RETEVMO ® ( selpercatinib ) capsules , for oral use Initial U . S . Approval : 2020
BRIEF SUMMARY : Consult the package insert for complete prescribing information .
INDICATIONS AND USAGE RETEVMO ( selpercatinib ) is a kinase inhibitor indicated for the treatment of :
• Adult patients with metastatic RET fusion-positive non-small cell lung cancer ( NSCLC )
• Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer ( MTC ) who require systemic therapy
• Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy are radioactive iodine-refractory ( if radioactive iodine is appropriate )
These indications are approved under accelerated approval based on overall response rate and duration of response . Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials .
CONTRAINDICATIONS : None WARNINGS AND PRECAUTIONS Hepatotoxicity
Serious hepatic adverse reactions occurred in 2.6 % of patients treated with RETEVMO . Increased AST occurred in 51 % of patients , including Grade 3 or 4 events in 8 % and increased ALT occurred in 45 % of patients , including Grade 3 or 4 events in 9 %. The median time to first onset for increased AST was 4.1 weeks ( range : 5 days to 2 years ) and increased ALT was 4.1 weeks ( range : 6 days to 1.5 years ).
Monitor ALT and AST prior to initiating RETEVMO , every 2 weeks during the first 3 months , then monthly thereafter and as clinically indicated . Withhold , reduce dose or permanently discontinue RETEVMO based on the severity .
Hypertension
Hypertension occurred in 35 % of patients , including Grade 3 hypertension in 17 % and Grade 4 in one ( 0.1 %) patient . Overall , 4.6 % had their dose interrupted and 1.3 % had their dose reduced for hypertension . Treatment-emergent hypertension was most commonly managed with anti-hypertension medications .
Do not initiate RETEVMO in patients with uncontrolled hypertension . Optimize blood pressure prior to initiating RETEVMO . Monitor blood pressure after 1 week , at least monthly thereafter and as clinically indicated . Initiate or adjust anti-hypertensive therapy as appropriate . Withhold , reduce dose , or permanently discontinue RETEVMO based on the severity .
QT Interval Prolongation
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 .
Hemorrhagic Events
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
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
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 .
Risk of Impaired Wound Healing
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 .
Embryo-Fetal Toxicity
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 .
ADVERSE REACTIONS Clinical Trial 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 .
RET Gene Fusion or Gene Mutation Positive Solid Tumors
The pooled safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent at 160 mg orally twice daily evaluated in 702 patients in LIBRETTO-001 . Among 702 patients who received RETEVMO , 65 % were exposed for 6 months or longer and 34 % were exposed for greater than one year . Among these patients , 95 % received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily .
The median age was 59 years ( range : 15 to 92 years ); 0.3 % were pediatric patients 12 to 16 years of age ; 52 % were male ; and 69 % were White , 22 % were Asian , 5 % were Hispanic / Latino , and 3 % were Black . The most common tumors were NSCLC ( 47 %), MTC ( 44 %), and non-medullary thyroid carcinoma ( 5 %).
Serious adverse reactions occurred in 33 % of patients who received RETEVMO . The most frequent 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 ).
Permanent discontinuation due to an adverse reaction occurred in 5 % of patients who received RETEVMO . Adverse reactions resulting in permanent discontinuation included increased ALT ( 0.4 %), sepsis ( 0.4 %), increased AST ( 0.3 %), drug hypersensitivity ( 0.3 %), fatigue ( 0.3 %), and thrombocytopenia ( 0.3 %).
Dosage interruptions due to an adverse reaction occurred in 42 % of patients who received RETEVMO . Adverse reactions requiring dosage interruption in > 2 % of patients included ALT increased , AST increased , hypertension , diarrhea , pyrexia , and QT prolongation .
RETEVMO ® ( selpercatinib ) capsules , for oral use SE HCP BS 25MAR2021 RETEVMO ® ( selpercatinib ) capsules , for oral use SE HCP BS 25MAR2021