IMPORTANT SAFETY INFORMATION FOR RETEVMO ® ( selpercatinib 40 mg , 80 mg capsules ) ( CONT ’ D )
Retevmo can cause concentration-dependent QT interval prolongation . An increase in QTcF interval to > 500 ms was measured in 6 % of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15 % of patients . Retevmo has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction . Monitor patients who are at significant risk of developing QTc prolongation , including patients with known long QT syndromes , clinically significant bradyarrhythmias , and severe or uncontrolled heart failure . Assess QT interval , electrolytes and TSH at baseline and periodically during treatment , adjusting frequency based upon risk factors including diarrhea . Correct hypokalemia , hypomagnesemia and hypocalcemia prior to initiating Retevmo and during treatment . Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval . Withhold and dose reduce or permanently discontinue Retevmo based on the severity .
Serious , including fatal , hemorrhagic events can occur with Retevmo . Grade ≥3 hemorrhagic events occurred in 2.3 % of patients treated with Retevmo including 3 ( 0.4 %) patients with fatal hemorrhagic events , including one case each of cerebral hemorrhage , tracheostomy site hemorrhage , and hemoptysis . Permanently discontinue Retevmo in patients with severe or life-threatening hemorrhage .
Hypersensitivity occurred in 4.3 % of patients receiving Retevmo , including Grade 3 hypersensitivity in 1.6 %. The median time to onset was 1.7 weeks ( range 6 days to 1.5 years ). Signs and symptoms of hypersensitivity included fever , rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis . If hypersensitivity occurs , withhold Retevmo and begin corticosteroids at a dose of 1 mg / kg prednisone ( or equivalent ). Upon resolution of the event , resume Retevmo at a reduced dose and increase the dose of Retevmo by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity . Continue steroids until patient reaches target dose and then taper . Permanently discontinue Retevmo for recurrent hypersensitivity .
Tumor lysis syndrome ( TLS ) occurred in 1 % of patients with medullary thyroid carcinoma receiving Retevmo . Patients may be at risk of TLS if they have rapidly growing tumors , a high tumor burden , renal dysfunction , or dehydration . Closely monitor patients at risk , consider appropriate prophylaxis including hydration , and treat as clinically indicated .
Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor ( VEGF ) signaling pathway . Therefore , Retevmo has the potential to adversely affect wound healing . Withhold Retevmo for at least 7 days prior to elective surgery . Do not administer for at least 2 weeks following major surgery and until adequate wound healing . The safety of resumption of Retevmo after resolution of wound healing complications has not been established .
Based on data from animal reproduction studies and its mechanism of action , Retevmo can cause fetal harm when administered to a pregnant woman . Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations . Advise pregnant women of the potential risk to a fetus . Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for at least 1 week after the final dose . There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production . Because of the potential for serious adverse reactions in breastfed children , advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose .
Severe adverse reactions ( Grade 3-4 ) occurring in ≥15 % of patients who received Retevmo in LIBRETTO-001 , were hypertension ( 18 %), prolonged QT interval ( 4 %), diarrhea ( 3.4 %), dyspnea ( 2.3 %), fatigue ( 2 %), abdominal pain ( 1.9 %), hemorrhage ( 1.9 %), headache ( 1.4 %), rash ( 0.7 %), constipation ( 0.6 %), nausea ( 0.6 %), vomiting ( 0.3 %), and edema ( 0.3 %).
Serious adverse reactions occurred in 33 % of patients who received Retevmo . The most frequently reported serious adverse reaction ( in ≥ 2 % of patients ) was pneumonia .
Fatal adverse reactions occurred in 3 % of patients ; fatal adverse reactions which occurred in > 1 patient included sepsis ( n = 3 ), cardiac arrest ( n = 3 ) and respiratory failure ( n = 3 ).
Common adverse reactions ( all grades ) occurring in ≥15 % of patients who received Retevmo in LIBRETTO-001 , were dry mouth ( 39 %), diarrhea ( 37 %), hypertension ( 35 %), fatigue ( 35 %), edema ( 35 %), rash ( 27 %), constipation ( 25 %), nausea ( 23 %), abdominal pain ( 23 %), headache ( 23 %), cough ( 18 %), prolonged QT interval ( 17 %), dyspnea ( 16 %), vomiting ( 15 %), and hemorrhage ( 15 %).
Laboratory abnormalities ( all grades ; Grade 3-4 ) ≥20 % worsening from baseline in patients who received Retevmo in LIBRETTO-001 , were AST increased ( 51 %; 8 %), ALT increased ( 45 %; 9 %), increased glucose ( 44 %; 2.2 %), decreased leukocytes ( 43 %; 1.6 %), decreased albumin ( 42 %; 0.7 %), decreased calcium ( 41 %; 3.8 %), increased creatinine ( 37 %; 1.0 %), increased alkaline phosphatase ( 36 %; 2.3 %), decreased platelets ( 33 %; 2.7 %), increased total cholesterol ( 31 %; 0.1 %), decreased sodium ( 27 %; 7 %), decreased magnesium ( 24 %; 0.6 %), increased potassium ( 24 %; 1.2 %), increased bilirubin ( 23 %; 2.0 %), and decreased glucose ( 22 %; 0.7 %).
Concomitant use of acid-reducing agents decreases selpercatinib plasma concentrations which may reduce Retevmo anti-tumor activity . Avoid concomitant use of proton-pump inhibitors ( PPIs ), histamine-2 ( H2 ) receptor antagonists , and locally-acting antacids with Retevmo . If coadministration cannot be avoided , take Retevmo with food ( with a PPI ) or modify its administration time ( with a H2 receptor antagonist or a locally-acting antacid ).
Concomitant use of strong and moderate CYP3A inhibitors increases selpercatinib plasma concentrations which may increase the risk of Retevmo adverse reactions including QTc interval prolongation . Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo . If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided , reduce the Retevmo dosage as recommended and monitor the QT interval with ECGs more frequently .
Concomitant use of strong and moderate CYP3A inducers decreases selpercatinib plasma concentrations which may reduce Retevmo antitumor activity . Avoid coadministration of Retevmo with strong and moderate CYP3A inducers .
Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increases their plasma concentrations which may increase the risk of adverse reactions related to these substrates . Avoid coadministration of Retevmo with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions . If coadministration cannot be avoided , follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling .
The safety and effectiveness of Retevmo have not been established in pediatric patients less than 12 years of age . The safety and effectiveness of Retevmo have been established in pediatric patients aged 12 years and older for medullary thyroid cancer ( MTC ) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodinerefractory ( if radioactive iodine is appropriate ). Use of Retevmo for these indications is supported by evidence from adequate and wellcontrolled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older . Monitor open growth plates in adolescent patients . Consider interrupting or discontinuing Retevmo if abnormalities occur .
No dosage modification is recommended for patients with mild to severe renal impairment ( estimated Glomerular Filtration Rate [ eGFR ] ≥15 to 89 mL / min , estimated by Modification of Diet in Renal Disease [ MDRD ] equation ). A recommended dosage has not been established for patients with end-stage renal disease .
Reduce the dose when administering Retevmo to patients with severe hepatic impairment ( total bilirubin greater than 3 to 10 times upper limit of normal [ ULN ] and any AST ). No dosage modification is recommended for patients with mild or moderate hepatic impairment . Monitor for Retevmo-related adverse reactions in patients with hepatic impairment .
SE HCP ISI All _ 25MAR2021
Please see Brief Summary of Prescribing Information for Retevmo on subsequent pages .
References : 1 . Retevmo ( selpercatinib ) [ package insert ]. Indianapolis , IN : Eli Lilly and Company ; 2021 . 2 . Drilon A , Hu ZI , Lai GGY , et al . Targeting RETdriven cancers : lessons from evolving preclinical and clinical landscapes . Nat Rev Clin Oncol . 2018 ; 15 ( 3 ): 151-167 . 3 . Data on File , Lilly USA , LLC , DOF-SE- US-0032 . 4 . Data on File , Lilly USA , LLC , DOF-SE-US-0033 . 5 . Phase 1 / 2 study of LOXO-292 in patients with advanced solid tumors , RET fusion-positive solid tumors , and medullary thyroid cancer ( LIBRETTO-001 ). https :// clinicaltrials . gov / ct2 / show / NCT03157128 . Updated July 2 , 2020 . Accessed July 16 , 2020 . 6 . Mulligan LM . GDNF and the RET receptor in cancer : new insights and therapeutic potential . Front Physiol . 2019 ; 9:1873 .