Lutetium Lu 177 dotatate, a lutetium 177 radiolabeled tetraazacyclododecane-tetra-acetic acid (DOTA)-somatostatin analog conjugate consisting of the somatostatin analog octreotide linked to a chelator (DOTA), is a peptide receptor radionuclide agent.1, 2, 3, 5, 8, 12, 13
Neuroendocrine Tumors of Gastroenteropancreatic Origin
Lutetium Lu 177 dotatate is used for the treatment of somatostatin receptor-positive neuroendocrine tumors of gastroenteropancreatic origin (GEP-NET), including foregut, midgut, and hindgut neuroendocrine tumors.1, 2, 3, 5 Lutetium Lu 177 dotatate has been designated an orphan drug by FDA for use in this condition.4
The current indication for lutetium Lu 177 dotatate is based principally on the results of a randomized, multicenter, open-label phase 3 study (Neuroendocrine Tumors Therapy [NETTER-1]) in patients with progressive, well-differentiated, somatostatin receptor-positive, unresectable, locally advanced or metastatic midgut neuroendocrine tumors, with supporting data from an open-label, noncomparative, retrospective phase 1/2 study (ERASMUS) in a cohort of patients with GEP-NETs of the foregut, midgut, and hindgut.1, 2, 3, 5
In the NETTER-1 study, 229 patients were randomized (stratified by somatostatin receptor expression and duration of octreotide) in a 1:1 ratio to receive either lutetium Lu 177 dotatate (7.4 GBq administered as an IV infusion every 8 weeks for up to 4 doses [maximum cumulative dose of 29.6 GBq] or until disease progression or unacceptable toxicity occurred or the patient withdrew from the study) plus best supportive care (long-acting [extended-release] octreotide 30 mg administered as an IM injection 4-24 hours following each dose of lutetium Lu 177 dotatate and then every 4 weeks until disease progression or week 76 of study enrollment) or high-dose long-acting octreotide (60 mg administered as an IM injection every 4 weeks) alone.1, 2 All patients were permitted to receive rescue therapy with short-acting octreotide; however, administration of short-acting octreotide was not permitted within 24 hours prior to administration of lutetium Lu 177 dotatate.1, 2 The primary measure of efficacy was progression-free survival (as evaluated by a blinded independent review committee according to Response Evaluation Criteria in Solid Tumors [RECIST]); additional outcome measures were objective response rate, duration of response, and overall survival.1, 2
The median age of patients enrolled in the NETTER-1 study was 64 years; 90% were Caucasian, 51% were male, 96% had liver metastases, 77% had serum chromogranin A (CgA) concentrations exceeding 2 times the upper limit of normal (ULN), 74% had received a stable dosage of octreotide for more than 6 months, 69% had low-grade primary tumors (defined as Ki67 expression in 2% or less of tumor cells as detected by immunohistochemistry assay), 65% had serum 5-hydroxyindoleacetic acid (5-HIAA) concentrations exceeding 2 times the ULN, 65% had alkaline phosphatase concentrations not more than the ULN, and 12% had received prior therapy with everolimus.1, 2 The most common primary tumor site was the ileum (74%), and the median Karnofsky performance score of patients enrolled in the study was 90.1, 2 Eligible patients also were required to have well-differentiated primary tumors (defined as Ki67 expression in 20% or less of tumor cells), Karnofsky performance status of at least 60, confirmed presence of somatostatin receptors on all lesions, and creatinine clearance of at least 50 mL/minute.1, 2 This study excluded patients who received prior peptide receptor radionuclide therapy (PRRT) or external beam radiation therapy to more than 25% of the bone marrow.1, 2
At a median follow-up of 10.5 months in the NETTER-1 study, median progression-free survival had not been reached in patients receiving lutetium Lu 177 dotatate in combination with long-acting octreotide; however, the risk of disease progression or death in patients receiving lutetium Lu 177 dotatate in combination with long-acting octreotide was reduced by 79% compared with those receiving high-dose long-acting octreotide.1, 2 At the time of the primary analysis, lutetium Lu 177 dotatate in combination with long-acting octreotide reduced the risk of death by 48% compared with high-dose long-acting octreotide; however, the prespecified level of statistical significance was not achieved.1 In addition, patients receiving lutetium Lu 177 dotatate in combination with long-acting octreotide had higher objective response rates compared with those receiving high-dose long-acting octreotide (13 versus 4%); complete responses were achieved in 1% of patients receiving lutetium Lu 177 dotatate in combination with long-acting octreotide and none of those receiving high-dose long-acting octreotide.1 At the time of the analysis, the median duration of response had not been reached in patients receiving lutetium Lu 177 dotatate in combination with long-acting octreotide and was 1.9 months in those receiving high-dose long-acting octreotide.1 Results of a subgroup analysis (based on age, gender, tumor grade, baseline CgA concentrations, baseline 5-HIAA concentrations, grade of somatostatin receptor expression, baseline alkaline phosphatase concentration, and presence of extrahepatic metastases) suggested that the effect of lutetium Lu 177 dotatate on progression-free survival was consistent across all subgroups.2
In the ERASMUS study, lutetium Lu 177 dotatate was initially provided under a PRRT expanded access program without a formal clinical protocol or prespecified statistical analysis plan; however, a protocol specific for lutetium Lu 177 dotatate was generated several years following initiation of the program and allowed for retrospective analysis.5 In this study, 360 patients with GEP-NETs of the foregut, midgut, or hindgut received lutetium Lu 177 dotatate (7.4 GBq) administered as an IV infusion every 6-13 weeks for up to 4 doses; patients enrolled in the study received a median dose of 29.6 GBq and approximately one-half of patients (55%) received concomitant therapy with a somatostatin analog.1, 5 Patients also received an amino acid solution containing l -lysine and l -arginine administered as an IV infusion over 4 hours beginning 30 minutes prior to administration of lutetium Lu 177 dotatate.3, 5 The primary measure of efficacy was objective response rate as assessed by the investigator according to RECIST.1, 5 The median age of patients enrolled in the cohort of patients with GEP-NETs of the foregut, midgut, or hindgut was 61 years; 61% had a baseline Karnofsky performance status of at least 90, 60% had disease progression within 12 months of study enrollment, 52% were male, and 15% had received prior chemotherapy.1 Baseline tumor assessments were obtained in 39% of patients.1 In the cohort of patients with GEP-NET of the foregut, midgut, or hindgut, the objective response rate was 16% with a median duration of response of 35 months; complete response was achieved in less than 1% of patients.1
Lutetium Lu 177 dotatate is a radiopharmaceutical and should be prepared and used only by a qualified clinician (i.e., authorized by an appropriate regulatory agency) experienced in the safe use and handling of radionuclides.1 Procedures for proper handling (e.g., use of waterproof gloves, shields, tongs) and disposal of radionuclides should be followed when preparing and administering lutetium Lu 177 dotatate.1
To minimize the risk of nephrotoxicity associated with lutetium Lu 177 dotatate,1, 5, 6 an amino acid solution containing l -lysine and l -arginine should be administered by IV infusion 30 minutes prior to each lutetium Lu 177 dotatate infusion and continued during and for at least 3 hours after the lutetium Lu 177 dotatate infusion.1 The amino acid solution may be administered through the same IV line (equipped with a 3-way valve) with lutetium Lu 177 dotatate or through a separate IV line in the opposite arm.1 The amino acid solution should be administered as a 1.5-2.2 L solution containing 18-24 g of l -lysine and 18-24 g of l -arginine with an osmolarity of less than 1050 mOsm/L.1 (See Renal Effects under Cautions: Warnings/Precautions.) To minimize the risk of nausea associated with the amino acid infusion, the manufacturer recommends premedication with an antiemetic (e.g., granisetron, ondansetron) 30 minutes prior to each amino acid infusion.1, 5 The manufacturer states that no dosage adjustment of the amino acid solution is necessary when the dosage of lutetium Lu 177 dotatate is reduced.1
Patients should be adequately hydrated (e.g., one glass of water every hour) during and after administration of lutetium Lu 177 dotatate to ensure good urinary output.1, 14 (See Renal Effects under Cautions: Warnings/Precautions.)
Lutetium Lu 177 dotatate is administered by IV infusion.1 The radiopharmaceutical should not be administered by rapid IV injection, such as IV push or bolus. 1 The IV line should be flushed with 25 mL of 0.9% sodium chloride injection after IV administration of lutetium Lu 177 dotatate.1
Lutetium Lu 177 dotatate should not be injected directly into any IV solution.1 Precautions for reducing the risk of radiation exposure (i.e., use of waterproof gloves, shielding, tongs) should be followed.1
Lutetium Lu 177 dotatate vials must be stored below 25ºC in the lead shielded container provided by the manufacturer; the shelf-life of lutetium Lu 177 dotatate is 72 hours.1
Prior to administration, lutetium Lu 177 dotatate injection should be inspected visually for particulate matter and discoloration.1 The solution should be clear and colorless to slightly yellow; the solution should not be used if it is discolored or if particulate matter is present.1 The level of radioactivity of lutetium Lu 177 dotatate in the vial should be confirmed with a calibrated radioactivity measurement system (e.g., Geiger counter14 ).1
For IV infusion, a short (2.5 cm in length) 20-gauge needle should be inserted into a vial containing 370 MBq/mL (equivalent to 10 mCi/mL) of lutetium Lu 177 dotatate and then connected to a primed administration set and infusion bag containing 500 mL of 0.9% sodium chloride injection; the short 20-gauge needle must remain above the lutetium Lu 177 dotatate solution.1 Lutetium Lu 177 dotatate should not be injected directly into the 0.9% sodium chloride solution.1 The administration set connected to the short needle should be clamped to prevent flow of 0.9% sodium chloride solution into the lutetium Lu 177 dotatate vial during preparation of the infusion.1 A longer (9 cm in length) 18-gauge needle should be inserted into the same vial containing 370 MBq/mL (equivalent to 10 mCi/mL) of lutetium Lu 177 dotatate.1 The tip of the long needle should be securely positioned at the bottom of the lutetium Lu 177 dotatate vial for the duration of the infusion.1 The long needle should be connected to a dedicated IV line, primed with 0.9% sodium chloride solution, for infusion of lutetium Lu 177 dotatate to the patient.1
During the infusion, the flow of 0.9% sodium chloride injection into the vial increases pressure in the vial, which facilitates flow of lutetium Lu 177 dotatate from the vial to the patient.14 The 0.9% sodium chloride solution should flow (regulated by clamp) into the lutetium Lu 177 dotatate vial via the short needle.1, 14 Alternatively, an infusion pump may be used to control the flow rate of 0.9% sodium chloride solution.1 If an infusion pump is used, the 0.9% sodium chloride solution should be set at an initial rate of 50-100 mL/hour for 5-10 minutes followed by an increase to 200-300 mL/hour for 25-30 minutes for a total infusion time of 30-40 minutes.1
To ensure complete administration of the radiopharmaceutical, the level of solution in the vial containing lutetium Lu 177 dotatate should remain constant during the entire infusion.1, 14 Once the radioactivity emission in the vial stabilizes for at least 5 minutes,1, 14 the lutetium Lu 177 dotatate infusion may be completed by removing the long needle from the vial and clamping the administration set connected to the 0.9% sodium chloride solution.1
Any unused portion in the vial or administration set should be discarded according to local and federal regulations.1
Neuroendocrine Tumors of Gastroenteropancreatic Origin
For the treatment of somatostatin receptor-positive neuroendocrine tumors of gastroenteropancreatic origin (GEP-NET), including foregut, midgut, and hindgut neuroendocrine tumors, the recommended adult dosage of lutetium Lu 177 dotatate is 7.4 GBq (equivalent to 200 mCi) administered by IV infusion over 30-40 minutes every 8 weeks for a total of 4 doses.1
In the NETTER-1 study, lutetium Lu 177 dotatate was used in combination with long-acting (extended-release) octreotide; rescue therapy with short-acting (immediate-release) octreotide also was permitted.1, 2 When lutetium Lu 177 dotatate is used in combination with short- or long-acting octreotide, the manufacturer states that short- or long-acting octreotide should not be administered within 24 hours or 4 weeks, respectively, prior to each dose of lutetium Lu 177 dotatate.1 (See Drug Interactions: Octreotide.)
When lutetium Lu 177 dotatate is used in combination with long-acting octreotide, the manufacturer states that a single 30-mg dose of long-acting octreotide acetate may be administered by IM injection between 4-24 hours following each dose of lutetium Lu 177 dotatate and should not be administered within 4 weeks prior to administration of lutetium Lu 177 dotatate.1 Following discontinuance of lutetium Lu 177 dotatate therapy, long-acting octreotide acetate (30 mg administered by IM injection every 4 weeks) may be continued until disease progression or for a treatment duration of up to 18 months.1
Dosage Modification for Toxicity
If adverse reactions occur, interruption of therapy, dosage reduction, and/or permanent discontinuance of lutetium Lu 177 dotatate may be necessary based on severity of the adverse effect.1
Dosage adjustment of amino acids is not necessary when the dosage of lutetium Lu 177 dotatate is reduced.1
If grade 2-4 thrombocytopenia occurs, lutetium Lu 177 dotatate therapy should be withheld until thrombocytopenia improves to grade 1 or less.1 Lutetium Lu 177 dotatate may then be resumed at a reduced dosage of 3.7 GBq (equivalent to 100 mCi); if grade 2-4 thrombocytopenia does not recur, the dosage of lutetium Lu 177 dotatate may be re-escalated to 7.4 GBq (equivalent to 200 mCi).1 If grade 2-4 thrombocytopenia recurs or does not improve within 16 weeks of withholding therapy, lutetium Lu 177 dotatate should be permanently discontinued.1 (See Hematologic Effects under Cautions: Warnings/Precautions.)
If grade 3 or 4 neutropenia or anemia occurs, lutetium Lu 177 dotatate therapy should be withheld until the toxicity improves to grade 2 or less.1 Lutetium Lu 177 dotatate may then be resumed at a reduced dosage of 3.7 GBq (equivalent to 100 mCi); if grade 3 or 4 neutropenia or anemia does not recur, the dosage of lutetium Lu 177 dotatate may be re-escalated to 7.4 GBq (equivalent to 200 mCi).1 If grade 3 or 4 neutropenia or anemia recurs or does not improve within 16 weeks of withholding therapy, lutetium Lu 177 dotatate should be permanently discontinued.1
If nephrotoxicity (i.e., increase in serum creatinine concentration from baseline of 40% or more; creatinine clearance less than 40 mL/minute; decrease in creatinine clearance from baseline of 40% or more) occurs, lutetium Lu 177 dotatate therapy should be withheld until the toxicity completely resolves.1 Lutetium Lu 177 dotatate may then be resumed at a reduced dosage of 3.7 GBq (equivalent to 100 mCi); if the toxicity does not recur, the dosage of lutetium Lu 177 dotatate may be re-escalated to 7.4 GBq (equivalent to 200 mCi).1 If nephrotoxicity recurs or does not improve within 16 weeks of withholding therapy, the drug should be permanently discontinued.1 (See Renal Effects under Cautions: Warnings/Precautions.)
If hepatotoxicity (i.e., elevations in bilirubin concentration exceeding 3 times the upper limit of normal [ULN]; serum albumin less than 3 g/dL with prothrombin ratio less than 70%) occurs, lutetium Lu 177 dotatate therapy should be withheld until the toxicity completely resolves.1 Lutetium Lu 177 dotatate may then be resumed at a reduced dosage of 3.7 GBq (equivalent to 100 mCi); if the toxicity does not recur, the dosage of lutetium Lu 177 dotatate may be re-escalated to 7.4 GBq (equivalent to 200 mCi).1 If hepatotoxicity recurs or does not improve within 16 weeks of withholding therapy, lutetium Lu 177 dotatate should be permanently discontinued.1 (See Hepatic Toxicity under Cautions: Warnings/Precautions.)
If grade 3 or 4 nonhematologic toxicity occurs, lutetium Lu 177 dotatate therapy should be withheld until the toxicity improves to grade 2 or less.1 Lutetium Lu 177 dotatate may then be resumed at a reduced dosage of 3.7 GBq (equivalent to 100 mCi); if the toxicity does not recur, the dosage of lutetium Lu 177 dotatate may be re-escalated to 7.4 GBq (equivalent to 200 mCi).1 If grade 3 or 4 nonhematologic toxicity recurs or does not improve within 16 weeks of withholding therapy, lutetium Lu 177 dotatate should be permanently discontinued.1
The manufacturer states that no adjustment to the initial dosage of lutetium Lu 177 dotatate is necessary in patients with mild or moderate hepatic impairment.1 Lutetium Lu 177 dotatate has not been studied in patients with severe hepatic impairment (total bilirubin concentration exceeding 3 times the upper limit of normal [ULN] with any AST concentration), and the manufacturer provides no specific dosage recommendations for such patients.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states that no adjustment to the initial dosage of lutetium Lu 177 dotatate is necessary in patients with mild to moderate renal impairment (creatinine clearance of 30 mL/minute or greater).1 Lutetium Lu 177 dotatate has not been studied in patients with severe renal impairment (creatinine clearance of less than 30 mL/minute) or end-stage renal disease, and the manufacturer provides no specific dosage recommendations for such patients.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states that there are no known contraindications to the use of lutetium Lu 177 dotatate.1
The radioactive component of lutetium Lu 177 dotatate (lutetium 177) contributes to a patient's lifetime cumulative radiation exposure, and development of new malignancies is a known risk of long-term radiation exposure.1 (See Myelodysplastic Syndrome and Acute Leukemia under Cautions: Warnings/Precautions.)
Because radioactivity can be detected in urine for up to 30 days following administration of lutetium Lu 177 dotatate, institutional good radiation safety practices and patient management procedures should be employed during and after administration of lutetium Lu 177 dotatate to minimize exposure of patients, medical personnel, and household contacts to radiation.1
Adverse hematologic effects (e.g., anemia, neutropenia, thrombocytopenia) occur frequently in patients receiving lutetium Lu 177 dotatate in combination with long-acting (extended-release) octreotide.1 In the Neuroendocrine Tumors Therapy (NETTER-1) study, anemia, thrombocytopenia, and neutropenia occurred in 81, 53, and 26%, respectively, of patients receiving lutetium Lu 177 dotatate in combination with long-acting octreotide, compared with 54, 17, and 11%, respectively, of patients receiving high-dose long-acting octreotide.1 Following the initial dose of lutetium Lu 177 dotatate, nadir platelet counts occurred in a median of 5.1 weeks.1 Thrombocytopenia resolved in 68% of patients in a median of 2 months and improved to grade 3 or less in an additional 25% of patients.1
Some data suggest that preexisting renal impairment, leukocyte count below 4000/mm3, advanced age (i.e., older than 70 years of age), extensive tumor mass, and high tumor uptake on octreotide scintigraphy (i.e., OctreoScan®) may result in increased potential for developing grade 3 or 4 hematologic toxicity.17
Complete blood cell (CBC) counts should be monitored prior to and periodically during lutetium Lu 177 dotatate therapy.1, 5, 11 Temporary interruption followed by dosage reduction or discontinuance of lutetium Lu 177 dotatate may be necessary if hematologic toxicity occurs during therapy with lutetium Lu 177 dotatate.1 (See Hematologic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Myelodysplastic Syndrome and Acute Leukemia
In the NETTER-1 study, myelodysplastic syndrome (MDS) was reported in 2.7% of patients receiving lutetium Lu 177 dotatate in combination with long-acting octreotide compared with none of those receiving high-dose long-acting octreotide.1 In the ERASMUS study, MDS or acute leukemia was reported in 1.8 or 0.5%, respectively, of patients receiving lutetium Lu 177 dotatate; the median time to occurrence was 28 months (range: 9-41 months) or 55 months (range: 32-155 months), respectively, following initiation of therapy.1
Because peptide analogs such as octreotide are extensively reabsorbed in the renal proximal tubules, accumulation of the radioactive component of lutetium Lu 177 dotatate (lutetium 177) in renal interstitium results in inflammation and fibrosis and subsequent acute or chronic renal damage.5, 8, 15, 16 In the ERASMUS study, renal failure was reported in 8 patients (less than 1%) receiving lutetium Lu 177 dotatate at 3-36 months following initiation of therapy; 2 of these patients had preexisting renal impairment or risk factors for renal failure (e.g., diabetes mellitus, hypertension) and required dialysis.1 Available data have suggested that advanced age (i.e., older than 60 years of age), poorly controlled diabetes mellitus, hypertension, prior platinum-containing therapy, and preexisting renal impairment may be risk factors for developing nephrotoxicity associated with peptide receptor radionuclide therapy (PRRT).1, 15
Coadministration of positively charged amino acids (e.g., l -lysine, l -arginine) with PRRT has been shown to minimize the risk of nephrotoxicity by reducing reabsorption of peptide receptor radionuclides, such as lutetium Lu 177 dotatate, in the proximal tubules which subsequently reduces the dose of radiation to the kidneys.1, 8, 15, 16 In the ERASMUS study, coadministration of the amino acids l -lysine and l -arginine reduced the median radiation dose to the kidneys by 47% and increased the mean beta-phase plasma clearance of lutetium Lu 177 dotatate by 36%.5 The manufacturer states that an amino acid solution containing l -lysine and l -arginine should be administered 30 minutes prior to each lutetium Lu 177 dotatate infusion and continued during and for at least 3 hours after the lutetium Lu 177 dotatate infusion.1 (See Dosage and Administration: General.) Patients also should be adequately hydrated (e.g., one glass of water every hour) during and after administration of lutetium Lu 177 dotatate to ensure good urinary output.1, 14
Renal function (i.e., serum creatinine) should be monitored prior to and periodically during lutetium Lu 177 dotatate therapy; monitoring should be more frequent in those with mild or moderate renal impairment.1, 5, 11 If nephrotoxicity occurs, temporary interruption of therapy followed by dosage reduction or discontinuance of lutetium Lu 177 dotatate may be necessary.1 (See Renal Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
In the ERASMUS study, hepatic tumor hemorrhage, edema, or necrosis was reported in 2 patients receiving lutetium Lu 177 dotatate,1 with one patient also experiencing intrahepatic congestion and cholestasis.5 The risk of developing hepatic toxicity is increased in patients with hepatic metastasis.1
Liver function tests (i.e., serum aminotransferase, bilirubin, serum albumin) should be monitored prior to and periodically during lutetium Lu 177 dotatate therapy.1, 11 If hepatotoxicity occurs, temporary interruption of therapy followed by dosage reduction or discontinuance of lutetium Lu 177 dotatate may be necessary.1 (See Hepatotoxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
In the ERASMUS study, carcinoid hormonal crisis (also known as neuroendocrine hormonal crisis), which may manifest as flushing, diarrhea, bronchospasm, or hypotension, was reported in 1% of patients, generally during or within 24 hours of the initial dose of lutetium Lu 177 dotatate.1, 6 Hypercalcemia also was reported in 2 patients.1
Patients receiving lutetium Lu 177 dotatate should be monitored for manifestations of carcinoid hormonal crisis and should be managed (e.g., IV somatostatin analog, hydration, corticosteroids, electrolytes) as clinically indicated if such crises occur.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action, lutetium Lu 177 dotatate may cause fetal harm.1 There are no available data regarding the risk of lutetium Lu 177 dotatate use in pregnant women or animals to date.1
Pregnancy should be avoided during lutetium Lu 177 dotatate therapy.1 Pregnancy status should be verified prior to initiation of lutetium Lu 177 dotatate, and women of reproductive potential should be advised to use effective contraceptive methods while receiving the radiopharmaceutical and for 7 months after the final dose.1 In addition, men with female partners of reproductive potential should use effective methods of contraception while receiving the radiopharmaceutical and for 4 months after the final dose.1 If lutetium Lu 177 dotatate is used during pregnancy or if the patient becomes pregnant while receiving the radiopharmaceutical, the patient should be apprised of the potential fetal hazard.1 (See Advice to Patients.)
Lutetium Lu 177 dotatate may impair male and female fertility.1 The cumulative radiation exposure following the recommended course of lutetium Lu 177 dotatate (29.6 GBq) results in an absorbed radiation dose in the testis and ovaries that is comparable to the dose at which external beam radiotherapy causes reversible or permanent infertility.1
Lutetium Lu 177 dotatate may cause fetal harm if administered to pregnant women based on its mechanism of action.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)
It is not known whether lutetium Lu 177 dotatate distributes into milk in human or animals or whether the radiopharmaceutical has any effects on nursing infants and on milk production.1 Because of the potential for serious adverse reactions to lutetium Lu 177 dotatate in nursing infants, women should be advised to discontinue nursing during lutetium Lu 177 dotatate therapy and for 2.5 months after the last dose.1
Safety and efficacy of lutetium Lu 177 dotatate have not been established in pediatric patients.1
In clinical trials, 33% of patients receiving lutetium Lu 77 dotatate were 65 years of age or older.1 No differences in serious adverse effects or response rate were observed between geriatric patients and younger adults;1 however, some data suggest that advanced age may increase the risk for developing nephrotoxicity or grade 3 or 4 hematologic toxicity.1, 15, 17 (See Hematologic Effects and also see Renal Effects under Cautions: Warnings/Precautions.)
A dedicated hepatic impairment trial for lutetium Lu 177 dotatate has not been conducted to date; however, lutetium Lu 177 dotatate does not undergo hepatic elimination.1, 5 (See Dosage and Administration: Special Populations.)
Safety of lutetium Lu 177 dotatate has not been established in patients with severe hepatic impairment (total bilirubin concentration exceeding 3 times the upper limit of normal [ULN] with any AST concentration).1
In the NETTER-1 study, an association between creatinine clearance and adverse hematologic effects was not observed in patients receiving lutetium Lu 177 dotatate.5 However, since lutetium Lu 177 dotatate is eliminated mainly by the kidneys, mild to moderate renal impairment may result in an increased potential for adverse reactions.1, 5 (See Hematologic Effects and also see Renal Effects under Cautions: Warnings/Precautions.) Renal function should be monitored more frequently in patients with mild to moderate renal impairment.1 Safety of lutetium Lu 177 dotatate has not been established in patients with severe renal impairment (creatinine clearance of less than 30 mL/minute) or end-stage renal disease.1 (See Dosage and Administration: Special Populations.)
Adverse effects reported in at least 10% of patients receiving lutetium Lu 177 dotatate in combination with long-acting octreotide in the NETTER-1 study include nausea,1, 2 vomiting,1, 2 fatigue,1, 2 musculoskeletal pain,1, 2 abdominal pain,1, 2 diarrhea,1, 2 decreased appetite,1, 2 dizziness,1, 2 headache,1, 2 peripheral edema,1, 2 flushing,1, 2 alopecia,1, 2 distension,2 anxiety,1 hypertension,1 renal failure,1 cough,1, 2 and constipation.1 Laboratory abnormalities reported in at least 10% of patients receiving lutetium Lu 177 dotatate in combination with long-acting octreotide include lymphopenia,1, 2 elevated concentrations of serum creatinine,1 hyperglycemia,1 anemia,1, 2 elevated concentrations of γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP),1 elevated concentrations of alkaline phosphatase,1 leukopenia,1, 2 thrombocytopenia,1, 2 elevated concentrations of aminotransferases (i.e., AST, ALT),1 hyperuricemia,1 hypocalcemia,1 elevated concentrations of bilirubin,1 hypokalemia,1 neutropenia,1, 6 hyperkalemia,1 hypernatremia,1 and hypoglycemia.1
In a retrospective analysis of data from the ERASMUS study for a subset of 811 patients with somatostatin receptor-positive tumors (neuroendocrine or other primary tumor sites), serious adverse reactions following a median follow-up exceeding 4 years included MDS, acute leukemia, renal failure, hypotension, cardiac failure, myocardial infarction, and carcinoid crisis.1 Most (81%) of these patients received a cumulative lutetium Lu 177 dotatate dose of 22.2 GBq or more.1
In vitro studies indicate that nonradioactive lutetium dotatate (lutetium Lu 175 dotatate) is not an inhibitor or inducer of cytochrome P-450 (CYP) isoenzyme 1A2, 2B6, 2C9, 2C19, or 2D6.1, 5
In vitro, nonradioactive lutetium dotatate is not an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1, OAT3, organic anion transport protein (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, or OCT2.1, 5
The prescribing information for lutetium Lu 177 dotatate in the US does not provide information concerning the concurrent use of corticosteroids during therapy.1 However, the manufacturer in the European Union recommends avoiding concomitant use of lutetium Lu 177 dotatate and long-term use of high-dose corticosteroids because some evidence suggests that corticosteroids may induce down-regulation of somatostatin receptor type 2 (SSRT2).14, 14 Patients receiving corticosteroid therapy for chronic conditions should be carefully evaluated for sufficient somatostatin receptor expression.14 The manufacturer in the European Union also states that intermittent use of corticosteroids should be avoided because of insufficient data; however, if concomitant use cannot be avoided, a single dose of a corticosteroid may be administered at least 1 hour following completion of the lutetium Lu 177 dotatate infusion.14
Because somatostatin analogs such as octreotide are competitive inhibitors with lutetium Lu 177 dotatate in binding to somatostatin receptors, concomitant use of lutetium Lu 177 dotatate with somatostatin analogs (e.g., octreotide) may reduce lutetium Lu 177 dotatate efficacy.1, 14
When lutetium Lu 177 dotatate is used in combination with short-acting (immediate-release) or long-acting (extended-release) octreotide, the manufacturer states that short- or long-acting octreotide should not be administered within 24 hours or 4 weeks, respectively, prior to each dose of lutetium Lu 177 dotatate.1
When lutetium Lu 177 dotatate is used in combination with long-acting octreotide, the manufacturer states that a single 30-mg dose of long-acting octreotide acetate may be administered by IM injection between 4-24 hours after each dose of lutetium Lu 177 dotatate and should not be administered within 4 weeks prior to administration of lutetium Lu 177 dotatate.1 Following discontinuance of lutetium Lu 177 dotatate therapy, long-acting octreotide acetate (30 mg administered by IM injection every 4 weeks) may be continued until disease progression or for a treatment duration of up to 18 months.1
Lutetium Lu 177 dotatate, a lutetium 177 radiolabeled tetraazacyclododecane-tetra-acetic acid (DOTA)-somatostatin analog conjugate consisting of the somatostatin analog octreotide linked to a chelator (DOTA), is a peptide receptor radionuclide agent.1, 2, 3, 5, 8, 12, 13 The peptide portion of lutetium Lu 177 dotatate binds specifically to somatostatin receptors, with the highest affinity for somatostatin receptor type 2 (SSRT2).1 Following binding of the somatostatin analog component of lutetium Lu 177 dotatate to somatostatin receptors, the resultant complex is internalized by the cell.1 The radioactive component of lutetium Lu 177 dotatate (lutetium 177) induces cellular damage by forming free radicals in target and neighboring cells and is responsible for the primary cytotoxic effect of the peptide receptor radionuclide agent.1, 2, 3, 6
Following IV administration, lutetium Lu 177 dotatate rapidly distributes into kidneys, tumor lesions, liver, spleen, and, sometimes, pituitary gland and thyroid within 4 hours.1, 14 In patients receiving lutetium Lu 177 dotatate at the recommended dosage, the mean effective half-life of lutetium Lu 177 dotatate in the blood is 3.5 hours.1, 5 Coadministration of the amino acids l -lysine and l -arginine reduces the median radiation dose to the kidneys by 47% and increases the mean β-phase plasma clearance of lutetium Lu 177 dotatate by 36%.1, 5 Lutetium Lu 177 dotatate does not undergo hepatic metabolism.1 Lutetium Lu 177 dotatate is eliminated by the kidneys; 44, 58, or 65% of the dose is recovered in urine within 5, 24, or 48 hours, respectively.1 Following IV administration of lutetium Lu 177 dotatate, more than 99% of the dose is expected to be eliminated within 14 days.1 In vivo, nonradioactive lutetium dotatate (lutetium Lu 175 dotatate) is 43% bound to plasma proteins.1, 5, 14 The mean effective and terminal half-lives of lutetium Lu 177 dotatate are 3.5 and 71 hours, respectively.1, 5
Importance of advising patients to follow standard precautions for minimizing radiation exposure to household contacts.1
Risk of myelosuppression (e.g., thrombocytopenia, neutropenia, anemia).1 Importance of monitoring complete blood cell (CBC) counts prior to and periodically during lutetium Lu 177 dotatate therapy.1, 11 Importance of informing clinician if any signs or symptoms of myelosuppression or infection (e.g., fever, chills, dizziness, shortness of breath, bleeding, easy bruising) occur.1
Risk of myelodysplastic syndrome (MDS) and acute leukemia.1
Risk of renal toxicity.1 Importance of monitoring renal function prior to and periodically during lutetium Lu 177 dotatate therapy.1 Importance of advising patients to maintain adequate hydration during and after administration of lutetium Lu 177 dotatate to ensure good urinary output.1
Risk of hepatotoxicity.1 Importance of liver function test monitoring prior to and periodically during lutetium Lu 177 dotatate therapy.1, 11
Risk of carcinoid hormonal crisis.1 Importance of informing clinician if manifestations of carcinoid hormonal crisis (e.g., severe flushing, diarrhea, bronchospasm, hypotension) occur.1
Risk of fetal harm.1 Necessity of advising women of reproductive potential that they should use effective methods of contraception while receiving lutetium Lu 177 dotatate and for 7 months after the final dose.1 Necessity of advising male patients with female partners of reproductive potential that they should use effective methods of contraception while receiving lutetium Lu 177 dotatate and for 4 months after the final dose.1 Importance of women informing clinicians if they are or plan to become pregnant.1 Apprise patient of potential fetal hazard if used during pregnancy.1
Importance of advising women to avoid breast-feeding while receiving lutetium Lu 177 dotatate and for 2.5 months after the last dose.1
Risk of impaired male and female fertility.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant diseases.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion only | 370 MBq/mL (equivalent to 10 mCi/mL) | Lutathera® (available in a lead-shielded container) |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions May 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Advanced Accelerator Applications USA Inc. Lutathera® (lutetium Lu 177 dotatate) injection for intravenous infusion prescribing information. Millburn, NJ; 2018 Jul.
2. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med . 2017; 376(2):125-35. [PubMed 28076709]
3. Brabander T, van der Zwan WA, Teunissen JJM et al. Long-Term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res . 2017; 23(16):4617-24. [PubMed 28428192]
4. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2019 Apr 29. [Web]
5. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208700Orig1s000: Multi-discipline review. From FDA website. [Web]
6. Hromadik LK, Sturges L. Caring for Patients Receiving 177Lu-DOTATATE, Lutathera®: A Treatment of Hope for Patients With Gastroenteropancreatic Neuroendocrine Tumors. J Radiol Nurs . 2019; 38:28-32.
7. Strosberg J, Wolin E, Chasen B et al. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol . 2018; 36(25):2578-84. [PubMed 29878866]
8. Cives M, Strosberg J. Radionuclide Therapy for Neuroendocrine Tumors. Curr Oncol Rep . 2017; 19(9):1-9. [PubMed 28220446]
9. Kam BLR, Teunissen JJM, Krenning EP et al. Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging . 2012; 39:S103.-112. [PubMed 22388631]
10. Anon.. Lutetium lu 177 dotatate (Lutathera) for gastroenteropancreatic neuroendocrine tumors. Med Lett Drugs Ther . 2018; 60:e152-53. [PubMed 30383735]
11. Advanced Accelerator Applications USA Inc. Lutathera® (lutetium Lu 177 dotatate) injection for intravenous infusion patient information. Millburn, NJ; 2018 Apr.
12. Asti M, Tegoni M, Farioli D et al. Influence of cations on the complexation yield of DOTATATE with yttrium and lutetium: a perspective study for enhancing the 90Y and 177Lu labeling conditions. Nucl Med Biol . 2012; 39:509-17. [PubMed 22172388]
13. de Araújo EB, Caldeira Filho JS, Nagamati LT et al. A comparative study of 131I and 177Lu labeled somatostatin analogues for therapy of neuroendocrine tumours. Appl Radiat Isot . 2009; 67:227-33. [PubMed 19027307]
14. Advanced Accelerator Applications. Lutathera® (Lutetium Lu 177 oxodotreotide) injection for intravenous infusion. Annex I: Summary of product characteristics. Saint Genis Pouilly France. (undated) [Web]
15. Löser A, Schwarzenböck SM, Heuschkel M et al. Peptide receptor radionuclide therapy with 177Lu-DOTA-octreotate: dosimetry, nephrotoxicity, and the effect of hematological toxicity on survival. Nucl Med Commun . 2018; 39:236-246. [PubMed 29315138]
16. de Jong M, Krenning E. New advances in peptide receptor radionuclide therapy. J Nucl Med . 2002; 43:617-20. [PubMed 11994523]
17. Bergsma H, Konijnenberg MW, Kam BL et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging . 2016; 43:453-63. [PubMed 26419852]