Safety and Tolerability Profile of LUTATHERA® (lutetium Lu 177 dotatate)

Radiation safety: general precautions for radiopharmaceuticals

LUTATHERA is a radiopharmaceutical. Radiopharmaceuticals, including LUTATHERA, 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.

Minimize radiation exposure during and after treatment with LUTATHERA consistent with institutional good radiation safety practices and patient management procedures. Always follow the principal of ALARA (as low as reasonably achievable) when handling and administering LUTATHERA. Use waterproof gloves and effective radiation shielding when handling LUTATHERA.

Adverse reactions1

The most common Grade 3-4 adverse reactions ≥ 4% with a higher incidence in LUTATHERA arm were:

  • Lymphopenia (44%)
  • Increased GGT (20%)
  • Vomiting (7%)
  • Nausea (5%)
  • Elevated AST (5%)
  • Increased ALT (4%)
  • Hyperglycemia (4%)
  • Hypokalemia (4%)

6% of patients required a dose reduction, and 13% of patients discontinued LUTATHERA.

  • 5 patients discontinued due to renal-related events
  • 4 patients discontinued due to hematological toxicities

*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 [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.

Laboratory abnormalities1

*Values are worst grade observed after randomization.

†National 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]).

Serious adverse reactions reported with a median follow-up time of more than 4 years1,2

Retrospective safety data are available from 1,214 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 for up to 4 doses with the recommended amino acid solution and antiemetic. Retrospective medical record review was conducted on a subset of 811 patients to document serious adverse reactions. 81% of patients in the subset received a cumulative dose ≥22.2 GBq (≥600 mCi).

Please see warnings and precautions for myelosuppression and secondary myelodysplastic syndrome and leukemia. Monitor blood cell counts. Withhold, reduce dose, or permanently discontinue based on severity of adverse reactions.

5-HIAA, 5-hydroxyindoleacetic acid; ALT, alanine aminotransferase; CrCl, creatinine clearance; AST, aspartate aminotransferase; ENETS, European Neuroendocrine Tumor Society; GGT, gamma-glutamyl transferase; IM, intramuscular; IV, intravenous; RECIST, Response Evaluation Criteria in Solid Tumors; ULN, upper limit of normal.

References: 1. LUTATHERA® [prescribing information]. Millburn, NJ: Advanced Accelerator Applications USA, Inc.; July 2018. 2. Brabander T, van der Zwan WA, Teunissen JJ, et al. Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3] octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017;23(16):4617-4624.

IMPORTANT SAFETY INFORMATION1

WARNINGS AND PRECAUTIONS

  • Radiation Exposure: Treatment with LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure and 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 and patient management procedures.
  • Myelosuppression: In NETTER-1 clinical trial, myelosuppression occurred more frequently in patients receiving LUTATHERA with long acting octreotide at the following rates (all grades/grade 3 or 4): anemia (81%/0), thrombocytopenia (53%/1%), and neutropenia (26%/3%). Blood cell counts must be monitored prior to, during, and after treatment. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.
  • Secondary Myelodysplastic Syndrome and Leukemia:  In NETTER-1, with a median follow-up time of 24 months, myelodysplastic syndrome (MDS) was reported in 2.7% of patients receiving LUTATHERA with long-acting octreotide. In ERASMUS, a Phase I/II clinical study, 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) and 55 months (32 to 155 months) for acute leukemia.
  • Renal Toxicity: Treatment with LUTATHERA will expose kidneys to radiation, which may impair renal function. In ERASMUS <1% of patients developed renal failure 3 to 36 months following LUTATHERA. Monitor serum creatinine and creatinine clearance to assess changes in renal function. Advise patients to urinate frequently during and after administration of LUTATHERA. A concomitant intravenous infusion of amino acids before, during and after LUTATHERA administration is mandatory for renal protection. 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. Withhold, reduce dose, or permanently discontinue based on severity of reaction. Do not decrease the dose of amino acid solution if the dose of LUTATHERA is reduced. LUTATHERA has not been studied in patients with severe renal impairment (CrCL < 30 mL/min).
  • Hepatotoxicity: In ERASMUS, <1% of patients 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 based on severity of reaction.
  • Neuroendocrine hormonal crisis: Manifesting with flushing, diarrhea, bronchospasm and hypotension, neuroendocrine hormonal crisis occurred in 1% of patients in ERASMUS and typically occurred during or within 24 hours following the initial LUTATHERA dose. 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: LUTATHERA can cause fetal harm. 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 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. Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA.
  • Risk of Infertility: LUTATHERA may cause infertility in males and females. Radiation absorbed by testis and ovaries from the recommended cumulative LUTATHERA dose falls within the range in which temporary or permanent infertility can be expected following external beam radiotherapy.

ADVERSE REACTIONS

The most common Grade 3-4 adverse reactions (≥ 4% with a higher incidence in LUTATHERA arm) observed in NETTER-1 were lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea (5%), elevated AST (5%), increased ALT (4%), hyperglycemia (4%), and hypokalemia (4%).

In ERASMUS, the following serious adverse reactions have been observed with a median follow-up time of more than 4 years after treatment with LUTATHERA: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%). Patients should be counseled and monitored in accordance with the LUTATHERA Prescribing Information.

DRUG INTERACTIONS

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.

SPECIFIC POPULATIONS

  • Lactation: 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.

To report SUSPECTED ADVERSE REACTIONS, contact Advanced Accelerator Applications USA, Inc. at 1-844-863-19301-844-863-1930, or us-pharmacovigilance@adacap.com, or FDA at 1-800-FDA-1088 or  www.fda.gov/medwatch.

Please see full Prescribing Information.

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

References: 1. LUTATHERA® [prescribing information]. Millburn, NJ: Advanced Accelerator Applications USA, Inc.; July 2018.

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