1/18. Lutetium Lu 177 Dotatate -(LUTHAERA)- (2018)- Anti-cancer
Drug Interaction:
Somastostain analogs: Discontinue long-acting analogs for at least 4 weeks and short-acting octreotide at least 24 hours prior to each LUTATHERA dose
Indication:
BRIEF SUMMARY
Lutetium Lu 177 (2018)
Indn- To treat a type of cancer that affects the pancreas or gastrointestinal tract called gastroenteropancreatic, neurorndocrine tumors(GEP- NETs)
Comp- Injection: 370MBq/ml (10mCi/ml ) in a single dose vial. ii. Administer 7.4GBq (200mC1) every 8 weeks for a total of 4 weeks
ADR- LUTATHERA arm) are lymphoma, increased GGT, vomiting,nausea, increased GGT, vomiting,nausea,increased AST,increased ALT, hyperglycemia,ans hypokalemia
CI- None
Warnings -
i.Risk of Radiation Exposure : Minimize radiation during and treatment consistent with institutional good radiation safety practices and patient management procedures
ii.Mylosuppression: Monitor blood cells counts, reduce dose,or permanently discontinue based on severity
Pat Inform- Radiation Risks- Advise patients to minimize radiation exposure to household contacts consistent with institutional good radiation safety practices and patient management procedures.
Myelosuppression-
Advise patients to contact their healthcare provider for any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, or increased bleeding or bruising.
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U.S. FDA APPROVED DRUGS DURING 2018
Sr.No- 1
Name of the Drug- LUTHATHERA
Active Ingredient - Lutetium Lu 177 doctate
Pharmacological Classification-
To treat a type of cancer that affects the pancreas or gastrointestinal
tract called gastroenteropancreatic, neurorndocrine tumors(GEP- NETs)
Date of Approval- 1-26-2018
(Ref- FDA approved List 2018)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use LUTATHERA safely and effectively. See full prescribing information for LUTATHERA
LUTATHERA® (lutetium Lu 177 dotatate) injection, for intravenous use administration use
Initial U.S. Approval: 2018
Adverse Reaction:
Most common Grade 3-4 adverse reactions (> 4% with a higher incidence in
LUTATHERA arm) are lymphoma, increased GGT, vomiting,nausea, increased GGT,
vomiting,nausea,increased AST,increased ALT, hyperglycemia,ans hypokalemia
Contra-Indications:
Contraindications- None
Warnings and Precautions-
i.Risk of Radiation Exposure : Minimize radiation during and treatment with LUATHERA consistent with institutional good radiation safety practices and patient management procedures
ii.Mylosuppression: Monitor blood cells counts, reduce dose,or permanently discontinue based on severity
iii.Secondary Mylodysplastic Syndrome(MDS) and Leukemia: Median time to development : MDS is 28 months: acute leukemia is 55 months.
iv. Renal Toxicity: Advise patients to urinate frequently during and after administration of LUTATHERA . Monitor serum serum creatinine and calculated creatinine clearance. Withhold, reduce dose, or permanently discontinue based on severity.
v.Hepatotoxicity: Monitor transaminases, bilirubin and albumin. Withhold, reduce dose, or permanently discontinue based on severity.Neuro
vi.Neuroendocrine Hormonal Crisis: Monitor for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms
vii.Embryo-Fetal Toxicity : LUTATHERA can cause fetal harm. Advise females and males of reproductive potential risk to the fetus and to use effecective contraception.
viii. Risk of inferttility- LUTATHERA may cause infertility
Dosages/ Overdosage Etc:
1.INDICATIONS AND USAGE
LUTATHERA is a radiolabelled somatostatin analog indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.
2 DOSAGE AND ADMINISTRATION
i. Verify pregnancy status in females of reproductive potential prior to initiating
LUTATHERA
ii. Administer 7.4GBq (200mC1) every 8 weeks for a total of 4 weeks
iii.Administer long acting octreotide 30mg intramuscularly 4 to 24 hours after
each LUTATHER dose and short -acting octreotide for symptomatic management
iv. Continue long acting octreotide 30mg intramuscularly every 4 weeks after
completing LUTATHERA until disease progression or for up to 18month
folowing treatment initiation
v. Premedicate with antiemerics 30 minutes before recommended amino acid solution
vi. Initiate recommended intravenous amino acid solution 30 minutes before
LUTATHERA INFUSION, continue during and 3 hours ater
LUTATHERA infusion . Do not reduce dose of amino acid solution
LUTATHERA dose is reduced
Modify LUTATHERA dose badsd on adverse reactions
Prepare and administer as recommended
DOSAGE FOR AND STRENGTHS-
Injection: 370MBq/ml (10mCi/ml ) in a single dose vial
Patient Information:
PATIENT COUNSELING INFORMATION
Radiation Risks-
Advise patients to minimize radiation exposure to household contacts consistent with institutional good radiation safety practices and patient management procedures.
Myelosuppression-
Advise patients to contact their healthcare provider for any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, or increased bleeding or bruising.
Secondary Myelodysplastic Syndrome and Acute Leukemia-
Advise patients of the potential for secondary cancers, including myelodysplastic syndrome and acute leukemia.
Renal Toxicity.
Advise patients to hydrate and urinate frequently during and after administration of LUTATHERA [see Warnings and Precautions (5.4)].
Hepatotoxicity.
Advise patients of the need for periodic laboratory tests to monitor for hepatotoxicity.
Neuroendocrine Hormonal Crises-
Advise patients to contact their health care provider for signs or symptoms that may occur following tumor-hormone release, including severe flushing, diarrhea, bronchospasm, and hypotension.
Embryo-Fetal Toxicity-
Advise pregnant women and males and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the final dose.
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 [
Lactation-
Advise females not to breastfeed during treatment with LUTATHERA and for 2.5 months after the final dose.
Infertility-
Advise female and male patients that LUTATHERA may impair fertility.
Manufactured by:
Advanced Accelerator Applications, S.r.l.
Via Ribes 5, 10010 Colleretto Giacosa (TO), Italy
Or
Advanced Accelerator Applications, S.r.l.
Via Piero Maroncelli 40/1, 47014 Meldola (FC), Italy
Distributed by:
Advanced Accelerator Applications USA, Inc., NJ 07041
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. 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.
2. 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.
3.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%.
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 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)].
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary
Based on its mechanism of action, LUTATHERA can cause fetal harm
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 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.
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 LUTATHERA and for 2.5 months after the final dose.
3. Females and Males of Reproductive Potential Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA
Contraception- Females- LUTATHERA can cause fetal harm when administered to a pregnant woman
Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the final dose of 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
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.
4. Pediatric Use
The safety and effectiveness of LUTATHERA have not been established in pediatric patients.
5. 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.
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 LUTATHERA in patients with severe renal impairment (creatinine clearance < 30 mL/min by Cockcroft-Gault) or end-stage renal disease has not been studied.