Lutathera Drug Information

LUTATHERA is indicated for the treatment of adult and pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors.

Important Safety Instructions LUTATHERA is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure. 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. 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.

Recommended Dosage

The recommended LUTATHERA dosage for adult and pediatric patients 12 years and older is 7.4 GBq (200 mCi) every 8 weeks (± 1 week) for a total of 4 doses. Administer premedications and concomitant medications as recommended.

Premedications and Concomitant Medications Somatostatin Analogs Before initiating LUTATHERA treatment: 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. 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 prior to 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 18 months following treatment initiation at the discretion of the physician.

Antiemetics Administer antiemetics before the recommended amino acid solution. Amino Acid Solution Initiate an intravenous infusion of a sterile amino acid solution containing L-lysine and L-arginine (Table 1) 30 minutes before the start of the LUTATHERA infusion. Use a three-way valve to administer the amino acid solution using the same venous access as LUTATHERA or administer the amino acid solution through a separate venous access in the patient’s other arm.

Continue the amino acid solution infusion during and for at least 3 hours after completion of the LUTATHERA infusion. Do not decrease the dose of the amino acid solution if a reduced dose of LUTATHERA is administered. Table 1.

Amino Acid Solution Hypersensitivity Prophylaxis Premedicate patients who have had prior Grade 1 or 2 hypersensitivity reactions to LUTATHERA. Do not re-challenge patients who experience Grade 3 or 4 hypersensitivity reactions to LUTATHERA.

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 Preparation and Administration Preparation Instructions Use aseptic technique and radiation shielding when handling or administering the LUTATHERA solution.

Use tongs when handling the vial to minimize radiation exposure. Inspect the product visually under a shielded screen for particulate matter and discoloration prior to administration. Discard the vial if particulates and/or discoloration are present.

Do not inject the LUTATHERA solution directly into any other intravenous solution. Confirm the amount of radioactivity of LUTATHERA delivered to the patient with an appropriate dose calibrator prior to and after each LUTATHERA administration. Dispose of any unused medicinal product or waste material in accordance with local and federal laws.

Administration Instructions Prior to administration, flush the intravenous catheter used for LUTATHERA administration with ≥ 10 mL of 0.9% Sodium Chloride Injection, USP to ensure patency and to minimize the risk of extravasation. Manage cases of extravasation as per institutional guidelines. The gravity method, peristaltic pump method, or the syringe pump method may be used for the administration of the recommended dosage.

Do not administer LUTATHERA as an intravenous bolus. When using the gravity or peristaltic pump method, infuse LUTATHERA directly from its original container. Use the peristaltic pump or syringe pump method when administering a reduced dose of LUTATHERA following a dosage modification for an adverse reaction.

When using the gravity method for a reduced dose, adjust the LUTATHERA dose before the administration to avoid the delivery of an incorrect volume of LUTATHERA. Intravenous Methods of Administration Instructions for the 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% Sodium Chloride Injection, USP (used to transport the LUTATHERA solution 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 the 0.9% Sodium Chloride Injection, USP to flow into the LUTATHERA vial prior to the initiation of the LUTATHERA infusion and do not inject the LUTATHERA solution directly into the 0.9% Sodium Chloride Injection, USP. 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% Sodium Chloride Injection, USP and that is used for the LUTATHERA infusion into the patient.

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 0.9% Sodium Chloride Injection, USP 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% Sodium Chloride Injection, USP through the intravenous catheter to the patient.

Instructions for the Peristaltic Pump Method Insert a filtered 2.5 cm, 20-gauge needle (short venting needle) into the LUTATHERA vial. Connect the long needle and a 0.9% Sodium Chloride Injection, USP 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 pump according to manufacturer’s instructions.

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% Sodium Chloride Injection, USP and pumping the 0.9% Sodium Chloride Injection, USP 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 peristaltic 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 peristaltic pump and then change the position of the 3-way stopcock valve so that the peristaltic pump is in line with the 0.9% Sodium Chloride Injection, USP. Restart the peristaltic pump and infuse an intravenous flush of 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient.

Instructions for the Syringe Pump Method Withdraw an appropriate volume of LUTATHERA solution to deliver the desired radioactivity by using a disposable syringe fitted with a syringe shield and a disposable sterile needle that is 9 cm, 18 gauge (long needle). To aid the withdrawal of the solution, a filtered 2.5 cm, 20-gauge needle (short venting needle) can be used to reduce the resistance from the pressurized vial. Fit the syringe into the shielded pump and include a 3-way stopcock valve between the syringe and an intravenous catheter pre-filled with 0.9% Sodium Chloride Injection, USP and used for LUTATHERA administration to the patient.

When the desired LUTATHERA radioactivity has been delivered, stop the syringe pump and then change the position of the 3-way stopcock valve to flush the syringe with 25 mL of 0.9% Sodium Chloride Injection, USP. Restart the syringe pump.

Radiation Dosimetry

The maximum penetration of lutetium-177 in tissue is 2.2 mm and the mean penetration is 0.67 mm. The mean and standard deviation (SD) of the estimated radiation absorbed doses for adults receiving LUTATHERA are shown in Table 3. The mean and SD of the estimated radiation absorbed doses for pediatric patients 12 years and older receiving LUTATHERA are shown in Table 4.

Table 3. Estimated Radiation Absorbed Dose for LUTATHERA in Adults in NETTER-1 Table 4. Estimated Radiation Absorbed Dose for LUTATHERA in Pediatric Patients 12 Years and Older in NETTER-P

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.

Adult Population NETTER-1 The safety data of LUTATHERA with octreotide was evaluated in NETTER-1. 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 5 and Table 6 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 gamma-glutamyltransferase (GGT) (20%), vomiting (7%), nausea and increased aspartate aminotransferase (AST) (5% each), and increased alanine aminotransferase (ALT), hyperglycemia and hypokalemia (4% each). Table 5.

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) a a National 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. b Includes the terms: Glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, renal impairment. c Includes the terms: Dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain and urinary incontinence. Table 6.

Only displays laboratory abnormalities occurring at a higher incidence in LUTATHERA-treated patients. 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). 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).

Pediatric Population NETTER-P Safety data are available from 9 pediatric patients in NETTER-P (NCT04711135), an international, multi-center, single-arm, open-label trial of patients with somatostatin receptor-positive tumors, including 4 patients with GEP-NETs. Patients received LUTATHERA 7.4 GBq (200 mCi) administered every 8 weeks concurrently with the recommended amino acid solution. Adverse reactions observed in NETTER-P were similar to those observed in adults treated with LUTATHERA.

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

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.

Glucocorticoids Glucocorticoids can induce down-regulation of subtype 2 somatostatin receptors (SSTR2). Avoid repeated administration of high doses of glucocorticoids during treatment with LUTATHERA.

Pregnancy Risk Summary Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman. 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, radioactive emissions, including those from LUTATHERA, can 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 respectively.

Pediatric Use Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors The safety and effectiveness of LUTATHERA have been established in pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Use of LUTATHERA for this indication is supported by evidence from an adequate and well-controlled study of LUTATHERA in adults with additional safety, pharmacokinetic, and dosimetry data in pediatric patients aged 12 years and older with somatostatin receptor-positive tumors, including 4 pediatric patients with GEP-NETs. The risks of radiation exposure associated with LUTATHERA are greater in pediatric patients than in adult patients due to longer life expectancy.

Continued follow-up is recommended for evaluation of long-term effects. There was no clinically relevant difference in lutetium Lu 177 dotatate exposure in pediatric patients aged 13 to 16 years versus adult patients. The pharmacokinetic profile and safety of LUTATHERA in pediatric patients 12 years and older with baseline renal impairment have not been studied.

The safety and effectiveness of LUTATHERA have not been established in pediatric patients younger than 12 years old with somatostatin receptor-positive GEP-NETs.