CLASSES
Other Therapeutic Radiopharmaceuticals
DESCRIPTION
A radiolabeled somatostatin analog
Used for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults
Use appropriate safety measures to minimize radiation exposure
HOW SUPPLIED
Lutathera Intravenous Inj Sol: 1mL, 370MBq
DOSAGE & INDICATIONS
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, at a rate of 50 mL/hour to 100 mL/hour for 5 to 10 minutes and then 200 mL/hour to 300 mL/hour for an additional 25 to 30 minutes, every 8 weeks for a total of 4 doses. Beginning 30 minutes prior to administration of lutetium Lu 177 dotatate, initiate an IV infusion of amino acid solution containing lysine HCl (18 g to 24 g) and arginine HCl (18 g to 24 g); continue this infusion for at least 3 hours after completion of the lutetium Lu 177 dotatate infusion. Do not decrease the dose of the amino acid solution 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 of 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 up to 18 months following the initiation of treatment. 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 overall survival (not reached vs. 27.4 months) compared with high-dose long-acting octreotide (60 mg IM) in patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumors. The objective response rate (ORR) was 13% vs. 4%, respectively. 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.
MAXIMUM DOSAGE
Adults
7.4 GBq (200 mCi) IV.
Geriatric
7.4 GBq (200 mCi) IV.
DOSING CONSIDERATIONS
Hepatic Impairment
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 hypoalbuminemia less than 30 g/L with a decreased prothrombin ratio less than 70%: Hold lutetium Lu 177 dotatate therapy. Upon complete resolution 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 of 16 weeks or longer.
Recurrent grade 3 or 4 hyperbilirubinemia, or hypoalbuminemia less than 30 g/L with a decreased prothrombin ratio less than 70%: Permanently discontinue lutetium Lu 177 dotatate therapy.
Renal Impairment
Baseline Renal Impairment
Mild to moderate renal impairment (Creatinine clearance (CrCL) greater than or equal to 30 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 complete resolution 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 of 16 weeks or longer.
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.
ADMINISTRATION
Lutetium Lu 177 dotatate is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure. 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.
Injectable Administration
Intravenous Administration
Administer antiemetics 30 minutes before the recommended amino acid solution.
Initiate an IV amino acid solution 30 minutes before administering lutetium Lu 177 dotatate, 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 infusion during, and for at least 3 hours after the lutetium Lu 177 dotatate infusion.
Amino Acid Solution:
Lysine HCl content: between 18 g to 24 g.
Arginine HCl content: between 18 g to 24 g.
Volume: 1.5 L to 2.2 L.
Osmolarity: less than 1,050 mOsmol.
Administration of lutetium Lu 177 dotatate:
Inspect the product visually for particulate matter and discoloration prior to administration under a shielded screen. Discard vial if particulates or discoloration are present.
Use aseptic technique and radiation shielding during administration. Use tongs when handling vial to minimize radiation exposure.
Do not inject lutetium Lu 177 dotatate directly into any other intravenous solution.
Confirm the amount of radioactivity of lutetium Lu 177 dotatate in the radiopharmaceutical vial with an appropriate dose calibrator prior to administration.
Insert a 2.5 cm, 20 gauge needle (short needle) into the lutetium Lu 177 dotatate vial and connect via catheter to 500 mL 0.9% sterile sodium chloride solution (used to transport lutetium Lu 177 dotatate during the infusion). Ensure that the short needle does not touch the lutetium Lu 177 dotatate solution in the vial and do not connect this short needle directly to the patient. Do not allow sodium chloride solution to flow into the lutetium Lu 177 dotatate vial prior to the initiation of the infusion. Do not inject lutetium Lu 177 dotatate directly into the sodium chloride 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 intravenous catheter that is prefilled with 0.9% sterile sodium chloride and that is used exclusively for the lutetium Lu 177 dotatate infusion into the patient.
Use a clamp or pump to regulate the flow of the sodium chloride solution via the short needle into the lutetium Lu 177 dotatate vial at a rate of 50 mL/hour to 100 mL/hour for 5 to 10 minutes and then 200 mL/hour to 300 mL/hour for an additional 25 to 30 minutes (the sodium chloride 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).
Do not administer as an intravenous bolus.
During the infusion, ensure that the level of solution 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 five minutes.
Follow the infusion with an intravenous flush of 25 mL of 0.9% sterile sodium chloride.
Confirm the amount of radioactivity of lutetium Lu 177 dotatate in the radiopharmaceutical vial with an appropriate dose calibrator after administration.
Dispose of any unused medicinal product or waste material in accordance with local and federal laws.
STORAGE
Generic:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard unused portion. Do not store for later use.
- Do not freeze
- See package insert for detailed storage information
- Store below 77 degrees F
- Store in original container
CONTRAINDICATIONS / PRECAUTIONS
Neuroendocrine hormonal crisis
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.
New primary malignancy, radiation exposure
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. Follow institutional good radiation safety practices and patient management procedures to minimize radiation exposure to patients, medical personnel, and household contacts. Radiation can be detected in the urine for up to 30 days after lutetium Lu 177 dotatate administration.
Hepatic disease
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, and serum albumin during treatment. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be necessary if hepatotoxicity occurs.
Anemia, bone marrow suppression, neutropenia, thrombocytopenia
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 weeks after the first dose of lutetium Lu 177 dotatate, with a median time to recovery of 2 months.
Renal disease, renal impairment
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. 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 urinate frequently during and 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).
Pregnancy
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 radiopharmaceuticals, 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.
Contraception requirements, infertility, pregnancy testing, reproductive risk
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.
Breast-feeding
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.
ADVERSE REACTIONS
Severe
lymphopenia / Delayed / 44.0-44.0
elevated hepatic enzymes / Delayed / 4.0-20.0
hyperkalemia / Delayed / 19.0-19.0
vomiting / Early / 7.0-7.0
hyperuricemia / Delayed / 6.0-6.0
nausea / Early / 5.0-5.0
hyperglycemia / Delayed / 4.0-4.0
hypokalemia / Delayed / 4.0-4.0
neutropenia / Delayed / 3.0-3.0
renal failure (unspecified) / Delayed / 0-3.0
diarrhea / Early / 3.0-3.0
abdominal pain / Early / 3.0-3.0
new primary malignancy / Delayed / 1.8-2.7
leukopenia / Delayed / 2.0-2.0
hyperbilirubinemia / Delayed / 2.0-2.0
back pain / Delayed / 2.0-2.0
hypertension / Early / 2.0-2.0
heart failure / Delayed / 0-2.0
thrombocytopenia / Delayed / 1.0-1.0
flushing / Rapid / 1.0-1.0
neuroendocrine hormonal crisis / Early / 0-1.0
bronchospasm / Rapid / 0-1.0
anxiety / Delayed / 1.0-1.0
cough / Delayed / 1.0-1.0
atrial fibrillation / Early / 1.0-1.0
myocardial infarction / Delayed / 0-1.0
fatigue / Early / 1.0-1.0
azotemia / Delayed / Incidence not known
Moderate
anemia / Delayed / 81.0-81.0
hypocalcemia / Delayed / 32.0-32.0
hypernatremia / Delayed / 17.0-17.0
peripheral edema / Delayed / 16.0-16.0
hypoglycemia / Early / 15.0-15.0
constipation / Delayed / 10.0-10.0
hypotension / Rapid / 0-1.0
cholestasis / Delayed / Incidence not known
colic / Delayed / Incidence not known
urethral pain / Early / Incidence not known
urinary incontinence / Early / Incidence not known
dysuria / Early / Incidence not known
Mild
anorexia / Delayed / 21.0-21.0
dizziness / Early / 17.0-17.0
headache / Early / 17.0-17.0
alopecia / Delayed / 12.0-12.0
dysgeusia / Early / 8.0-8.0
fever / Early / 8.0-8.0
myalgia / Early / 5.0-5.0
nocturia / Early / Incidence not known
pelvic pain / Delayed / Incidence not known
DRUG INTERACTIONS
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.
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.
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.
Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
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.
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.
PREGNANCY AND LACTATION
Pregnancy
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 radiopharmaceuticals, 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.
MECHANISM OF ACTION
Lutetium Lu 177 dotatate binds to somatostatin receptors, including those on malignant somatostatin receptor-positive tumors, with the highest affinity for subtype 2 receptors (SSRT2). After binding, it is internalized and the beta emission from Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells.
PHARMACOKINETICS
Lutetium Lu 177 dotatate is administered intravenously. The non-radioactive form of lutetium 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 radiation with a maximum energy of 0.498 MeV and photonic radiation (gamma) of 0.208 MeV (11%) and 0.113 MeV (6.4%). The mean effective blood elimination half-life is 3.5 (+/- 1.4) hours and 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% will be eliminated within 14 days after administration.
Affected cytochrome P450 isoenzymes and drug transporters: None.
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.