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Lutathera

Package insert / prescribing information
Generic name: lutetium lu 177 dotatate
Dosage form: injection
Drug class: Therapeutic radiopharmaceuticals

Medically reviewed by Drugs.com. Last updated on Jun 1, 2022.

INDICATIONS AND USAGE

Lutathera is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

DOSAGE AND ADMINISTRATION

Important Safety Instructions

Lutathera is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.1)]. Use waterproof gloves and effective radiation shielding when handling Lutathera. Radiopharmaceuticals, including Lutathera, should be used by or under the control of healthcare providers 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 Lutathera [see Use in Specific Populations (8.1, 8.3)].

Monitor patients closely for signs and symptoms of hypersensitivity reactions during and following the Lutathera administration for a minimum of 2 hours in a setting where cardiopulmonary resuscitation medication and equipment are available [see Warnings and Precautions (5.6)].

Recommended Dosage

The recommended Lutathera dosage is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses. Administer premedications and concomitant medications as recommended [see Dosage and Administration (2.3)].

Premedication and Concomitant Medications

Somatostatin Analogs

  • Before initiating Lutathera: Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) at least 4 weeks prior to initiating Lutathera. Administer short-acting octreotide as needed; discontinue at least 24 hours prior to initiating Lutathera [see Drug Interactions (7.1)].
  • During Lutathera treatment: Administer long-acting octreotide 30 mg intramuscularly between 4 to 24 hours after each Lutathera dose. Do not administer long-acting octreotide within 4 weeks of each subsequent Lutathera dose. Short-acting octreotide may be given for symptomatic management during Lutathera treatment, but must be withheld at least 24 hours before each Lutathera dose.
  • Following Lutathera treatment: Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing Lutathera until disease progression or for up to 18 months following treatment initiation.

Antiemetic
Administer antiemetics 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 Lutathera. Use a three-way valve to administer amino acids using the same venous access as Lutathera 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 the Lutathera infusion. Do not decrease the dose of the amino acid solution if the dose of Lutathera is reduced [see Warnings and Precautions (5.4)].

Table 1. Amino Acid Solution

Item

Specification

*equivalent to 14.4 to 20 g lysine.
**equivalent to 14.9 to 20.7 g arginine.

L-Lysine HCl content

Between 18 g and 25 g*

L-Arginine HCl content

Between 18 g and 25 g**

Volume

1 L to 2 L

Osmolarity

< 1050 mOsmol/L

Hypersensitivity Prophylaxis

Premedicate patients who have had prior Grade 1 or 2 hypersensitivity reactions to Lutathera. Do not re-challenge patients who experience a Grade 3 or 4 hypersensitivity reactions to Lutathera [see Warnings and Precautions (5.6)].

Dosage Modifications for Adverse Reactions

Recommended dose modifications of Lutathera for adverse reactions are provided in Table 2.

Table 2. Recommended Dosage Modifications of Lutathera for Adverse Reactions
aGrading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE).
bIncluding allergic reaction and anaphylaxis.

Adverse Reaction

Severity of Adverse Reactiona

Dose Modification

Thrombocytopenia
[see Warnings and Precautions (5.2)]

Grade 2, 3 or 4

Withhold dose until complete or partial resolution (Grade 0 to 1).

Resume Lutathera at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 2, 3, or 4 thrombocytopenia, administer Lutathera at 7.4 GBq (200 mCi) for next dose.

Permanently discontinue Lutathera for Grade 2 or higher thrombocytopenia requiring a treatment delay of 16 weeks or longer.

Recurrent Grade 2, 3 or 4

Permanently discontinue Lutathera.

Anemia and Neutropenia
[see Warnings and Precautions (5.2)]

Grade 3 or 4

Withhold dose until complete or partial resolution (Grade 0, 1, or 2).

Resume Lutathera at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 anemia or neutropenia, administer Lutathera at 7.4 GBq (200 mCi) for next dose.

Permanently discontinue Lutathera for Grade 3 or higher anemia or neutropenia requiring a treatment delay of 16 weeks or longer.

Recurrent Grade 3 or 4

Permanently discontinue Lutathera.

Renal Toxicity
[see Warnings and Precautions (5.4)]

Defined as:

  • Creatinine clearance less than 40 mL/min; calculate using Cockcroft Gault with actual body weight, or
  • 40% increase in baseline serum creatinine, or
  • 40% decrease in baseline creatinine clearance; calculate using Cockcroft Gault with actual body weight.

Withhold dose until complete resolution or return to baseline.

Resume Lutathera at 3.7 GBq (100 mCi) in patients with complete resolution or return to baseline. If reduced dose does not result in renal toxicity, administer Lutathera at 7.4 GBq (200 mCi) for next dose.

Permanently discontinue Lutathera for renal toxicity requiring a treatment delay of 16 weeks or longer.

Recurrent renal toxicity

Permanently discontinue Lutathera.

Hepatotoxicity
[see Warnings and Precautions (5.5)]

Defined as:

  • Bilirubinemia greater than 3 times the upper limit of normal (Grade 3 or 4), or
  • Serum albumin less than 30 g/L with international normalized ratio (INR) > 1.5.

Withhold dose until complete resolution or return to baseline.

Resume Lutathera at 3.7 GBq (100 mCi) in patients with complete resolution or return to baseline. If reduced Lutathera dose does not result in hepatotoxicity, administer Lutathera at 7.4 GBq (200 mCi) for next dose.

Permanently discontinue Lutathera for hepatotoxicity requiring a treatment delay of 16 weeks or longer.

Recurrent hepatotoxicity

Permanently discontinue Lutathera.

Hypersensitivity Reactionsb
[see Warnings and Precautions (5.6)]
Grade 3 or 4 Permanently discontinue Lutathera.

Other Non-Hematologic Adverse Reactions
[see Adverse Reactions (6.1)]

Grade 3 or 4

Withhold dose until complete or partial resolution (Grade 0 to 2).

Resume Lutathera at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 toxicity, administer Lutathera at 7.4 GBq (200 mCi) for next dose.

Permanently discontinue Lutathera for Grade 3 or higher adverse reactions requiring treatment delay of 16 weeks or longer.

Recurrent Grade 3 or 4

Permanently discontinue Lutathera.

Preparation and Administration

  • Use aseptic technique and radiation shielding when administering the Lutathera solution. Use tongs when handling the vial to minimize radiation exposure.
  • Do not inject Lutathera directly into any other intravenous solution.
  • Confirm the amount of radioactivity of Lutathera in the radiopharmaceutical vial with an appropriate dose calibrator prior to and after Lutathera administration.
  • Inspect the product visually under a shielded screen for particulate matter and discoloration prior to administration. Discard the vial if particulates or discoloration are present.
  • Dispose of any unused medicinal product or waste material in accordance with local and federal laws.

Administration Instructions

The gravity method or infusion pump method may be used for administration of the recommended dosage. Use the infusion pump method when administering a reduced dose of Lutathera following a dosage modification for an adverse reaction; using the gravity method to administer a reduced dose of Lutathera may result in delivery of the incorrect volume of Lutathera, if the dose is not adjusted prior to administration.

Instructions for Gravity Method

  • Insert a 2.5 cm, 20 gauge needle (short needle) into the Lutathera vial and connect via a catheter to 500 mL 0.9% sterile sodium chloride solution (used to transport Lutathera during the infusion). Ensure that the short needle does not touch the Lutathera 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 Lutathera vial prior to the initiation of the Lutathera infusion and do not inject Lutathera directly into the sodium chloride solution.
  • Insert a second needle that is 9 cm, 18 gauge (long needle) into the Lutathera vial ensuring that this long needle touches and is secured to the bottom of the Lutathera vial during the entire infusion. Connect the long needle to the patient by an intravenous catheter that is pre-filled with 0.9% sterile sodium chloride solution and that is used exclusively for the Lutathera infusion into the patient.
  • Use a clamp or pump to regulate the flow of the sodium chloride solution via the short needle into the Lutathera 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 Lutathera from the vial to the patient via the catheter connected to the long needle over a total duration of 30 to 40 minutes).
  • During the infusion, ensure that the level of solution in the Lutathera 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 solution.

Instructions for Infusion Pump Method

  • Insert a 2.5 cm, 20 gauge needle (short venting needle) into the Lutathera vial. Ensure that the short needle does not touch the Lutathera solution in the vial and do not connect this short needle directly to the patient or the infusion pump.
  • Insert a second needle that is 9 cm, 18 gauge (long needle) into the Lutathera vial ensuring that this long needle touches and is secured to the bottom of the Lutathera vial during the entire infusion. Connect the long needle and a 0.9% sterile sodium chloride solution to a 3-way stopcock valve via appropriate tubing.
  • Connect the output of the 3-way stopcock valve to tubing installed on the input side of the peristaltic infusion pump according to manufacturer’s instruction.
  • Prime the line by opening the 3-way stopcock valve and pumping the Lutathera solution through the tubing until it reaches the exit of the valve.
  • Prime the intravenous catheter that will be connected to the patient by opening the 3-way stopcock valve to the 0.9% sterile sodium chloride solution and pumping the 0.9% sterile sodium chloride solution until it exits the end of the catheter tubing.
  • Connect the primed intravenous catheter to the patient and set the 3-way stopcock valve such that the Lutathera solution is in line with the infusion pump.
  • Infuse an appropriate volume of Lutathera solution over a 30-40 min period to deliver the desired radioactivity.
  • When the desired Lutathera radioactivity has been delivered, stop the infusion pump and then change the position of the 3-way stopcock valve so that the infusion pump is in line with the 0.9% sterile sodium chloride solution. Restart the infusion pump and infuse an intravenous flush of 25 mL of 0.9% sterile sodium chloride solution through the intravenous catheter to the patient.

Radiation Dosimetry

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

Table 3. Estimated Radiation Absorbed Dose for Lutathera in NETTER-1
aN = 18 (two patients excluded because the liver absorbed dose was biased by the uptake of the liver metastases).
bN = 9 (female patients only).
cN = 11 (male patients only).

Absorbed dose per unit activity

(Gy/GBq)

(N = 20)

Calculated absorbed dose for 4 x 7.4 GBq

(29.6 GBq cumulative activity)

(Gy)

Organ

Mean

SD

Mean

SD

Adrenals

0.037

0.016

1.1

0.5

Brain

0.027

0.016

0.8

0.5

Breasts

0.027

0.015

0.8

0.4

Gallbladder Wall

0.042

0.019

1.2

0.6

Heart Wall

0.032

0.015

0.9

0.4

Kidneys

0.654

0.295

19.4

8.7

Livera

0.299

0.226

8.9

6.7

Lower Large Intestine Wall

0.029

0.016

0.9

0.5

Lungs

0.031

0.015

0.9

0.4

Muscle

0.029

0.015

0.8

0.4

Osteogenic Cells

0.151

0.268

4.5

7.9

Ovariesb

0.031

0.013

0.9

0.4

Pancreas

0.038

0.016

1.1

0.5

Red Marrow

0.035

0.029

1.0

0.8

Skin

0.027

0.015

0.8

0.4

Small Intestine

0.031

0.015

0.9

0.5

Spleen

0.846

0.804

25.1

23.8

Stomach Wall

0.032

0.015

0.9

0.5

Testesc

0.026

0.018

0.8

0.5

Thymus

0.028

0.015

0.8

0.5

Thyroid

0.027

0.016

0.8

0.5

Total Body

0.052

0.027

1.6

0.8

Upper Large Intestine Wall

0.032

0.015

0.9

0.4

Urinary Bladder Wall

0.437

0.176

12.8

5.3

Uterusb

0.032

0.013

1.0

0.4

DOSAGE FORMS AND STRENGTHS

Injection: 370 MBq/mL (10 mCi/mL) of lutetium Lu 177 dotatate as a clear and colorless to slightly yellow solution in a single-dose vial.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Risk From Radiation Exposure

Lutathera 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 Lutathera administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with Lutathera consistent with institutional good radiation safety practices, patient management procedures, Nuclear Regulatory Commission patient-release guidance, and instructions to the patient for follow-up radiation protection at home [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].

Myelosuppression

In NETTER-1, myelosuppression occurred more frequently in patients receiving Lutathera 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 myelosuppression [see Dosage and Administration (2.4)].

Secondary Myelodysplastic Syndrome and Leukemia

In NETTER-1, with a median follow-up time of 76 months in the main study, myelodysplastic syndrome (MDS) was reported in 2.3% of patients receiving Lutathera with long-acting octreotide compared to no patients receiving high-dose long-acting octreotide.

In ERASMUS, 16 patients (2.0%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to onset was 29 months (9 to 45 months) for MDS and 55 months (32 to 125 months) for acute leukemia.

Renal Toxicity

In ERASMUS, 8 patients (< 1%) developed renal failure 3 to 36 months following Lutathera. 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 Lutathera [see Dosage and Administration (2.3)] 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 Lutathera is reduced. Advise patients to urinate frequently during and after administration of Lutathera. Monitor serum creatinine and calculated creatinine clearance. Withhold, reduce dose, or permanently discontinue Lutathera based on severity of renal toxicity [see Dosage and Administration (2.4)].

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. Lutathera 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 Lutathera based on severity of hepatotoxicity [see Dosage and Administration (2.4)].

Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema, occurred in patients treated with Lutathera [see Adverse Reactions (6.2)]. Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis, during and following Lutathera administration for a minimum of 2 hours in a setting where cardiopulmonary resuscitation medication and equipment are available. Discontinue the infusion upon the first observation of any signs or symptoms consistent with a severe hypersensitivity reaction, and initiate appropriate therapy.

Premedicate patients with a history of Grade 1 or 2 hypersensitivity reactions to Lutathera before subsequent doses [see Dosage and Administration (2.3)]. Permanently discontinue Lutathera in patients who experience Grade 3 or 4 hypersensitivity reactions [see Dosage and Administration (2.4)].

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 Lutathera 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, Lutathera can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on Lutathera 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 Lutathera, have the potential to cause fetal harm.

Verify pregnancy status of females of reproductive potential prior to initiating Lutathera [see Dosage and Administration (2.1)].

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Lutathera and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Lutathera and for 4 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

Risk of Infertility

Lutathera may cause infertility in males and females. The recommended cumulative dose of 29.6 GBq of Lutathera 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 [see Dosage and Administration (2.6), Use in Specific Populations (8.3)].

ADVERSE REACTIONS

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

  • Myelosuppression [see Warnings and Precautions (5.2)]
  • Secondary Myelodysplastic Syndrome and Leukemia [see Warnings and Precautions (5.3)]
  • Renal Toxicity [see Warnings and Precautions (5.4)]
  • Hepatotoxicity [see Warnings and Precautions (5.5)]
  • Hypersensitivity Reactions [see Warnings and Precautions (5.6)]
  • Neuroendocrine Hormonal Crisis [see Warnings and Precautions (5.7)]

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 Lutathera 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 sub-study of NETTER-1 and in a subset of patients (811 of 1214) with advanced somatostatin receptor-positive tumors enrolled in ERASMUS [see Warnings and Precautions (5)].

NETTER-1

The safety data of Lutathera with octreotide was evaluated in NETTER-1 [see Clinical Studies (14.1)]. Patients with progressive, somatostatin receptor-positive midgut carcinoid tumors received Lutathera 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 Lutathera 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 Lutathera 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 Lutathera. Five patients discontinued Lutathera for renal-related events and 4 discontinued for hematological toxicities.

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 Lutathera 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).

Table 4. Adverse Reactions Occurring at Higher Incidence in Patients Receiving Lutathera with Long-Acting Octreotide Compared to High-dose Long-Acting Octreotide (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4)1
1National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays adverse reactions occurring at a higher incidence in Lutathera-treated patients [between arm difference of ≥ 5% (all Grades) or ≥ 2% (Grades 3-4)].
aIncludes the terms: Glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, renal impairment.
bIncludes the terms: Dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain and urinary incontinence.

Adverse Reaction1

Lutathera with Long-Acting Octreotide
(30 mg)
(N = 111)
Long-Acting Octreotide
(60 mg)
(N = 112)
All Grades
%

Grades 3-4
%

All Grades
%

Grades 3-4
%

Gastrointestinal disorders

Nausea

65

5

12

2

Vomiting

53

7

10

0

Abdominal pain

26

3

19

3

Diarrhea

26

3

18

1

Constipation

10

0

5

0

General disorders

Fatigue

38

1

26

2

Peripheral edema

16

0

9

1

Pyrexia

8

0

3

0

Metabolism and nutrition disorders

Decreased appetite

21

0

11

3

Nervous system disorders

Headache 17 0 5 0
Dizziness 17 0 8 0
Dysgeusia 8 0 2 0
Vascular disorders
Flushing 14 1 9 0
Hypertension 12 2 7 2

Musculoskeletal and connective tissue disorders

Back pain

13

2

10

0

Pain in extremity

11

0

5

0

Myalgia

5

0

0

0

Neck Pain

5

0

0

0

Renal and urinary disorders

Renal failurea

13

3

4

1

Radiation-related urinary tract adverse reactionsb

8

0

3

0

Psychiatric disorders

Anxiety

12

1

5

0

Skin and subcutaneous tissue disorders

Alopecia

12

0

2

0

Respiratory, thoracic and mediastinal disorders

Cough

11

1

6

0

Cardiac disorders

Atrial fibrillation

5

1

0

0

Table 5. Laboratory Abnormalities Occurring at Higher Incidence in Patients Receiving Lutathera with Long-Acting Octreotide Compared to High-Dose Long-Acting Octreotide (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4)1,2
1Values are worst grade observed after randomization.
2National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays laboratory abnormalities occurring at a higher incidence in Lutathera-treated patients [between arm difference of ≥ 5% (all Grades) or ≥ 2% (Grades 3-4)].
Laboratory Abnormality2 Lutathera with Long-Acting Octreotide
(30 mg)
(N = 111)
Long-Acting Octreotide
(60 mg)
(N = 112)
All Grades
%
Grades 3-4
%
All Grades
%
Grades 3-4
%

Hematology

Lymphopenia

90

44

39

5

Anemia

81

0

55

1

Leukopenia

55

2

20

0

Thrombocytopenia

53

1

17

0

Neutropenia

26

3

11

0

Renal/Metabolic

Creatinine increased

85

1

73

0

Hyperglycemia

82

4

67

2

Hyperuricemia

34

6

30

6

Hypocalcemia

32

0

14

0

Hypokalemia

26

4

21

2

Hyperkalemia

19

0

11

0

Hypernatremia

17

0

7

0

Hypoglycemia

15

0

8

0

Hepatic

GGT increased

66

20

67

16

Alkaline phosphatase increased

65

5

55

9

AST increased

50

5

35

0

ALT increased

43

4

34

0

Blood bilirubin increased

30

2

28

0

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 Lutathera 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

The following adverse reactions have been identified during post approval use of Lutathera. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Immune System Disorders: hypersensitivity reactions, including angioedema

DRUG INTERACTIONS

Somatostatin Analogs

Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of Lutathera. Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each Lutathera dose. Administer short- and long-acting octreotide during Lutathera treatment as recommended [see Dosage and Administration (2.3)].

Corticosteroids

Corticosteroids can induce down-regulation of subtype 2 somatostatin receptors (SST2). Avoid repeated administration of high-doses of glucocorticosteroids during treatment with Lutathera.

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Based on its mechanism of action, Lutathera can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on Lutathera 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 Lutathera, have the potential to cause fetal harm. Advise pregnant women of the potential 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.

Lactation

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 Lutathera and for 2.5 months after the final dose.

Females and Males of Reproductive Potential

Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating Lutathera [see Use in Specific Populations (8.1)].

Contraception
Females
Lutathera can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the final dose of Lutathera.

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 Lutathera [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].

Infertility
The recommended cumulative dose of 29.6 GBq of Lutathera 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 [see Dosage and Administration (2.6)].

Pediatric Use

The safety and effectiveness of Lutathera have not been established in pediatric patients.

Geriatric Use

Of the 1325 patients treated with Lutathera 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.

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 Lutathera in patients with severe renal impairment (creatinine clearance < 30 mL/min by Cockcroft-Gault) or end-stage renal disease has not been studied [see Warnings and Precautions (5.4)].

Hepatic Impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment. The safety of Lutathera in patients with severe hepatic impairment (total bilirubin > 3 times upper limit of normal, regardless of AST level) has not been studied.

DESCRIPTION

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:

Lutathera (lutetium Lu 177 dotatate) 370 MBq/mL (10 mCi/mL) Injection is a sterile, clear, colorless to slightly yellow solution for intravenous use. Each single-dose vial contains acetic acid (0.48 mg/mL), ascorbic acid (2.8 mg/mL), diethylene triamine pentaacetic acid (0.05 mg/mL), gentisic acid (0.63 mg/mL), sodium acetate (0.66 mg/mL), sodium chloride (6.85 mg/mL), sodium hydroxide (0.65 mg/mL), and Water for Injection (ad 1 mL). The pH range of the solution is 4.5 to 6.

Physical Characteristics

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%). The main radiations are detailed in Table 6.

Table 6. Lu 177 Main Radiations

Radiation

Energy (keV)

Iβ%

Iγ%

β-

176.5

12.2

β-

248.1

0.05

β-

384.9

9.1

β-

497.8

78.6

γ

71.6

0.15

γ

112.9

6.40

γ

136.7

0.05

γ

208.4

11.0

γ

249.7

0.21

γ

321.3

0.22

External Radiation

Table 7 summarizes the radioactive decay properties of Lu 177.

Table 7. Physical Decay Chart: Lutetium Lu 177 Half-life = 6.647 days

Hours

Fraction Remaining

Hours

Fraction Remaining

0

1.000

48 (2 days)

0.812

1

0.996

72 (3 days)

0.731

2

0.991

168 (7 days)

0.482

5

0.979

336 (14 days)

0.232

10

0.958

720 (30 days)

0.044

24 (1 day)

0.901

1080 (45 days)

0.009

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

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

Cardiac Electrophysiology

The ability of Lutathera 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 (Cmax) for lutetium Lu 177 dotatate is 10 ng/mL (CV 50%), which generally occurred at the end of the Lutathera 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%) and the mean terminal half-life is 71 (±28) hours for lutetium 177 dotatate.

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 Lutathera 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 Lutathera [see Warnings and Precautions (5.1)].

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 mcg/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 Lutathera 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 beam radiation therapy to more than 25% of the bone marrow.

At the time of the primary analysis, two hundred twenty-nine (229) patients were randomized (1:1) to receive either Lutathera 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 Lutathera arm also received long-acting octreotide 30 mg as an intramuscular injection 4 to 24 hours after each Lutathera dose and every 4 weeks after completion of Lutathera 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 at least 24 hours before each Lutathera 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 229 patients, 82% were White, 4% were Black, 3% were Hispanic or Latino, 0.4% were Asian, 0.4% were Other, and 9% were not reported. The median age was 64 years (28 to 87 years); 51% were male, 74% had an ileal 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 times ULN, and 65% had alkaline phosphatase ≤ ULN.

At the time of the final OS analysis, which occurred 66 months after the primary PFS analysis, 117 patients were randomized to the Lutathera arm and 114 patients were randomized to the octreotide arm. In the final OS analysis, there was no statistically significant difference in OS between the two treatment arms.

Efficacy results for NETTER-1 are presented in Table 8 and Figure 1.

Table 8. Efficacy Results in NETTER-1
Abbreviations: CI, confidence interval; IRC, independent radiology committee; NE, not evaluable; NR, not reached; ORR, overall response rate; PFS, progression-free survival.
aHazard ratio based on the unstratified Cox model.
bUnstratified log rank test.
cFisher’s Exact test.
Lutathera with Long-Acting Octreotide
(30 mg)
N = 116
Long-Acting Octreotide
(60 mg)
N = 113
PFS by IRC
Events (%) 27 (23%) 78 (69%)
Progressive disease, n (%) 15 (13%) 61 (54%)
Death, n (%) 12 (10%) 17 (15%)
Median in months (95% CI) NR (18.4, NE) 8.5 (6.0, 9.1)
Hazard ratioa (95% CI) 0.21 (0.13, 0.32)
P-Valueb < 0.0001
ORR by IRC
ORR, % (95% CI) 13% (7%,19%) 4% (0.1%, 7%)
Complete response rate, n (%) 1 (1%) 0
Partial response rate, n (%) 14 (12%) 4 (4%)
P-Valuec 0.0148
Duration of response, median in months (95% CI) NR (2.8, NE) 1.9 (1.9, NE)

Figure 1. Kaplan-Meier Curves for Progression-Free Survival in NETTER-1

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

The efficacy of Lutathera in patients with foregut, midgut, and hindgut gastroenteropancreatic neuroendocrine tumors (GEP-NETs) was assessed in 360 patients in the ERASMUS study. In ERASMUS, Lutathera was initially provided as expanded access under a general peptide receptor radionuclide therapy protocol at a single site in the Netherlands. A subsequent Lutathera-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 Lutathera in ERASMUS, of whom 578 patients had baseline tumor assessments. Of the 578 patients, 360 (62%) had gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and long-term follow-up. Of these 360 patients, 145 (40%) had their tumors prospectively evaluated according to RECIST criteria. Lutathera 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 60 years (30 to 85 years), 51% were male, 71% had a baseline Karnofsky performance status ≥ 90, 51% had progressed within 12 months of treatment, and 7% had received prior chemotherapy. Fifty-two percent (52%) of patients received a concomitant somatostatin analog. The median dose of Lutathera was 29.6 GBq (800 mCi). The investigator-assessed ORR was 17% (95% CI: 13, 21) based on an analysis that required responders to have had prospective response assessments according to RECIST criteria. Three complete responses were observed (< 1%). Median DoR in the 60 responding patients was 35 months (95% CI: 17, 38).

HOW SUPPLIED/STORAGE AND HANDLING

Lutathera 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).

Store below 25°C (77°F). Do not freeze Lutathera. Store in the original package to protect from ionizing radiation.

The shelf life is 72 hours. Discard appropriately at 72 hours.

PATIENT COUNSELING INFORMATION

Risk From Radiation Exposure

Advise patients to minimize radiation exposure to household contacts consistent with institutional good radiation safety practices and patient management procedures [see Dosage and Administration (2.1), Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.2)].

Secondary Myelodysplastic Syndrome and Leukemia

Advise patients of the potential for secondary cancers, including myelodysplastic syndrome and acute leukemia [see Warnings and Precautions (5.3)].

Renal Toxicity

Advise patients to hydrate and urinate frequently during and after administration of Lutathera [see Warnings and Precautions (5.4)].

Hepatotoxicity

Advise patients of the need for periodic laboratory tests to monitor for hepatotoxicity [see Warnings and Precautions (5.5)].

Hypersensitivity

Advise patients that Lutathera may cause hypersensitivity reactions, including angioedema, and seek immediate medical attention for signs or symptoms of hypersensitivity [see Warnings and Precautions (5.6)].

Neuroendocrine Hormonal Crises

Advise patients to contact their healthcare provider for signs or symptoms that may occur following tumor-related hormonal release, including severe flushing, diarrhea, bronchospasm, and hypotension [see Warnings and Precautions (5.7)].

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 [see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential to use effective contraception during treatment with Lutathera and for 7 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Lutathera and for 4 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

Lactation

Advise females not to breastfeed during treatment with Lutathera and for 2.5 months after the final dose [see Use in Specific Populations (8.2)].

Infertility

Advise female and male patients that Lutathera may impair fertility [see Warnings and Precautions (5.9), Use in Specific Populations (8.3)].

Distributed by:
Advanced Accelerator Applications USA, Inc., NJ 07041

©2022 Advanced Accelerator Applications USA, Inc.
Lutathera® is a registered trademark of Novartis AG and/or its affiliates.

T2022-40

PRINCIPAL DISPLAY PANEL

Vial Label

Lutathera
lutetium Lu 177 dotatate injection
For Intravenous Infusion
Single-dose vial. Discard Unused Portion. Rx Only
NDC# 69488-003-01

PRINCIPAL DISPLAY PANEL

Lead Shielding

Lutathera
lutetium Lu 177 dotatate injection
For Intravenous Infusion
Single-dose vial. Discard Unused Portion. Rx Only
NDC# 69488-003-01

PRINCIPAL DISPLAY PANEL

Type A Label (ADR)

Lutetium Lu 177 dotatate injection
Activity at calibration time:
370 MBq/mL (10 mCi/mL)
Rx Only
NDC# 69488-003-70

PRINCIPAL DISPLAY PANEL

Type A Label (IATA)

Lutetium Lu 177 dotatate injection
Activity at calibration time:
370 MBq/mL (10 mCi/mL)
Rx Only
NDC# 69488-003-70

Lutathera
lutetium lu 177 dotatate injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:69488-003
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LUTETIUM OXODOTREOTIDE LU-177 (LUTETIUM OXODOTREOTIDE LU-177) LUTETIUM OXODOTREOTIDE LU-177 10 mCi in 1 mL
Inactive Ingredients
Ingredient Name Strength
ACETIC ACID
SODIUM ACETATE
GENTISIC ACID
SODIUM HYDROXIDE
PENTETIC ACID
SODIUM CHLORIDE
ASCORBIC ACID
WATER
Packaging
# Item Code Package Description
1 NDC:69488-003-01 1 VIAL in 1 PACKAGE
1 20.5 mL in 1 VIAL
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA208700 01/26/2018
Labeler - Advanced Accelerator Applications USA, Inc (051714355)
Establishment
Name Address ID/FEI Operations
Advanced Accelerator Applications USA, Inc. 080178357 API MANUFACTURE(69488-003), MANUFACTURE(69488-003), ANALYSIS(69488-003), LABEL(69488-003), PACK(69488-003)
Establishment
Name Address ID/FEI Operations
Advanced Accelerator Applications (Italy) srl 516796146 API MANUFACTURE(69488-003), MANUFACTURE(69488-003), ANALYSIS(69488-003), LABEL(69488-003), PACK(69488-003)
Establishment
Name Address ID/FEI Operations
Advanced Accelerator Applications Ibérica SL 464939761 MANUFACTURE(69488-003)
Establishment
Name Address ID/FEI Operations
Advanced Accelerator Applications (Italy) S.r.l. 441182729 ANALYSIS(69488-003)
Establishment
Name Address ID/FEI Operations
IDB Radiopharmacy B.V. 489201088 API MANUFACTURE(69488-003)
Establishment
Name Address ID/FEI Operations
University of Missouri System 030000603 API MANUFACTURE(69488-003), ANALYSIS(69488-003)
Advanced Accelerator Applications USA, Inc

Frequently asked questions