rsi ad
 
drx ad
 
ad space

Lutetium Lu 177 Dotatate Injection

TABLE OF CONTENTS

1. DESCRIPTION 7. DRUG INTERACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING

 

1. 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 structural formula is as follows:

Molecular weight: 1609.6 Daltons

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), sodium acetate (0.66 mg/mL), gentisic acid (0.63 mg/mL), sodium hydroxide (0.65 mg/mL), ascorbic acid (2.8 mg/mL), diethylene triamine pentaacetic acid (0.05 mg/mL), sodium chloride (6.85 mg/mL), and Water for Injection (ad 1 mL). The pH range of the solution is 4.5 to 6.

1.1 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 1.

Table 1. Lu 177 Main Radiations

1.2 External Radiation

Table 2 summarizes the radioactive decay properties of Lu 177.

Table 2. Physical Decay Chart: Lutetium Lu 177 Half-life = 6.647 days

2. INDICATIONS AND USAGE

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

3. DOSAGE AND ADMINISTRATION

3.1 Important Safety Instructions

Lutetium Lu 177 dotatate 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 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 [see Use in Specific Populations (8.1, 8.3)].

3.2 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 [see Dosage and Administration (3.3, 3.5)].

3.3 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 [see Drug Interactions (7.1)].

• 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 [see Warnings and Precautions (5.4)].

Table 1. Amino Acid Solution

3.4 Dose Modifications for Adverse Reactions

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

Table 2. Recommended Dose Modifications of Lutetium Lu 177 Dotatate for Adverse Reactions

1 National Cancer Institute, Common Toxicity Criteria for Adverse Events, version 4.03

3.5 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.

3.6 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.

Table 3. Estimated Radiation Absorbed Dose for Lutetium Lu 177 Dotatate in NETTER-1

* N=18 (two patients excluded because the liver absorbed dose was biased by the uptake of the liver metastases)

** N=9 (female patients only)

*** N=11 (male patients only)

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 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 [see Dosage and Administration (3.1)].

5.2 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 [see Dosage and Administration (3.4)].

5.3 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.

5.4 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 [see Dosage and Administration (3.3)] 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 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 [see Dosage and Administration (3.4)].

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. Lutetium Lu 177 dotatate has not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min).

5.5 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 [see Dosage and Administration (3.2)].

5.6 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.

5.7 Embryo-Fetal Toxicity

Based on its mechanism of action, lutetium Lu 177 dotatate can cause fetal harm [see Clinical Pharmacology]. 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 [see Dosage and Administration (3.1)].

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 [see Use in Specific Populations (8.1, 8.3)].

5.8 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 [see Dosage and Administration (2.6) and Use in Specific Populations (8.3)].

6. ADVERSE REACTIONS

The following serious 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)]

• Neuroendocrine Hormonal Crisis [see Warnings and Precautions (5.6)]

6.1 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 [see Warnings and Precautions (5)].

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]. 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).

Table 4. Adverse Reactions Occurring in ≥ 5% (All Grades) of Patients Receiving Lutetium Lu 177 Dotatate with Octreotide in NETTER-11

1 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays adverse reactions occurring at a higher incidence in lutetium Lu 177 dotatate-treated patients [between arm difference of ≥5% (all grades) or ≥2% (grades 3-4)]

* Includes the terms: Glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, renal impairment

** Includes the terms: Dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain and urinary incontinence

Table 5. Laboratory Abnormalities Occurring in ≥ 5% (All Grades) of Patients Receiving Lutetium Lu 177 Dotatate with Octreotide in NETTER-1*1

* Values are worst grade observed after randomization

1 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays laboratory abnormalities occurring at a higher incidence in lutetium Lu 177 dotatate-treated patients [between arm difference of ≥5% (all grades) or ≥2%(grades 3-4)]

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%).

7. DRUG INTERACTIONS

7.1 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 [see Dosage and Administration (3.3)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, lutetium Lu 177 dotatate can cause fetal harm [see Clinical Pharmacology]. 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.

8.2 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 lutetium Lu 177 dotatate and for 2.5 months after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating lutetium Lu 177 dotatate [see Use in Specific Populations (8.1)].

Contraception

Females

Lutetium Lu 177 dotatate 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 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 [see Clinical Pharmacology and Nonclinical Toxicology].

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 [see Dosage and Administration (3.6)].

8.4 Pediatric Use

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

8.5 Geriatric 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.

8.6 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.

8.7 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.

10. 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.

11. 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.

12. 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 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 [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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

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).

Storage and Handling:

Store below 25 °C (77 °F).

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

Rx only

Rev 01/18