs. 0%), increased ALT (all grade, 43% vs. 34%; grade 3 or 4, 4% vs. 0%), and hyperbilirubinemia (all grade, 30% vs. 28%; grade 3 or 4, 2% vs. 0%). Less than 1% of patients in a separate single-center, single-arm trial were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, gastrointestinal adverse reactions were reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone, including nausea (all grade, 65% vs. 12%; grade 3 or 4, 5% vs. 2%), vomiting (all grade, 53% vs. 9%; grade 3 or 4, 7% vs. 0%), abdominal pain (all grade, 26% vs. 19%; grade 3 or 4, 3% vs. 3%), diarrhea (all grade, 26% vs. 18%; grade 3 or 4, 3% vs. 1%), anorexia (all grade, 21% vs. 11%; grade 3 or 4, 0% vs. 3%), and constipation (grade 1 or 2, 10% vs. 5%).
Neuroendocrine hormonal crisis, manifesting with flushing, diarrhea, bronchospasm, and hypotension, occurred in 1% of patients in a subset of patients with somatostatin receptor-positive tumors (neuroendocrine and other primaries) treated with lutetium Lu 177 dotatate plus long-acting octreotide from a single-center, single-arm trial; hypotension was also reported separately in 1% of patients in this trial. In a separate randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, flushing was reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone (all grade, 14% vs. 9%; grade 3 or 4, 1% vs. 0%). Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms of tumor-related hormonal release. Administer intravenous somatostatin analogs, fluids, corticosteroids, and electrolytes as indicated.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, mostly mild musculoskeletal adverse reactions were reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone, including back pain (all grade, 13% vs. 10%; grade 3 or 4, 2% vs. 0%), pain in extremity (grade 1 or 2, 11% vs. 5%), myalgia (grade 1 or 2, 5% vs. 0%), and neck pain (grade 1 or 2, 5% vs. 0%).
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, headache (grade 1 or 2, 17% vs. 5%), dizziness (grade 1 or 2, 17% vs. 8%), and dysgeusia (grade 1 or 2, 8% vs. 2%) were reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, anxiety (all grade, 12% vs. 5%; grade 3 or 4, 1% vs. 0%) was reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, mild alopecia (grade 1 or 2, 12% vs. 2%) was reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, cough (all grade, 11% vs. 6%; grade 3 or 4, 1% vs. 0%) was reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, peripheral edema (all grade, 16% vs. 9%; grade 3 or 4, 0% vs. 1%) was reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, cardiovascular adverse reactions were reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone, including hypertension (all grade, 12% vs. 7%; grade 3 or 4, 2% vs. 2%) and atrial fibrillation (all grade, 5% vs. 0%; grade 3 or 4, 1% vs. 0%). Heart failure was reported in 2% and myocardial infarction in 1% of a subset of patients with somatostatin receptor-positive tumors (neuroendocrine and other primaries) treated with lutetium Lu 177 dotatate from a separate single-center, single arm trial.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, mild radiation-related urinary tract toxicity was reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone (grade 1 or 2, 8% vs. 3%), including dysuria, micturition urgency, nocturia, pollakiuria, renal colic (pelvic pain), urinary tract pain (urethral pain), and urinary incontinence.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, fatigue (all grade, 38% vs. 26%; grade 3 or 4, 1% vs. 2%) and mild fever (grade 1 or 2, 8% vs. 2%) were reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone.
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, electrolyte disturbances were reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone (grade 1 or 2, 8% vs. 3%), including hyperglycemia (all grade, 82% vs. 67%; grade 3 or 4, 4% vs. 2%), mild hypocalcemia (grade 1 or 2, 32% vs. 14%), hypokalemia (all grade, 26% vs. 21%; grade 3 or 4, 4% vs. 2%), mild hyperkalemia (grade 1 or 2, 19% vs. 11%), mild hypernatremia (grade 1 or 2, 17% vs. 7%), and mild hypoglycemia (grade 1 or 2, 15% vs. 8%).
In a randomized, clinical trial of patients with advanced, progressive midgut neuroendocrine tumors, hyperuricemia (all grade, 34% vs. 29%; grade 3 or 4, 6% vs. 6%) was reported more often in patients treated with lutetium Lu 177 dotatate plus long-acting octreotide compared with long-acting octreotide alone.
Hypersensitivity reactions, including angioedema, have been reported in postmarketing experience with lutetium Lu 177 dotatate treatment. Closely monitor patients for signs and symptoms of serious hypersensitivity reactions or anaphylaxis during administration and for at least 2 hours following administration in a setting where CPR medication and equipment are available. Permanently discontinue lutetium Lu 177 dotatate therapy upon the first occurrence of a grade 3 or 4 hypersensitivity reaction; premedicate patients with a history of grade 1 or 2 hypersensitivity reactions before subsequent doses.
A neuroendocrine hormonal crisis has been reported in patients treated with lutetium Lu 177 dotatate, usually occurring during or within 24 hours of the initial dose. Symptoms include flushing, diarrhea, bronchospasm, and hypotension; hypercalcemia may also rarely occur. Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms of tumor-related hormonal release. Administer intravenous somatostatin analogs, fluids, corticosteroids, and electrolytes as indicated.
Lutetium Lu 177 dotatate contributes to a patient's overall long-term cumulative radiation exposure, which is associated with an increased risk of cancer or new primary malignancy. An increased incidence of myelodysplastic syndrome (MDS) and acute leukemia have been reported in patients treated with lutetium Lu 177 dotatate compared with long-acting octreotide monotherapy. Minimize radiation exposure to patients, medical personnel, and household contacts with institutional good radiation safety practices, patient management procedures, Nuclear Regulatory Commission patient-release guidance, and instructions to the patient for follow-up radiation protection at home. Radiation can be detected in the urine for up to 30 days after lutetium Lu 177 dotatate administration.
Use lutetium Lu 177 dotatate with caution in patients with baseline hepatic disease or hepatic metastasis, as these patients may be at increased risk of hepatotoxicity (e.g., hepatic tumor hemorrhage, edema, or necrosis, hyperbilirubinemia, etc.) due to radiation exposure. Monitor transaminases, bilirubin, serum albumin, and international normalized ratio (INR) during treatment. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary if hepatotoxicity occurs.
Bone marrow suppression, including anemia, neutropenia, and thrombocytopenia, has been reported during lutetium Lu 177 dotatate treatment. Monitor blood cell counts; an interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary if myelosuppression occurs. In a clinical trial, the median platelet nadir was 5.1 months after the first dose of lutetium Lu 177 dotatate, with a median time to recovery of 2 months.
Renal failure has rarely been reported with lutetium Lu 177 dotatate therapy; patients with baseline renal disease or renal impairment may be at an increased risk of toxicity due to increased exposure to radiation. The recommended amino acid solution should be administered before, during, and after lutetium Lu 177 dotatate administration to decrease reabsorption through the proximal tubules, and decrease the radiation dose to the kidneys; do not decrease the dose of the amino acid solution if the dose of lutetium Lu 177 dotatate is reduced. Patients should be advised to hydrate and to urinate frequently before, during, and the day after administration of lutetium Lu 177 dotatate. Monitor serum creatinine (SCr) and calculated creatinine clearance (CrCl); an interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary if nephrotoxicity occurs. Monitor SCr and CrCl more frequently in patients with baseline mild or moderate renal impairment; lutetium Lu 177 dotatate has not been studied in patients with severe renal impairment (CrCl less than 30 mL/min) or renal failure (end-stage renal disease).
Pregnancy should be avoided by females of reproductive potential during lutetium Lu 177 dotatate treatment and for at least 7 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, lutetium Lu 177 dotatate, as with other radioactive emissions, can cause fetal harm when administered during pregnancy based on its mechanism of action. Women who are pregnant or who become pregnant while receiving lutetium Lu 177 dotatate should be apprised of the potential hazard to the fetus.
Counsel patients about the reproductive risk and contraception requirements during lutetium Lu 177 dotatate treatment. Lutetium Lu 177 dotatate can cause fetal harm if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 7 months after treatment with lutetium Lu 177 dotatate. Males with female partners of reproductive potential should use effective contraception during treatment and for 4 months after the last dose of lutetium Lu 177 dotatate. Females of reproductive potential should undergo pregnancy testing prior to initiation of lutetium Lu 177 dotatate. Women who become pregnant while receiving lutetium Lu 177 dotatate should be apprised of the potential hazard to the fetus. The recommended cumulative dose of lutetium Lu 177 dotatate results in a radiation absorbed dose to the testis and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy.
Due to the potential for serious adverse reactions in nursing infants from lutetium Lu 177 dotatate, advise women to discontinue breast-feeding during treatment and for 2.5 months after the final dose. It is not known whether lutetium Lu 177 dotatate is present in human milk, although many drugs are excreted in human milk.
For the treatment of somatostatin receptor-positive gastroenteropancreatic malignant neuroendocrine tumor (NET), including foregut, midgut, and hindgut neuroendocrine tumors:
Intravenous dosage:
Adults: 7.4 GBq (200 mCi) IV infusion, at a rate of 50 to 100 mL/hour for 5 to 10 minutes and then 200 to 300 mL/hour for an additional 25 to 30 minutes, every 8 weeks (+/- 1 week) for a total of 4 doses. Beginning 30 minutes prior to the start of a lutetium Lu 177 dotatate infusion, initiate an IV infusion of a sterile amino acid solution containing lysine HCl (18 g to 24 g) and arginine HCl (18 g to 24 g); continue this infusion during and for at least 3 hours after completion of the lutetium Lu 177 dotatate infusion. Do not decrease the dose of the amino acid solution even if the dose of lutetium Lu 177 dotatate is reduced. Administer long-acting octreotide 30 mg IM between 4 to 24 hours after each lutetium Lu 177 dotatate dose; do not administer long-acting octreotide within 4 weeks prior to each subsequent lutetium Lu 177 dotatate dose. After completion of lutetium Lu 177 dotatate, continue long-acting octreotide every 4 weeks until disease progression, or for 18 months following the initiation of treatment at the physician's discretion. In a multicenter, randomized, open-label, active-controlled trial (NETTER-1), treatment with lutetium Lu 177 dotatate plus long-acting octreotide (30 mg IM) significantly improved median progression-free survival (PFS) (not reached vs. 8.5 months) and objective response rate (13% vs. 4%) in patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumors. There was not a significant difference in overall survival (OS) between treatment arms in the final OS analysis. In patients with foregut, midgut, and hindgut gastroenteropancreatic neuroendocrine tumors (GEP-NETs), treatment with lutetium Lu 177 dotatate resulted in an ORR of 16%, with 3 complete responses (n = 360); the median duration of response was 35 months.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Hematologic
NOTE: No dose modification is required for lymphopenia.
-Anemia and Neutropenia (grade 3 or 4), first occurrence: Hold lutetium Lu 177 dotatate therapy. Upon complete or partial resolution to grade 0, 1, or 2 within 16 weeks, resume lutetium Lu 177 dotatate at a reduced dose of 3.7 GBq (100 mCi). If this dose does not result in grade 3 or 4 anemia or neutropenia, increase the dose of lutetium Lu 177 dotatate to 7.4 GBq (200 mCi) for the next dose. Permanently discontinue lutetium Lu 177 dotatate for grade 3 or higher anemia or neutropenia that requires a treatment delay resulting in a dosing interval beyond 16 weeks.
-Anemia and Neutropenia (grade 3 or 4), recurrent: Permanently discontinue lutetium Lu 177 dotatate therapy.
-Thrombocytopenia (grade 2, 3, or 4), first occurrence: Hold lutetium Lu 177 dotatate therapy. Upon complete or partial resolution to grade 0 or 1 within 16 weeks, resume lutetium Lu 177 dotatate at a reduced dose of 3.7 GBq (100 mCi). If this dose does not result in grade 2, 3, or 4 thrombocytopenia, increase the dose of lutetium Lu 177 dotatate to 7.4 GBq (200 mCi) for the next dose. Permanently discontinue lutetium Lu 177 dotatate for grade 2 or higher thrombocytopenia that requires a treatment delay resulting in a dosing interval beyond 16 weeks.
-Thrombocytopenia (grade 2, 3, or 4), recurrent: Permanently discontinue lutetium Lu 177 dotatate therapy.
Hypersensitivity
-Grade 1 or 2: Manage with appropriate supportive care. Premedicate patients with grade 1 or 2 hypersensitivity reactions before subsequent doses.
-First occurrence of grade 3 or 4: Permanently discontinue lutetium Lu 177 dotatate therapy.
Any Other Toxicity (excluding renal or hepatic)
-Grade 3 or 4, first occurrence: Hold lutetium Lu 177 dotatate therapy. Upon complete or partial resolution to grade 0, 1, or 2 within 16 weeks, resume lutetium Lu 177 dotatate at a reduced dose of 3.7 GBq (100 mCi). If this dose does not result in grade 3 or 4 toxicity, increase the dose of lutetium Lu 177 dotatate to 7.4 GBq (200 mCi) for the next dose. Permanently discontinue lutetium Lu 177 dotatate for grade 3 or higher toxicity that requires a treatment delay resulting in a dosing interval beyond 16 weeks.
-Grade 3 or 4, recurrent: Permanently discontinue lutetium Lu 177 dotatate therapy.
Maximum Dosage Limits:
-Adults
7.4 GBq (200 mCi) IV.
-Geriatric
7.4 GBq (200 mCi) IV.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Mild to moderate hepatic impairment (total bilirubin less than or equal to 3 times the upper limit of normal): No dosage adjustment necessary.
-Severe hepatic impairment (total bilirubin greater than 3 times the upper limit of normal and any AST): The safety of lutetium Lu 177 dotatate has not been studied in this population; specific guidelines for dosage adjustments are not available.
Treatment-Related Hepatotoxicity
-Grade 3 or 4 hyperbilirubinemia (bilirubin greater than 3 times the upper limit of normal), or serum albumin less than 30 g/L with international normalized ratio (INR) greater than 1.5: Hold lutetium Lu 177 dotatate therapy. Upon resolution or return to baseline within 16 weeks, resume lutetium Lu 177 dotatate at a reduced dose of 3.7 GBq (100 mCi). If this dose does not result in hepatotoxicity, increase the dose of lutetium Lu 177 dotatate to 7.4 GBq (200 mCi) for the next dose. Permanently discontinue lutetium Lu 177 dotatate for hepatotoxicity that requires a treatment delay resulting in a dosing interval beyond 16 weeks.
-Recurrent grade 3 or 4 hyperbilirubinemia, or serum albumin less than 30 g/L with INR greater than 1.5: Permanently discontinue lutetium Lu 177 dotatate therapy.
Patients with Renal Impairment Dosing
Baseline Renal Impairment
-Mild to moderate renal impairment (Creatinine clearance (CrCl) 30 to 89 mL/min): No dosage adjustment necessary.
-Severe renal impairment (CrCl less than 30 mL/min) or end-stage renal impairment: The safety of lutetium Lu 177 dotatate has not been studied in this population; specific guidelines for dosage adjustments are not available.
Treatment-Related Nephrotoxicity
-CrCl less than 40 mL/min using actual body weight, 40% increase in baseline serum creatinine, or a 40% decrease in baseline CrCl using actual body weight: Hold lutetium Lu 177 dotatate therapy. Upon resolution or return to baseline within 16 weeks, resume lutetium Lu 177 dotatate at a reduced dose of 3.7 GBq (100 mCi). If this dose does not result in nephrotoxicity, increase the dose of lutetium Lu 177 dotatate to 7.4 GBq (200 mCi) for the next dose. Permanently discontinue lutetium Lu 177 dotatate for nephrotoxicity that requires a treatment delay resulting in a dosing interval beyond 16 weeks.
-Recurrent CrCl less than 40 mL/min using actual body weight, 40% increase in baseline serum creatinine, or a 40% decrease in baseline CrCl using actual body weight: Permanently discontinue lutetium Lu 177 dotatate therapy.
*non-FDA-approved indication
Albuterol; Budesonide: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Betamethasone: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Budesonide: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Budesonide; Formoterol: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Corticosteroids (systemic): (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Corticotropin, ACTH: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Cortisone: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Deflazacort: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexamethasone: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Hydrocortisone: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Lanreotide: (Major) Discontinue long-acting lanreotide at least 4 weeks prior to beginning treatment with lutetium Lu 177 dotatate. A short-acting somatostatin analog may be administered as-needed, but must be discontinued at least 24 hours prior to each lutetium Lu 177 dotatate dose. Somatostatin and its analogs, such as lanreotide, competitively bind to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate.
Methylprednisolone: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Octreotide: (Major) Discontinue long-acting octreotide at least 4 weeks prior to beginning treatment with lutetium Lu 177 dotatate. Short-acting octreotide may be administered as-needed; discontinue at least 24 hours prior to each lutetium Lu 177 dotatate dose. Somatostatin and its analogs, such as octreotide, competitively bind to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate.
Prednisolone: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Prednisone: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Triamcinolone: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Vamorolone: (Major) Avoid repeated administration of high doses of glucocorticoids during treatment with lutetium Lu 177 dotatate due to the risk of decreased efficacy of lutetium Lu 177 dotatate. Lutetium Lu 177 dotatate binds to somatostatin receptors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2); glucocorticoids can induce down-regulation of SSTR2.
Lutetium Lu 177 dotatate binds to somatostatin receptors, including those on malignant somatostatin receptor-positive tumors, with the highest affinity for subtype 2 somatostatin receptors (SSTR2). After binding, it is internalized and the beta-minus emission from Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells.
Lutetium Lu 177 dotatate is administered intravenously. The non-radioactive lutetium Lu 175 dotatate is 43% bound to human plasma proteins. The mean volume of distribution (Vd) for lutetium Lu 177 dotatate is 460 L (CV, 54%). Within 4 hours of the infusion, lutetium Lu 177 dotatate distributes in kidneys, liver, spleen, and in some patients, pituitary gland and thyroid. The maximum radiation penetration in tissue is 2.2 mm; the mean penetration is 0.67 mm. The coadministration of amino acids reduced the median radiation dose to the kidneys by 47% (range, 34% to 59%). The mean clearance (CL) is 4.5 L/h (CV, 31%); coadministration of amino acids increased the mean beta-phase blood clearance of lutetium Lu 177 dotatate by 36%. Lutetium Lu 177 dotatate decays to stable hafnium (Hf 177) with a half-life of 6.647 days, by emitting beta-minus radiation with a maximum energy of 0.498 MeV (79%) and photonic radiation (gamma) of 0.208 MeV (11%) and 0.113 MeV (6.2%). The mean terminal half-life is 71 (+/- 28) hours.
Lutetium Lu 177 dotatate is primarily renally eliminated, with cumulative excretion of 44% within 5 hours, 58% within 24 hours, and 65% within 48 hours following administration. The fraction of radiation remaining after 2 hours is 99.1%; 90.1% of radiation remains after 24 hours, 81.2% after 2 days, 73.1% after 3 days, 48.2% after 7 days, 23.2% after 14 days, 4.4% after 30 days, and 0.9% after 45 days. Prolonged elimination of lutetium Lu 177 dotatate in the urine is expected; however, based on the half-life of lutetium 177 and terminal half-life of lutetium Lu 177 dotatate, greater than 99% of the administered radioactivity will be eliminated within 14 days after administration.
Affected cytochrome P450 isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Intravenous Route
The mean AUC of lutetium Lu 177 dotatate at the recommended dose is 41 ng*h/mL (CV, 36%); the mean Cmax is 10 ng/mL (CV, 50%), generally occurring at the end of the infusion.
-Special Populations
Renal Impairment
Lutetium LU 177 dotatate is primariily eliminated renally. While no dosage adjustment is recommended in patients with baseline mild to moderate renal impairment (CrCl 30 to 89 mL/minute), these patients may have increased radiation exposure that may increase the risk of toxicity. The pharmacokinetic profile and safety of Lutetium LU 177 dotatate have not been studied in patients with baseline severe renal impairment (creatinine clearance less than 30 mL/minute by Cockcroft-Gault formula) or end-stage renal disease.