Lutetium lu 177 dotatate

Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Zach Leibowitz [2]

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## Overview

Lutetium lu 177 dotatate is a radiolabeled somatostatin analog that is FDA approved for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and handgun neuroendocrine tumors in adults. Common adverse reactions include lymphopenia, increased GGT, vomiting, nausea, increased AST, increased ALT, hyperglycemia and hypokalemia.

## Adult Indications and Dosage

### FDA-Labeled Indications and Dosage (Adult)

Indication

* Lutetium Lu 177 dotatate is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and handgun neuroendocrine tumors in adults.

Dosage

* The recommended lutetium Lu 177 dotatate dose is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses.

### Off-Label Use and Dosage (Adult)

#### Guideline-Supported Use

There is limited information regarding lutetium Lu 177 dotatate Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

#### Non–Guideline-Supported Use

There is limited information regarding lutetium Lu 177 dotatate Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

## Pediatric Indications and Dosage

### FDA-Labeled Indications and Dosage (Pediatric)

The safety and effectiveness of lutetium Lu 177 dotatate have not been established in pediatric patients.

### Off-Label Use and Dosage (Pediatric)

#### Guideline-Supported Use

There is limited information regarding lutetium Lu 177 dotatate Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

#### Non–Guideline-Supported Use

There is limited information regarding lutetium Lu 177 dotatate Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

## Contraindications

None.

## Warnings

##### Risk from Radiation Exposure

* Lutetium Lu 177 dotatate contributes to a patient’s overall long-term radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer.
* Radiation can be detected in the urine for up to 30 days following lutetium Lu 177 dotatate administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with lutetium Lu 177 dotatate consistent with institutional good radiation safety practices and patient management procedures.

##### Myelosuppression

* In NETTER-1, myelosuppression occurred more frequently in patients receiving lutetium Lu 177 dotatate with long-acting octreotide compared to patients receiving high-dose long-acting octreotide (all grades/grade 3 or 4): anemia (81%/0) versus (54%/1%); thrombocytopenia (53%/1%) versus (17%/0); and neutropenia (26%/3%) versus (11%/0). In NETTER-1, platelet nadir occurred at a median of 5.1 weeks following the first dose. Of the 59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels. The median time to platelet recovery was 2 months. Fifteen of the nineteen patients in whom platelet recovery was not documented had post-nadir platelet counts. Among these 15 patients, 5 improved to Grade 1, 9 to Grade 2, and 1 to Grade 3.
* Monitor blood cell counts. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

##### Secondary Myelodysplastic Syndrome and Leukemia

* In NETTER-1, with a median follow-up time of 24 months, myelodysplastic syndrome (MDS) was reported in 2.7% of patients receiving lutetium Lu 177 dotatate with long-acting octreotide compared to no patients receiving high-dose long-acting octreotide. In ERASMUS, 15 patients (1.8%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to the development of MDS was 28 months (9 to 41 months) for MDS and 55 months (32 to 155 months) for acute leukemia.

##### Renal Toxicity

* In ERASMUS, 8 patients (<1%) developed renal failure 3 to 36 months following lutetium Lu 177 dotatate. Two of these patients had underlying renal impairment or risk factors for renal failure (e.g., diabetes or hypertension) and required dialysis.
* Administer the recommended amino acid solution before, during and after lutetium Lu 177 dotatate to decrease reabsorption of lutetium Lu 177 dotatate 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. Advise patients to urinate frequently during and after administration of lutetium Lu 177 dotatate. Monitor serum creatinine and calculated creatinine clearance. Withhold, reduce dose, or permanently discontinue lutetium Lu 177 dotatate based on severity of reaction.

Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of renal function in patients with mild or moderate impairment. Lutetium Lu 177 dotatate has not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min).

##### Hepatotoxicity

* In ERASMUS, 2 patients (<1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure.
* Monitor transaminases, bilirubin and serum albumin during treatment. Withhold, reduce dose, or permanently discontinue lutetium Lu 177 dotatate based on severity of reaction.

##### Neuroendocrine Hormonal Crisis

* Neuroendocrine hormonal crises, manifesting with flushing, diarrhea, bronchospasm and hypotension, occurred in 1% of patients in ERASMUS and typically occurred during or within 24 hours following the initial lutetium Lu 177 dotatate dose. Two (<1%) patients were reported to have hypercalcemia.
* 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.

##### Embryo-Fetal Toxicity

* Based on its mechanism of action, lutetium Lu 177 dotatate can cause fetal harm. There are no available data on the use of lutetium Lu 177 dotatate in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including lutetium Lu 177 dotatate, have the potential to cause fetal harm.
* Verify pregnancy status of females of reproductive potential prior to initiating lutetium Lu 177 dotatate.
* Advise females and males of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with lutetium Lu 177 dotatate and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the final dose.

##### Risk of Infertility

* Lutetium Lu 177 dotatate may cause infertility in males and females. The recommended cumulative dose of 29.6 GBq 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.

## Adverse Reactions

### Clinical Trials Experience

* Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
* The data in Warnings and Precautions reflect exposure to lutetium Lu 177 dotatate in 111 patients with advanced, progressive midgut neuroendocrine tumors (NETTER-1). Safety data in Warnings and Precautions were also obtained in an additional 22 patients in a non-randomized pharmacokinetic substudy of NETTER-1 and in a subset of patients (811 of 1214) with advanced somatostatin receptor-positive tumors enrolled in ERASMUS.

NETTER-1

* The safety data described below are from NETTER-1, which randomized (1:1) patients with progressive, somatostatin receptor-positive midgut carcinoid tumors to receive lutetium Lu 177 dotatate 7.4 GBq (200 mCi) administered every 8 to 16 weeks concurrently with the recommended amino acid solution and with long-acting octreotide (30 mg administered by intramuscular injection within 24 hours of each lutetium Lu 177 dotatate dose) (n = 111), or high-dose octreotide (defined as long-acting octreotide 60 mg by intramuscular injection every 4 weeks) (n = 112) [see Clinical Studies ( 14.1)] . Among patients receiving lutetium Lu 177 dotatate with octreotide, 79% received a cumulative dose > 22.2 GBq (> 600 mCi) and 76% of patients received all four planned doses. Six percent (6%) of patients required a dose reduction and 13% of patients discontinued lutetium Lu 177 dotatate. Five patients discontinued lutetium Lu 177 dotatate for renal-related events and 4 discontinued for hematological toxicities. The median duration of follow-up was 24 months for patients receiving lutetium Lu 177 dotatate with octreotide and 20 months for patients receiving high-dose octreotide.
* Table 4 and Table 5 summarize the incidence of adverse reactions and laboratory abnormalities, respectively. The most common Grade 3-4 adverse reactions occurring with a greater frequency among patients receiving lutetium Lu 177 dotatate with octreotide compared to patients receiving high-dose octreotide include: lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea and elevated AST (5% each), and increased ALT, hyperglycemia and hypokalemia (4% each).

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

ERASMUS

* Safety data are available from 1214 patients in ERASMUS, an international, single-institution, single-arm, open-label trial of patients with somatostatin receptor-positive tumors (neuroendocrine and other primaries). Patients received lutetium Lu 177 dotatate 7.4 GBq (200 mCi) administered every 6 to 13 weeks with or without octreotide. Retrospective medical record review was conducted on a subset of 811 patients to document serious adverse reactions. Eighty-one (81%) percent of patients in the subset received a cumulative dose ≥ 22.2 GBq (≥ 600 mCi). With a median follow-up time of more than 4 years, the following rates of serious adverse reactions were reported: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%).

### Postmarketing Experience

There is limited information regarding Lutetium lu 177 dotatate Postmarketing Experience in the drug label.

## Drug Interactions

##### Somatostatin Analogs

* Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each lutetium Lu 177 dotatate dose. Administer short- and long-acting octreotide during lutetium Lu 177 dotatate treatment as recommended.

## Use in Specific Populations

#### Pregnancy

Pregnancy Category (FDA):  Risk Summary

* Based on its mechanism of action, lutetium Lu 177 dotatate can cause fetal harm. There are no available data on lutetium Lu 177 dotatate use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including lutetium Lu 177 dotatate, have the potential to cause fetal harm. Advise pregnant women of the risk to a fetus.
* In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Pregnancy Category (AUS):  There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lutetium lu 177 dotatate in women who are pregnant.

#### Labor and Delivery

There is no FDA guidance on use of Lutetium lu 177 dotatate during labor and delivery.

#### Nursing Mothers

Risk Summary

* There are no data on the presence of lutetium Lu 177 dotatate in human milk, or its effects on the breastfed infant or milk production. No lactation studies in animals were conducted. Because of the potential risk for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with lutetium Lu 177 dotatate and for 2.5 months after the final dose.

#### Pediatric Use

* The safety and effectiveness of lutetium Lu 177 dotatate have not been established in pediatric patients.

#### Geriatic Use

* Of the 1325 patients treated with lutetium Lu 177 dotatate in clinical trials, 438 patients (33%) were 65 years and older. The response rate and number of patients with a serious adverse event were similar to that of younger subjects.

#### Gender

There is no FDA guidance on the use of Lutetium lu 177 dotatate with respect to specific gender populations.

#### Race

There is no FDA guidance on the use of Lutetium lu 177 dotatate with respect to specific racial populations.

#### Renal Impairment

* No dose adjustment is recommended for patients with mild to moderate renal impairment; however, patients with mild or moderate renal impairment may be at greater risk of toxicity. Perform more frequent assessments of renal function in patients with mild to moderate impairment. The safety of lutetium Lu 177 dotatate in patients with severe renal impairment (creatinine clearance < 30 mL/min by Cockcroft-Gault) or end-stage renal disease has not been studied.

#### Hepatic Impairment

* No dose adjustment is recommended for patients with mild or moderate hepatic impairment. The safety of lutetium Lu 177 dotatate in patients with severe hepatic impairment (total bilirubin > 3 times upper limit of normal and any AST) has not been studied.

#### Females of Reproductive Potential and Males

Pregnancy Testing

* Verify pregnancy status of females of reproductive potential prior to initiating lutetium Lu 177 dotatate.

Contraception Females

* Lutetium Lu 177 dotatate can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the final dose of lutetium Lu 177 dotatate.

Males

* Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of lutetium Lu 177 dotatate.

Infertility

* The recommended cumulative dose of 29.6 GBq 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.

#### Immunocompromised Patients

There is no FDA guidance one the use of Lutetium lu 177 dotatate in patients who are immunocompromised.

## Administration and Monitoring

#### Administration

##### Important Safety Instructions

* 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. Radiopharmaceuticals, including 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.
* Verify pregnancy status of females of reproductive potential prior to initiating lutetium Lu 177 dotatate.

##### Recommended Dosage

* The recommended lutetium Lu 177 dotatate dose is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses. Administer pre- and concomitant medications and administer lutetium Lu 177 dotatate as recommended.

##### Premedication and Concomitant Medications

Somatostatin Analogs

* Before initiating lutetium Lu 177 dotatate: Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) for at least 4 weeks prior to initiating lutetium Lu 177 dotatate. Administer short-acting octreotide as needed; discontinue at least 24 hours prior to initiating lutetium Lu 177 dotatate.
* During lutetium Lu 177 dotatate treatment: Administer long-acting octreotide 30 mg intramuscularly 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. Short-acting octreotide may be given for symptomatic management during lutetium Lu 177 dotatate treatment, but must be withheld for at least 24 hours before each lutetium Lu 177 dotatate dose.
* Following lutetium Lu 177 dotatate treatment: Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing lutetium Lu 177 dotatate until disease progression or for up to 18 months following treatment initiation.

Antiemetic

* Administer antiemetics 30 minutes before the recommended amino acid solution.

Amino Acid Solution

* Initiate an intravenous amino acid solution containing L-lysine and L-arginine (Table 1) 30 minutes before administering lutetium Lu 177 dotatate. Use a three-way valve to administer amino acids using the same venous access as lutetium Lu 177 dotatate or administer amino acids through a separate venous access in the patient’s other arm. Continue the infusion during, and for at least 3 hours after 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.

This image is provided by the National Library of Medicine.

##### Dose Modifications for Adverse Reactions

* Recommended dose modifications of lutetium Lu 177 dotatate for adverse reactions are provided in Table 2.

This image is provided by the National Library of Medicine.

##### Preparation and Administration

* Use aseptic technique and radiation shielding when administering the lutetium Lu 177 dotatate solution. 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 and after lutetium Lu 177 dotatate administration.
* Inspect the product visually for particulate matter and discoloration prior to administration under a shielded screen. Discard vial if particulates or discoloration are present.

Administration Instructions

* Insert a 2.5 cm, 20 gauge needle (short needle) into the lutetium Lu 177 dotatate vial and connect via a 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 lutetium Lu 177 dotatate infusion and 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 ensuring that this long needle touches and is 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 lutetium Lu 177 dotatate 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.
* Dispose of any unused medicinal product or waste material in accordance with local and federal laws.

##### Radiation Dosimetry

* The mean and standard deviation (SD) of the estimated radiation absorbed doses for adults receiving lutetium Lu 177 dotatate are shown in Table 3. The maximum penetration in tissue is 2.2 mm and the mean penetration is 0.67 mm.

This image is provided by the National Library of Medicine.

#### Monitoring

There is limited information regarding Lutetium lu 177 dotatate Monitoring in the drug label.

## IV Compatibility

* Lutetium lu 177 dotatate is an intravenous injection.

## Overdosage

There is limited information regarding Lutetium lu 177 dotatate overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

## Pharmacology

This image is provided by PubChem and the National Library of Medicine.

### Mechanism of Action

* Lutetium Lu 177 dotatate binds to somatostatin receptors with highest affinity for subtype 2 receptors (SSRT2). Upon binding to somatostatin receptor expressing cells, including malignant somatostatin receptor-positive tumors, the compound is internalized. The beta emission from Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells.

### Structure

* Lutetium Lu 177 dotatate is a radiolabeled somatostatin analog. The drug substance lutetium Lu 177 dotatate is a cyclic peptide linked with the covalently bound chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid to a radionuclide.
* Lutetium Lu 177 dotatate is described as lutetium (Lu 177)-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl) acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-threoninyl-L-cysteinyl-L-threonine-cyclic (2-7) disulfide. The molecular weight is 1609.6 Daltons and the structural formula is as follows:

This image is provided by the National Library of Medicine.

* Lutetium (Lu 177) 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 (γ) of 0.208 MeV (11%) and 0.113 MeV (6.4%).

### Pharmacodynamics

* Lutetium Lu 177 exposure-response relationships and the time course of pharmacodynamics response are unknown.

Cardiac Electrophysiology

* The ability of lutetium Lu 177 dotatate to prolong the QTc interval at the therapeutic dose was assessed in an open label study in 20 patients with somatostatin receptor-positive midgut carcinoid tumors. No large changes in the mean QTc interval (i.e., >20 ms) were detected.

### Pharmacokinetics

* The pharmacokinetics (PK) of lutetium Lu 177 dotatate have been characterized in patients with progressive, somatostatin receptor-positive neuroendocrine tumors. The mean blood exposure (AUC) of lutetium Lu 177 dotatate at the recommended dose is 41 ng.h/mL [coefficient of variation (CV) 36 %]. The mean maximum blood concentration (C max) for lutetium Lu 177 dotatate is 10 ng/mL (CV 50%), which generally occurred at the end of the lutetium Lu 177 dotatate infusion.

Distribution

* The mean volume of distribution for lutetium Lu 177 dotatate is 460 L (CV 54%).
* Within 4 hours after administration, lutetium Lu 177 dotatate distributes in kidneys, tumor lesions, liver, spleen, and, in some patients, pituitary gland and thyroid. The co-administration of amino acids reduced the median radiation dose to the kidneys by 47% (34% to 59%) and increased the mean beta-phase blood clearance of lutetium Lu 177 dotatate by 36%.
* The non-radioactive form of lutetium dotatate is 43% bound to human plasma proteins.

Elimination

* The mean clearance (CL) is 4.5 L/h (CV 31%) for lutetium Lu 177 dotatate. The mean (± standard deviation) effective blood elimination half-life is 3.5 (±1.4) hours and the mean terminal blood half-life is 71 (± 28) hours.

Metabolism

* Lutetium Lu 177 dotatate does not undergo hepatic metabolism.

Excretion

* Lutetium Lu 177 dotatate is primarily eliminated renally with cumulative excretion of 44% within 5 hours, 58% within 24 hours, and 65% within 48 hours following lutetium Lu 177 dotatate administration. 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 of lutetium Lu 177 dotatate.

Drug Interaction Studies

* The non-radioactive form of lutetium is not an inhibitor or inducer of cytochrome P450 (CYP) 1A2, 2B6, 2C9, 2C19 or 2D6 in vitro. It is not an inhibitor of P-glycoprotein, BCRP, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, or OCT1 in vitro.

### Nonclinical Toxicology

##### Carcinogenesis, Mutagenesis, Impairment of Fertility

* Carcinogenicity and mutagenicity studies have not been conducted with Lutetium Lu 177 dotatate; however, radiation is a carcinogen and mutagen.
* No animal studies were conducted to determine the effects of lutetium Lu 177 dotatate on fertility.

##### Animal Toxicology and/or Pharmacology

* The primary target organ in animal studies using a non-radioactive form of lutetium Lu 177 dotatate (lutetium Lu 175 dotatate) was the pancreas, a high SSTR2 expressing organ. Pancreatic acinar apoptosis occurred at lutetium Lu 175 dotatate doses ≥ 5 mg/kg in repeat dose toxicology studies in rats. Pancreatic acinar cell atrophy also occurred in repeat dose toxicology studies in dogs at doses ≥ 500 mg/kg. These findings were consistent with high uptake of the radiolabeled peptide in the pancreas in animal biodistribution studies.

## Clinical Studies

##### Progressive, Well-differentiated Advanced or Metastatic Somatostatin Receptor-Positive Midgut Carcinoid Tumors

* The efficacy of lutetium Lu 177 dotatate in patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumors was established in NETTER-1 (NCT01578239), a randomized, multicenter, open-label, active-controlled trial. Key eligibility criteria included Ki67 index ≤ 20%, Karnofsky performance status ≥ 60, confirmed presence of somatostatin receptors on all lesions (OctreoScan uptake ≥ normal liver), creatinine clearance ≥ 50 mL/min, no prior treatment with peptide receptor radionuclide therapy (PRRT), and no prior external radiation therapy to more than 25% of the bone marrow.
* Two hundred twenty-nine (229) patients were randomized (1:1) to receive either lutetium Lu 177 dotatate 7.4 GBq (200 mCi) every 8 weeks for up to 4 administrations (maximum cumulative dose of 29.6 GBq) or high-dose long-acting octreotide (defined as 60 mg by intramuscular injection every 4 weeks). Patients in the lutetium Lu 177 dotatate arm also received long-acting octreotide 30 mg as an intramuscular injection 4 to 24 hours after each lutetium Lu 177 dotatate dose and every 4 weeks after completion of lutetium Lu 177 dotatate treatment until disease progression or until week 76 of the study. Patients in both arms could receive short-acting octreotide for symptom management; however, short-acting octreotide was withheld for at least 24 hours before each lutetium Lu 177 dotatate dose. Randomization was stratified by OctreoScan tumor uptake score (Grade 2, 3 or 4) and the length of time that patients had been on the most recent constant dose of octreotide prior to randomization (≤ 6 or > 6 months). The major efficacy outcome measure was progression free survival (PFS) as determined by a blinded independent radiology committee (IRC) per RECIST v1.1. Additional efficacy outcome measures were overall response rate (ORR) by IRC, duration of response, and overall survival (OS).
* Demographic and baseline disease characteristics were balanced between the treatment arms. Of the 208 patients, whose race/ethnicity was reported, 90% were White, 5% were Black, and 4% were Hispanic or Latino. The median age was 64 years (28 to 87 years); 51% were male, 74% had an illial primary, and 96% had metastatic disease in the liver. The median Karnofsky performance score was 90 (60 to 100), 74% received a constant dose of octreotide for > 6 months and 12% received prior treatment with everolimus. Sixty-nine percent of patients had Ki67 expression in ≤ 2% of tumor cells, 77% had CgA > 2 times the upper limit of normal (ULN), 65% had 5-HIAA > 2 x ULN, and 65% had alkaline phosphatase ≤ ULN. Efficacy results for NETTER-1 are presented in Table 8 and Figure 1.

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

##### Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

* The efficacy of lutetium Lu 177 dotatate in patients with foregut, midgut, and hindgut gastroenteropancreatic neuroendocrine tumors (GEP-NETs) was assessed in 360 patients in the ERASMUS study. In ERASMUS, lutetium Lu 177 dotatate was initially provided as expanded access under a general peptide receptor radionuclide therapy protocol at a single site in the Netherlands. A subsequent lutetium Lu 177 dotatate-specific protocol written eight years after study initiation did not describe a specific sample size or hypothesis testing plan but allowed for retrospective data collection. A total of 1214 patients received lutetium Lu 177 dotatate in ERASMUS, of which 601 (50%) were assessed per RECIST criteria. Of the 601 patients evaluated by investigators using RECIST criteria, 360 (60%) had gastroentero-pancreatic neuroendocrine tumors (GEP-NETs). Lutetium Lu 177 dotatate 7.4 GBq (200 mCi) was administered every 6 to 13 weeks for up to 4 doses concurrently with the recommended amino acid solution. The major efficacy outcome was investigator-assessed ORR. The median age in the efficacy subset was 61 years (25 to 88 years), 52% were male, 61% had a baseline Karnofsky performance status ≥ 90 (60 to 100), 60% had progressed within 12 months of treatment, and 15% had received prior chemotherapy. Fifty five percent (55%) of patients received a concomitant somatostatin analog. The median dose of lutetium Lu 177 dotatate was 29.6 GBq (800 mCi). Baseline tumor assessments were obtained in 39% of patients. The investigator assessed ORR was 16% (95% CI 13, 20) in the 360 patients with GEP-NETs. Three complete responses were observed (< 1%). Median DoR in the 58 responding patients was 35 months (95% CI: 17, 38).

## How Supplied

* Lutetium Lu 177 dotatate Injection containing 370 MBq/mL (10 mCi/ml) of lutetium Lu 177 dotatate is a sterile, preservative-free and clear, colorless to slightly yellow solution for intravenous use supplied in a colorless Type I glass 30 mL single-dose vial containing 7.4 GBq (200 mCi) ± 10% of lutetium Lu 177 dotatate at the time of injection (NDC# 69488-003-01). The solution volume in the vial is adjusted from 20.5 mL to 25 mL to provide a total of 7.4 GBq (200 mCi) of radioactivity.
* The product vial is in a lead shielded container placed in a plastic sealed container ( NDC# 69488-003-01). The product is shipped in a Type A package ( NDC# 69488-003-70).

### Storage

* Store below 25 °C (77 °F).
* The shelf life is 72 hours. Discard appropriately at 72 hours.

## Images

### Drug Images

### Package and Label Display Panel

This image is provided by the National Library of Medicine.

## Patient Counseling Information

Radiation Risks

* Advise patients to minimize radiation exposure to household contacts consistent with institutional good radiation safety practices and patient management procedures.

Myelosuppression

* Advise patients to contact their healthcare provider for any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, or increased bleeding or bruising.

Secondary Myelodysplastic Syndrome and Acute Leukemia

* Advise patients of the potential for secondary cancers, including myelodysplastic syndrome and acute leukemia.

Renal Toxicity

* Advise patients to hydrate and urinate frequently during and after administration of lutetium Lu 177 dotatate.

Hepatotoxicity

* Advise patients of the need for periodic laboratory tests to monitor for hepatotoxicity.

Neuroendocrine Hormonal Crises

* Advise patients to contact their health care provider for signs or symptoms that may occur following tumor-hormone release, including severe flushing, diarrhea, bronchospasm, and hypotension.

Embryo-Fetal Toxicity

* Advise pregnant women and males and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.
* Advise females of reproductive potential to use effective contraception during treatment with lutetium Lu 177 dotatate and for 7 months after the final dose.
* Advise male patients with female partners of reproductive potential to use effective contraception during treatment with lutetium Lu 177 dotatate and for 4 months after the final dose.

Lactation

* Advise females not to breastfeed during treatment with lutetium Lu 177 dotatate and for 2.5 months after the final dose.

Infertility

* Advise female and male patients that lutetium Lu 177 dotatate may impair fertility.

## Precautions with Alcohol

Alcohol-Lutetium lu 177 dotatate interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

## Brand Names

Lutathera

## Look-Alike Drug Names

There is limited information regarding Lutetium lu 177 dotatate Look-Alike Drug Names in the drug label.

## Drug Shortage Status

## Price

## References

The contents of this FDA label are provided by the National Library of Medicine.