CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Selpercatinib is kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and at higher concentrations that were still clinically achievable. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and and approximately 8-fold lower concentration than VEGFR3.Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with patient-derived RET fusion positive tumor.. 12.2 Pharmacodynamics. Exposure-Response RelationshipSelpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.. Cardiac ElectrophysiologyThe effect of RETEVMO on the QTc interval was evaluated in thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.. 12.3 Pharmacokinetics. The pharmacokinetics of selpercatinib capsules were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. The capsule and tablet dosage forms of selpercatinib are bioequivalent. Steady state selpercatinib AUC and Cmax increased in slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily [0.06 to 1.5 times the maximum recommended total daily dosage].Steady-state was reached by approximately days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] Cmax was 2,980 (53%) ng/mL and AUC0-24h was 51,600 (58%) ngh/mL.. AbsorptionThe median tmax of selpercatinib is hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects.. Effect of FoodFor both the capsule and tablet dosage forms no clinically significant differences in selpercatinib AUC or Cmax were observed following administration of high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects.. DistributionThe apparent volume of distribution (Vss/F) of selpercatinib is 203 L.Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7.. EliminationThe apparent clearance (CL/F) of selpercatinib is L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects.. MetabolismSelpercatinib is metabolized predominantly by CYP3A4. Following oral administration of single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma.. ExcretionFollowing oral administration of single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged).. Specific PopulationsThe apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (9.6 kg to 179 kg).No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (2 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR >=15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied.. Pediatric patientsThe exposures of selpercatinib in pediatric patients are comparable to those in adult patients administered at the recommended dosages.. Patients with Hepatic ImpairmentThe selpercatinib AUC0-INF increased 1.1-fold in subjects with mild (total bilirubin <= ULN with AST ULN or total bilirubin 1 to 1.5 ULN with any AST), 1.3-fold in subjects with moderate (total bilirubin 1.5 to x ULN and any AST), and 1.8-fold in subjects with severe (total bilirubin 3 to 10 ULN and any AST) hepatic impairment, compared to subjects with normal hepatic function.. Drug Interaction Studies. Clinical Studies and Model-Informed ApproachesProton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when RETEVMO was administered with food (Table 14).Table 14: Change in Selpercatinib Exposure After Coadministration with PPI1 High-fat meal: approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; approximately 800 to 1,000 calories total.2 Low-fat meal: approximately 390 calories and 10 of fat.SelpercatinibAUC0-INFSelpercatinibCmaxRETEVMO fastingReferenceReferenceRETEVMO fasting PPI 69% 88%RETEVMO with high-fat meal1 PPI 2% 49%RETEVMO with low-fat meal2 PPINo change 22%H2 Receptor Antagonists: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and hours after the RETEVMO dose (administered fasting).Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC0-INF 2.3-fold and Cmax 1.3-fold.Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC 1.6 to 2-fold and Cmax 1.5 to 1.8-fold.Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC0-INF by 87% and Cmax by 70%.Moderate CYP3A Inducers: Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the selpercatinib AUC by 40-70% and Cmax by 34-57%.Weak CYP3A Inducers: Coadministration of multiple doses of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and Cmax by 26%.CYP2C8 Substrates: Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC0-INF 2.9-fold and Cmax 1.9-fold.CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A substrate) increased the midazolam AUC0-INF 1.5-fold and Cmax 1.4-fold.P-glycoprotein (P-gp) Substrates: Coadministration of RETEVMO with dabigatran (P-gp substrate) increased the dabigatran AUC0-INF 1.4-fold and Cmax 1.4-fold.BCRP Substrates: Coadministration of RETEVMO with rosuvastatin (BCRP substrate) increased the rosuvastatin AUC0-INF by 1.9-fold and Cmax by 1.7-fold.P-gp Inhibitors: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with single dose of rifampin (P-gp inhibitor).MATE1 Substrates: No clinically significant differences in glucose levels were observed when metformin (MATE1 substrate) was coadministered with selpercatinib.. In Vitro StudiesCYP Enzymes: Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.Transporter Systems: Selpercatinib inhibits MATE1. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Adverse Reactions (6.1)].Selpercatinib does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations.Selpercatinib is substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 RET Fusion-Positive Non-Small Cell Lung Cancer. LIBRETTO-001The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive NSCLC enrolled in multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and patients with locally advanced (stage III who were not candidates for surgical resection or definitive chemoradiation) or metastatic NSCLC without prior systemic therapy in separate cohorts. Identification of RET gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH) or other local testing methods. Adult patients received RETEVMO 160 mg orally twice daily until unacceptable toxicity or disease progression; patients enrolled in the dose escalation phase were permitted to adjust their dose to 160 mg twice daily. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), as determined by blinded independent review committee (BIRC) according to RECIST v1.1.. RETFusion-Positive NSCLC Previously Treated with Platinum ChemotherapyEfficacy was evaluated in 247 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy enrolled into cohort of LIBRETTO-001.The median age was 61 years (range: 23 to 81); 57% were female; 44% were White, 48% were Asian, 4.9% were Black or African American; and 2.8% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or (3%) and 97% of patients had metastatic disease. Patients received median of prior systemic therapies (range 1-15); 58% had prior anti-PD1/PD-L1 therapy. RET fusions were detected in 94% of patients using NGS (84.6% tumor samples; 9.3% blood or plasma samples), 4.0% using FISH, 1.6% using PCR and 0.4% by other local testing methods.Efficacy results for previously treated RET fusion-positive NSCLC are summarized in Table 15.Table 15: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy)1 Confirmed overall response rate assessed by BIRC.2 Based on observed duration of response.NE not estimableRETEVMO(n 247)Overall Response Rate1(95% CI)61% (55%, 67%) Complete response7.3% Partial response54%Duration of Response Median in months (95% CI)28.6 (20, NE) with >= 12 months2 63%For the 144 patients who received an anti-PD-1 or anti-PD-L1 therapy, either sequentially or concurrently with platinum-based chemotherapy, an exploratory subgroup analysis of ORR was 63% (95% CI: 54%, 70%) and the median DOR was 28.6 months (95% CI: 14.8, NE).Among the 247 patients with previously treated RET fusion-positive NSCLC, 16 had measurable CNS metastases at baseline as assessed by BIRC. One patient received radiation therapy (RT) to the brain within months prior to study entry. Responses in intracranial lesions were observed in 14 of these 16 patients; 39% of responders had an intracranial DOR of >= 12 months.. Treatment-naiveRETFusion-Positive NSCLCEfficacy was evaluated in 69 patients with treatment-naive RET fusion-positive NSCLC enrolled into cohort of LIBRETTO-001.The median age was 63 years (range 23 to 92); 62% were female; 70% were White, 19% were Asian, and 6% were Black or African American. ECOG performance status was 0-1 (94%) or (6%) and 99% of patients had metastatic disease. RET fusions were detected in 91% of patients using NGS (60.9% tumor samples; 30.4% in blood), 7.2% using FISH and 1.4% using PCR.Efficacy results for treatment naive RET fusion-positive NSCLC are summarized in Table 16.Table 16: Efficacy Results in LIBRETTO-001 (Treatment-Naive RET Fusion-Positive NSCLC)1 Confirmed overall response rate assessed by BIRC.2 Based on observed duration of response.NE not estimableRETEVMO(n =69)Overall Response Rate1(95% CI)84% (73%, 92%) Complete response5.8% Partial response78%Duration of Response Median in months (95% CI)20.2 (13, NE) with >= 12 months2 50%Among the 69 patients with treatment-naive RET fusion-positive NSCLC, had measurable CNS metastases at baseline as assessed by BIRC. Two patients received RT to the brain within months prior to study entry. Responses in intracranial lesions were observed in of these patients; 38% of responders had an intracranial DOR of >= 12 months.. LIBRETTO-431The efficacy of RETEVMO was evaluated in patients with unresectable, locally advanced or metastatic, RET fusion-positive NSCLC enrolled in multicenter, open-label, active-controlled, randomized trial (LIBRETTO-431, NCT04194944). The trial evaluated RETEVMO compared to platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with RET fusion-positive, unresectable locally advanced or metastatic NSCLC with no previous systemic therapy for metastatic disease.Patients (N=261) were randomized to receive either RETEVMO (160 mg orally twice daily) in continuous 21-day cycles or pemetrexed intravenously (IV) (500 mg per square meter of body-surface area) along with the investigators choice of platinum therapy (carboplatin IV [AUC 5, maximum dose 750 mg] or cisplatin IV [75 mg per square meter]) with or without pembrolizumab IV (200 mg) every 21 days. Treatment continued until disease progression or unacceptable toxicity. Crossover from the control arm to RETEVMO was permitted following disease progression. Patients were stratified according to geographic region (East Asia vs. elsewhere), brain metastases at baseline (presence vs. absence or unknown), and the investigators intent (before randomization) to treat the patient with or without pembrolizumab. Tumor assessments were performed every weeks for two assessments, then every weeks for four assessments, and then every 12 weeks thereafter.The major efficacy outcome measure was progression-free survival (PFS) in patients intended to be treated with chemotherapy in combination with pembrolizumab and in the overall study population as determined by blinded independent review committee (BIRC) according to RECIST v1.1. Other efficacy outcome measures included overall survival (OS) and overall response rate (ORR).A total of 212 patients were enrolled in LIBRETTO-431 with an intent to treat with pembrolizumab if randomized to the control arm (129 into RETEVMO arm and 83 into chemotherapy with pembrolizumab arm). The median age was 61.5 years (range: 31 to 84 years); 47% were male; 41% White, 55% Asian, and 0.9% Black or African American, 1.4% American Indian or Alaska Native, 1.9% were race not reported; ethnicity was not reported in 96% of patients. ECOG performance status was 0-1 (97%) or (3%), 68% were never smokers, 93% of patients had metastatic disease, and 14% had measurable intracranial metastases at baseline, as determined by neuroradiologic BIRC. RET fusions were detected in 60% of patients using NGS and 40% using PCR (89% tumor samples; 11% in blood).Efficacy results from the pre-planned interim efficacy analysis are summarized in Table 17.Table 17: Efficacy Results in LIBRETTO-431: RETEVMO versus Chemotherapy with Pembrolizumab1 Based on the stratified Cox proportional hazard model, stratified by geographic location (East Asia versus elsewhere), brain metastases at baseline according to investigator (presence versus absence or unknown).2 Based on stratified log-rank test, stratified by geographic location (East Asia versus elsewhere), brain metastases at baseline according to investigator (presence versus absence or unknown).3 Based on observed duration of response.NE not estimableRETEVMO(n 129)Chemotherapywith pembrolizumab(n 83)Progression-Free Survival Number (%) of patients with an event49 (38%)49 (59%) Medians in months (95% CI)24.8 (16.9, NE)11.2 (8.8, 16.8) Hazard ratio1 (95% CI)0.46 (0.31, 0.70) p-value2 0.0002Overall Response Rate (95% CI)84% (76, 90)65% (54, 75) Complete response7%6% Partial response77%59%Duration of Response Median in months (95% CI) with >= 12 months3 24.2 (17.9, NE)60%11.5 (9.7, 23.3)30%Figure 1: Kaplan-Meier Curves of Progression-Free Survival in LIBRETTO-431: RETEVMO versus Chemotherapy with PembrolizumabAmong the 212 randomized patients, 29 had measurable CNS metastases at baseline as assessed by BIRC. Responses in intracranial lesions were observed in 14 of 17 patients treated with RETEVMO and of 12 patients treated with chemotherapy with pembrolizumab.Overall survival was immature at the time of the PFS interim analysis. At the time of an updated descriptive analysis of OS (43% of prespecified OS events needed for the final analysis), total of 49 (31%) and 26 (25%) patients died in the RETEVMO and the control arm, respectively. The OS HR was 1.26 (95% CI: 0.78, 2.04). Overall survival may be affected by the imbalance in post-progression therapies. Of 68 control arm patients who had disease progression, 50 patients (74%) received RETEVMO at progression. Of 71 RETEVMO arm patients who had disease progression, 16 (23%) received chemotherapy and/or immune checkpoint inhibitor therapy, and 44 (62%) continued receiving RETEVMO.. Figure 1. 14.2 RET-Mutant Medullary Thyroid Cancer. LIBRETTO-001The efficacy of RETEVMO was evaluated in patients with RET-mutant MTC enrolled in multicenter, open-label, multi-cohort clinical trial (NCT03157128). The study enrolled patients with advanced or metastatic RET-mutant MTC who had been previously treated with cabozantinib or vandetanib (or both) and patients with advanced or metastatic RET-mutant MTC who were naive to cabozantinib and vandetanib in separate cohorts.. RET-Mutant MTC Previously Treated with Cabozantinib or VandetanibEfficacy was evaluated in 55 patients with RET-mutant advanced MTC who had previously treated with cabozantinib or vandetanib enrolled into cohort of LIBRETTO-001.The median age was 57 years (range: 17 to 84); 66% were male; 89% were White, 7% were Hispanic/Latino, and 1.8% were Black. ECOG performance status was 0-1 (95%) or (5%) and 98% of patients had metastatic disease. Patients received median of prior systemic therapies (range - 8). RET mutation status was detected in 82% of patients using NGS (78% tumor samples; 4% blood or plasma), 16% using PCR, and 2% using an unknown test. The protocol excluded patients with synonymous, frameshift or nonsense RET mutations; the specific mutations used to identify and enroll patients are described in Table 18.Table 18: Mutations used to Identify and Enroll Patients with RET-Mutant MTC in LIBRETTO-0011 Somatic or germline mutations; protein change.2 Extracellular cysteine mutations involving cysteine residues 609, 611, 618, 620, 630, and 634.3 Other included: K666N (1), D631L633delinsV (2), D631L633delinsE (5), D378G385delinsE (1), D898E901del (2), A883F (4), E632L633del (4), L790F (2), T636V637insCRT(1), D898E901del D903S904delinsEP (1).4 One patient also had M918T mutation.RET Mutation Type1PreviouslyTreated(n 55)Cabozantinib/VandetanibNaive(n 88)Total(n 143)M918T334982Extracellular cysteine mutation2 72027V804M or V804L54 611Other3 101323Efficacy results for RET-mutant MTC are summarized in Table 19.Table 19: Efficacy Results in LIBRETTO-001 (RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib)1 Confirmed overall response rate assessed by BIRC.2 Based on observed duration of response.NE not estimableRETEVMO(n 55)Overall Response Rate1(95% CI)76% (63%, 87%) Complete response18% Partial response58%Duration of Response Median in months (95% CI)45.3 (29.9, NE) with >= 12 months2 76%. Cabozantinib and Vandetanib-naiveRET-Mutant MTCEfficacy was evaluated in 88 patients with RET-mutant MTC who were cabozantinib and vandetanib treatment-naive enrolled into cohort of LIBRETTO-001.The median age was 58 years (range: 15 to 82) with two patients (2.3%) aged 12 to 16 years; 66% were male; and 86% were White, 4.5% were Asian, and 2.3% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or (3.4%). All patients (100%) had metastatic disease and 18% had received or prior systemic therapies (including 8% kinase inhibitors, 4.5% chemotherapy, 2.3% anti-PD1/PD-L1 therapy, and 1.1% radioactive iodine). RET mutation status was detected in 77.3% of patients using NGS (75.0% tumor samples; 2.3% blood samples), 18.2% using PCR, and 4.5% using an unknown test. The mutations used to identify and enroll patients are described in Table 18.Efficacy results for cabozantinib and vandetanib-naive RET-mutant MTC are summarized in Table 20.Table 20: Efficacy Results in LIBRETTO-001 (Cabozantinib and Vandetanib-naive RET-Mutant MTC)1 Confirmed overall response rate assessed by BIRC.2 Based on observed duration of response.NR not reached, NE not estimableRETEVMO(n 88)Overall Response Rate1(95% CI)81% (71%, 88%) Complete response28% Partial response52%Duration of Response Median in months (95% CI)NR (51.3, NE) with >= 12 months2 90%. LIBRETTO-531LIBRETTO-531 was randomized (2:1), multicenter, open-label study (NCT04211337) in adults and adolescents with advanced or metastatic RET-mutant MTC. The study evaluated the efficacy of RETEVMO versus physicians choice of cabozantinib or vandetanib in patients with progressive, advanced, kinase inhibitor naive, RET-mutant medullary thyroid cancer.Patients were randomized to receive either RETEVMO (160 mg twice daily) or physicians choice of cabozantinib (140 mg once daily) or vandetanib (300 mg once daily). Patients were stratified based on RET mutation (M918T vs. other) and intended treatment if randomized to the control arm (cabozantinib vs. vandetanib). The primary outcome was progression-free survival (PFS), as determined by blinded independent review committee (BIRC) according to RECIST v1.1.The median age was 55 years (range: 12 to 84), 63% were male, 58% were White, 23% were Asian, 2.4% were Black or African American, and 17% had unknown race. ECOG performance status was 0-1 (98%) or (1.0%) with 0.7% unknown status. 77% of patients had metastatic disease and patients (2.1%) had received prior systemic therapy. RET mutation status was detected in 90% of patients using NGS (89% tumor samples; 8% blood or plasma), and 10% using PCR. Of patients enrolled in LIBRETTO-531, 63% had M918T RET mutations and 37% had other RET mutations.Efficacy results for LIBRETTO-531 based on the preplanned interim efficacy analysis are provided in Table 21 and Figure 2. At the time of this analysis, overall survival data were immature with 18 deaths observed (14% of pre-specified events).Table 21: Efficacy Results in LIBRETTO-531: RETEVMO versus Cabozantinib or VandetanibData from the pre-planned interim efficacy analysis.1 Based on the stratified Cox proportional hazard model.2 Based on stratified log-rank test.NR Not reached; NE not evaluableRETEVMON 193Cabozantinib or VandetanibN 98PFS Number (%) of patients with an event26 (14%)33 (34%) Median in months (95% CI)NR (NE, NE)16.8 (12.2, 25.1) Hazard ratio (95% CI)10.280 (95% CI: 0.165, 0.475) p-value2<0.0001Overall Response Rate ORR (95% CI)69% (62%, 76%)39% (29%, 49%) Complete response12%4% Partial response58%35%Duration of Response Median in months (95% CI)NR (NE, NE)16.6 (10.4, NE) Median follow-up time (months)11.112.8Figure 2: Kaplan-Meier Curves of Progression-Free Survival in LIBRETTO-531: RETEVMO versus Cabozantinib or VandetanibPatient-reported overall side effect impact was evaluated weekly in 222 patients (RETEVMO = 145; cabozantinib or vandetanib N=77) who received at least one dose of treatment by at least months prior to the data cutoff date and responded to the Functional Assessment of Cancer Therapy text GP5 (FACT GP5). Patient-reported overall side effect impact was derived as proportion of time on treatment with high side effect bother (defined as response of Quite bit or Very much) per FACT GP5.Patient-reported overall side effect impact results for LIBRETTO-531 are provided in Table 22.Table 22. Descriptive Summary of Patient-reported Overall Side Effect Impact While on Treatment in LIBRETTO-531RETEVMO(N=145)Cabozantinib or Vandetanib(N=77)Mean proportion of time with high side effect bother (95% CI)8% (4.8%, 10%)24% (17%, 31%)% Patients with high side effect bother 0% of time <=25% of time61%90%30%66%Patient-reported overall side effect impact results were supported by lower incidence of treatment discontinuation due to adverse reactions for RETEVMO (4.7%) compared to cabozantinib or vandetanib (27%) in patients who received at least one dose of study treatment. The median time on treatment at the data cutoff was 14.5 months in the RETEVMO arm and 8.3 months in the cabozantinib or vandetanib arm in patients who received at least one dose of study treatment.. Figure 2. LIBRETTO-121The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792). Patients received RETEVMO 92 mg/m2 orally twice daily until disease progression, unacceptable toxicity, or other reason for treatment discontinuation. Tumor assessments were performed every weeks for one year, then every 12 weeks; responses were assessed according to RECIST 1.1 per BIRC.Efficacy was evaluated in 14 patients with RET-mutant MTC who were non-responsive to available therapies or had no standard systemic curative therapy available. The median age was 14 years (range to 20); 64% were male; 71% were White, 14% were Black or African American; and 14% were Hispanic/Latino. Patients had metastatic (71%) or locally advanced (29%) disease; 43% had measurable disease at baseline; 21% had received prior systemic therapy. RET-mutant status was detected in 79% of patients using NGS tumor samples and in 21% using PCR.Efficacy results for RET-mutant MTC in pediatric and young adult patients are summarized in Table 23.Table 23: Efficacy Results in LIBRETTO-121 (RET-Mutant MTC)1 Confirmed overall response rate assessed by BIRC.2 Based on observed duration of response.+ Denotes ongoing response.RETEVMO(n 14)Overall Response Rate1 (95% CI)57% (29, 82) Complete response36% Partial response21%Duration of Response Median in months (range)Not reached (8.3+, 49.7+) with >= 18 months2 88% with >= 24 months2 75%. 14.3 RET Fusion-Positive Thyroid Cancer. LIBRETTO-001The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive thyroid cancer enrolled in multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 65 patients with RET fusion-positive thyroid cancer who were radioactive iodine (RAI)-refractory (if RAI was an appropriate treatment option) and were systemic therapy naive and patients who were previously treated, in separate cohorts.The median age was 59 years (range 20 to 88); 49% were male; 65% were White, 20% were Asian, 4.6% were Black or African American; and 11% were Hispanic/Latino. ECOG performance status was 0-1 (94%) or (6%). All (100%) patients had metastatic disease with primary tumor histologies including papillary thyroid cancer (83%), poorly differentiated thyroid cancer (9%), anaplastic thyroid cancer (6%) and Hurthle cell thyroid cancer (1.5%). Previously treated patients had received median of prior therapy (range 1-4). RET fusion-positive status was detected in 97% of patients using NGS (89% tumor samples; 8% blood or plasma samples), and 3% using other local testing methods.Efficacy results for RET fusion-positive thyroid cancer are summarized in Table 24.Table 24: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive Thyroid Cancer)1 Confirmed overall response rate assessed by BIRC.2 Based on observed duration of response.NE not estimableRETEVMOPreviously Treated(n 41)RETEVMOSystemic Therapy Naive(n 24)Overall Response Rate1 (95% CI)85% (71%, 94%)96% (79%, 100%) Complete response12%21% Partial response73%75%Duration of Response Median in months (95% CI)26.7 (12.1, NE)NE (42.8, NE) with >= 12 months2 5465Responses were observed in patients with each histology represented, including of patients with anaplastic thyroid cancer (all partial responses) and of patients with poorly differentiated thyroid cancer (1 complete response, partial responses).. LIBRETTO-121The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792) [see Clinical Studies (14.2)]. Efficacy was evaluated in 15 patients with RET fusion-positive thyroid cancer who were non-responsive to available therapies or had no standard systemic curative therapy available. The median age was 12 years (range to 20); 53% were male; 40% were White, 47% were Asian, 13% were other races; and 27% were Hispanic/Latino Patients had metastatic (87%) or locally advanced (13%) disease and 100% had papillary thyroid cancer histology; 47% had measurable disease at baseline; 20% had received prior systemic therapy. RET fusion-positive status was detected in 93% of patients using NGS tumor samples and in 7% using FISH. Efficacy results for RET fusion-positive thyroid cancer in pediatric and young adult patients are summarized in Table 25.Table 25: Efficacy Results in LIBRETTO-121 (RET Fusion-Positive Thyroid Cancer)1 Confirmed overall response rate assessed by BIRC.2 Based on observed duration of response.+ Denotes ongoing response.RETEVMO(n 15)Overall Response Rate1 (95% CI)53% (27, 79) Complete response27% Partial response27%Duration of Response Median in months (range)Not reached (12.9+, 44.2) with >= 18 months2 88% with >= 24 months2 75%. 14.4 Other RET Fusion-Positive Solid Tumors. LIBRETTO-001The efficacy of RETEVMO was evaluated in patients with locally advanced or metastatic RET fusion-positive solid tumors enrolled in multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128) and supported by results in RET fusion-positive NSCLC and RET fusion-positive thyroid cancer [see Clinical Studies (14.1, 14.3)]. Efficacy was evaluated in 75 patients with RET fusion-positive tumors other than NSCLC and thyroid cancer with disease progression on or following prior systemic treatment or who had no satisfactory alternative treatment options.The median age was 59 years (range 21 to 92), 51% were female, 60% were White, 35% were Asian, and 4% were Black; and 4% were Hispanic/Latino. ECOG performance status was 0-1 (91%) or (9%) and 96% of patients had metastatic disease. Sixty-nine patients (92%) received prior systemic therapy (median [range - 9]; 36% received or more). The most common cancers were colorectal (29%), pancreatic adenocarcinoma (24%), salivary, cholangiocarcinoma, and sarcoma (7% each). RET fusion-positive status was detected in 92% of patients using NGS and 1.3% using FISH.Efficacy results for RET fusion-positive solid tumors other than NSCLC and thyroid cancer are summarized in Table 26 and Table 27.Table 26: Efficacy Results in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors)1 Confirmed overall response rate assessed by BIRC.2 Based on observed duration of response.RETEVMO(n 75)Overall Response Rate1 (95% CI)47% (35, 59) Complete response5% Partial response41%Duration of Response Median in months (95% CI)24.5 (11.2, 49.1) with >=12 months2 54% with >= 24 months2 34%Table 27: Efficacy Results by Tumor Type in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors)+ denotes ongoing response.1 Confirmed overall response rate assessed by BIRC.2 Best overall response for each patient is presented for tumor types with <=2 patients.CI confidence interval, CR complete response, DOR duration of response, NA not applicable, NE not evaluable, ORR overall response rate, PR partial response, SD stable disease.Tumor TypePatients(n 75)ORR1,2DORRange (months)n (%)95% CIColorectal2210 (45%)(24, 68)4.6, 36.1+Pancreatic adenocarcinoma189 (50%)(26, 74)2.5, 52.1Salivary53 (60%)(15, 95)5.7, 37.2Sarcoma (soft tissue)52 (40%)(5, 85)3.7, 56.5+Cholangiocarcinoma52 (40%)(5, 85)7.4, 14.8Carcinoma of the skin31 (33%)(0.8, 91)27.1Unknown primary31 (33%)(0.8, 91)9.2Breast2PR, CRNA2.3+, 17.3Xanthogranuloma2NE, NENANACarcinoid (bronchial)1PRNA49.1Gastroesophageal junction1SDNANANeuroendocrine1PRNA23.1Ovarian1PRNA28.6+Pancreatic neuroendocrine1PRNA17.5+Pulmonary carcinosarcoma1NENANARectal neuroendocrine1NENANASmall cell lung cancer1SDNANASmall intestine1CRNA24.5Stomach1SDNANA. LIBRETTO-121The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792) [see Clinical Studies (14.2)]. Efficacy was evaluated in patients with locally advanced refractory RET-fusion positive other solid tumors who were unresponsive to available therapies or had no standard systemic curative therapy available. The median age was 15 years (range to 15). One patient with congenital infantile fibrosarcoma and one patient with spindle cell sarcoma had partial response. One patient with malignant peripheral nerve sheath tumor did not respond. Responses were observed in patients with RET fusion-positive thyroid cancer [see Clinical Studies (14.3)].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as single agent administered at 160 mg orally twice daily evaluated in 857 patients with advanced solid tumors in LIBRETTO-001 [see Clinical Studies (14)].. RETGene Fusion or Gene Mutation Positive Solid Tumors. LIBRETTO-001Among the 857 patients who received RETEVMO, 74% were exposed for 12 months or longer and 57% were exposed for 24 months or longer. Among these patients, 97% 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); 0.2% were pediatric patients 12 to 16 years of age; 51% were male; and 68% were White, 24% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino. The most common tumors were NSCLC (43%), MTC (39%), and non-medullary thyroid carcinoma (8%).Serious adverse reactions occurred in 58% of patients who received RETEVMO. The most frequent serious adverse reactions (>=2% of patients) were pneumonia, hemorrhage, abdominal pain, dyspnea, pleural effusion, sepsis, musculoskeletal pain, hyponatremia, vomiting, diarrhea, and increased blood creatinine. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n 6), respiratory failure (n 5), hemorrhage (n 4), pneumonia (n 4), cardiac arrest (n=3), pneumonitis, cardiac failure (n=2 each), sudden death, cerebral infarction and dyspnea (n 1 each).Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in >=0.5% of patients included increased ALT (0.7%), fatigue (0.6%), sepsis (0.5%), pneumonia (0.5%), and increased AST (0.5%).Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in >=5% of patients included increased ALT, increased AST, diarrhea, hypertension, and QT prolongation.Dose reductions due to an adverse reaction occurred in 45% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in >=2% of patients included increased ALT, increased AST, fatigue, QT prolongation, diarrhea, drug hypersensitivity, and ascites.The most common adverse reactions (>=25%) were musculoskeletal pain, edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, rash, nausea, constipation, headache, vomiting, cough, dyspnea, and hemorrhage.The most common Grade or laboratory abnormalities (>=5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), decreased sodium, increased aspartate aminotransferase (AST), decreased calcium, and decreased phosphate.Table summarizes the adverse reactions in LIBRETTO-001.Table 6: Adverse Reactions (>=20%) in Patients Who Received RETEVMO in LIBRETTO-001Adverse ReactionRETEVMO(n 857)Grades 1-4(%)Grades 3-4(%)1 Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal pain, neck pain, musculoskeletal chest pain, non-cardiac chest pain, bone pain, musculoskeletal stiffness, spinal pain.2 Edema includes edema peripheral, face edema, periorbital edema, eye edema, eyelid edema, orbital edema, localized edema, lymphedema, scrotal edema, peripheral swelling, scrotal swelling, swelling, swelling face, eye swelling, generalized edema, genital edema, angioedema, penile edema, skin edema, testicular swelling, vulvovaginal swelling3 Fatigue includes asthenia, malaise.4 Diarrhea includes defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence.5 Dry mouth includes mucosal dryness6 Abdominal pain includes abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain.7 Vomiting includes regurgitation, retching.8 Hypertension includes blood pressure increased9 Rash includes skin exfoliation, rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular, dermatitis, urticaria, dermatitis allergic, rash pustular.10 Cough includes productive cough, upper airway cough syndrome11 Dyspnea includes dyspnea exertional, dyspnea at rest12 Headache includes sinus headache, tension headache.13 Dizziness includes vertigo, presyncope, dizziness postural.14 Hemorrhage includes epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, international normalized ratio increased, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, hematocrit decreased, gastric hemorrhage, hemorrhage intracranial, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, arterial hemorrhage, coagulopathy, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye contusion, eye hematoma, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemothorax, hemorrhoidal hemorrhage, hepatic hemorrhage, menorrhagia, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, esophageal hemorrhage, post procedural hemorrhage, postmenopausal hemorrhage, pulmonary hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, activated partial thromboplastin time prolonged, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, subdural hematoma, testicular hemorrhage, tracheal hemorrhage, traumatic hemothorax, tumor hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma.15 Prolonged QT interval includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal. Only includes grade adverse reaction. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain1 594.1General Disorders and Administration Site ConditionsEdema2 531.3Fatigue3 494.7Gastrointestinal DisordersDiarrhea4 526.2Dry mouth5 440Abdominal pain6 393.5Nausea361.9Constipation350.8Vomiting7 292.9Vascular DisordersHypertension8 4320Skin and Subcutaneous Tissue DisordersRash9 380.8Respiratory, Thoracic and Mediastinal DisordersCough10 300Dyspnea11 284.1Nervous System DisordersHeadache12 301.8Dizziness13 220.5Blood and Lymphatic System DisordersHemorrhage14 263.9Metabolism and Nutrition DisordersDecreased appetite230.9InvestigationsProlonged QT interval15 215Infections and InfestationsUrinary tract infection202.2 Clinically relevant adverse reactions in <=15% of patients who received RETEVMO include hypothyroidism (15%); pneumonia (14%), hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all 3%).Table summarizes the laboratory abnormalities in LIBRETTO-001.Table 7: Select Laboratory Abnormalities (>=20%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-0011 Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available, which ranged from 823 to 855 patients. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03Laboratory AbnormalityRETEVMO1Grades 1-4(%)Grades 3-4(%)ChemistryIncreased AST6211Decreased calcium617Decreased albumin613.6Increased ALT5813Increased glucose564.0Increased creatinine513.6Decreased sodium4913Increased alkaline phosphatase434.4Increased potassium393.5Decreased glucose391.5Increased total cholesterol371.7Decreased magnesium370.7Increased bilirubin322.9Decreased phosphate255HematologyDecreased lymphocytes5622Decreased platelets414.0Decreased hemoglobin364.1Decreased neutrophils273.8. LIBRETTO-121The safety population described below reflects exposure to RETEVMO as single agent at 92 mg/m2 orally twice daily evaluated in 36 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121 [see Clinical Studies (14)]. Among the 36 pediatric and adolescent patients who received RETEVMO, 86% were exposed for months or longer and 72% were exposed for greater than one year.The median age was 13 years (range: to 20 years); 31% were pediatric patients to 12 years of age; 53% were male; and 47% were White, 28% were Asian, and 8% were Black or African American; and 19% were Hispanic/Latino. The most common cancers were MTC (42%), and papillary thyroid cancer (42%).Serious adverse reactions occurred in 42% of patients who received RETEVMO. Serious adverse reactions occurring in more than patient were vomiting and fracture (2 patients each).Dosage interruptions due to an adverse reaction occurred in 42% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in >=5% of patients included increased ALT, increased AST, ascites, increased bilirubin, decreased neutrophils, and pyrexia.Dose reductions due to an adverse reaction occurred in 22% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in >=2% of patients included increased ALT, decreased neutrophils, increased weight, and increased bilirubin.The most common adverse reactions (>=25%) were musculoskeletal pain, diarrhea, nausea, hemorrhage, pyrexia, abdominal pain, headache, vomiting, fatigue, cough, rash, coronavirus infection, upper respiratory tract infection, and edema.The most common Grade or laboratory abnormalities (>=5%) were decreased lymphocytes, decreased calcium, decreased hemoglobin, decreased neutrophils, increased ALT, decreased magnesium, and decreased potassium.Table summarizes the adverse reactions in LIBRETTO-121.Table 8: Adverse Reactions (>=15%) in Patients Who Received RETEVMO in LIBRETTO-121Adverse ReactionsRETEVMON= 36Grades 1-4%Grades 3-4%1 Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, non-cardiac chest pain, neck pain, pain in extremity2 Diarrhea includes anal incontinence3 Abdominal pain includes abdominal pain upper, abdominal discomfort4 Hemorrhage includes epistaxis, hematuria, anal hemorrhage, blood urine present, hemoptysis, menorrhagia, mouth hemorrhage5 Fatigue includes asthenia, malaise6 Edema includes face edema, edema peripheral, periorbital edema, localized edema, generalized edema, gastrointestinal edema, swelling7 Rash includes rash maculopapular, rash erythematous, urticaria8 Urinary tract infection includes cystitis9 Hypothyroidism includes blood thyroid stimulating hormone increased, thyroglobulin increased No Grade events were reported. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain1 580Gastrointestinal DisordersDiarrhea2 472.8Nausea422.8Abdominal pain3 360Vomiting318Constipation226 Blood and Lymphatic System DisordersHemorrhage4 390General Disorders and Administration Site ConditionsPyrexia390Fatigue5 310Edema6 250Nervous System DisordersHeadache330Respiratory, Thoracic and Mediastinal DisordersCough310Oropharyngeal pain220Skin and Subcutaneous Tissue DisordersRash7 280Infections and InfestationsCoronavirus infection280Upper respiratory tract infection282.8Urinary tract infection8 192.8Endocrine DisordersHypothyroidism9 220InvestigationsIncreased weight1911Clinically relevant adverse reactions in <15% of patients who received RETEVMO include dizziness (14%), electrocardiogram QT prolonged (14%), hypersensitivity (11%), stomatitis (14%), proteinuria (11%), hypertension (8%), decreased appetite (8%), erectile dysfunction (6%), chylous ascites (2.8%), dry mouth (2.8%), epiphysiolysis (2.8%), and pneumonia (2.8%).Table summarizes the laboratory abnormalities in LIBRETTO-121.Table 9: Select Laboratory Abnormalities (>=15%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-1211 Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available, which ranged from 18 to 36 patients. No Grade abnormalities were reported. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.Laboratory AbnormalityRETEVMO1Grades 1-4(%)Grades 3-4(%)ChemistryDecreased calcium6111Increased ALT588Decreased albumin530Increased alkaline phosphatase500Increased AST502.8Increased bilirubin312.8Increased cholesterol280Decreased magnesium286Increased potassium282.8Increased creatinine192.8Decreased potassium196Decreased sodium170HematologyDecreased neutrophils408Decreased hemoglobin3611Increased hemoglobin332.8Decreased platelets282.8Decreased lymphocytes2814. Treatment-naive RET Fusion-Positive Non-Small Cell Lung Cancer. LIBRETTO-431The safety population described below reflects exposure to RETEVMO as single agent administered at 160 mg orally twice daily evaluated in 158 patients with unresectable locally advanced or metastatic RET fusion-positive NSCLC in LIBRETTO-431 [see Clinical Studies (14)]. Among the 158 patients who received RETEVMO, the median duration of exposure was 16.7 months (range: days to 37.9 months); 87% were exposed for months or longer and 70% were exposed for one year or longer.The median age was 61 years (range: 31 to 87 years); 46% were male; and 36% were White, 58% were Asian, 1.3% were Black or African American, 1.3% were American Indian or Alaska Native, and 3.2% were missing.Serious adverse reactions occurred in 35% of patients who received RETEVMO. The most frequent serious adverse reactions (>=2% of patients) were pleural effusion, and abnormal hepatic function. Fatal adverse reactions occurred in 4.4% of patients who received RETEVMO; fatal adverse reactions included myocardial infarction (n 2), respiratory failure (n 2), cardiac arrest, malnutrition, and sudden death (n 1, each).Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in >=1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%).Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in >=5% of patients included increased ALT, hypertension, increased AST, QT prolongation, diarrhea, and COVID-19 infection.Dose reductions due to an adverse reaction occurred in 51% of patients who received RETEVMO. Adverse reactions requiring dose reductions in >=5% of patients included increased ALT, increased AST, QT prolongation.The most common adverse reactions (>=25%) in patients who received RETEVMO were hypertension, diarrhea, edema, dry mouth, rash, fatigue, abdominal pain, and musculoskeletal pain.The most common Grade or laboratory abnormalities (>=5%) in patients who received RETEVMO were increased ALT, increased AST, and decreased lymphocytes.Table 10 summarizes the adverse reactions in LIBRETTO-431.Table 10: Adverse Reactions (>=15%) in Patients on Either Arm in LIBRETTO-4311 Diarrhea includes diarrhea, anal incontinence.2 Dry mouth includes dry mouth, mucosal dryness.3 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain.4 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation.5 Vomiting includes vomiting, retching, regurgitation.6 Edema includes edema, edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, orbital edema, eye edema, scrotal edema, penile edema, orbital swelling, periorbital swelling.7 Fatigue includes fatigue, asthenia, malaise.8 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash papular, dermatitis allergic, rash pustular, rash vesicular, genital rash.9 Musculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, musculoskeletal chest pain, non-cardiac chest pain, neck pain, pain in extremity. No Grade abnormalities were reported. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.Adverse ReactionRETEVMO(n=158)Chemotherapywith or without pembrolizumab(n=98)Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Vascular disordersHypertension482073.1Gastrointestinal disordersDiarrhea1 441.3242.0Dry mouth2 39060Abdominal pain3 250.6192.0Constipation220401.0Stomatitis4 180160Nausea130441.0Vomiting5 130231.0General disorders and administration site conditionsEdema6 412.5280Fatigue7 323.2505Pyrexia130.6230Skin and subcutaneous tissue disordersRash8 331.9301.0Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain9 250280InvestigationsElectrocardiogram QT prolonged2091.00Infections and infestationsCOVID-19 infection190.6180Metabolism and nutrition disordersDecreased appetite170342.0Clinically relevant adverse reactions in <15% of patients who received RETEVMO include headache (14%); hemorrhage (13%); urinary tract infections (12%); hypothyroidism (9%); pneumonia (9%); dizziness (8%); interstitial lung disease/pneumonitis (4.4%); hypersensitivity, chylous ascites, and chylothorax (all 2%).Table 11 summarizes the laboratory abnormalities in LIBRETTO-431.Table 11: Select Laboratory Abnormalities (>=20%) Worsening from Baseline in Patients on Either Arm in LIBRETTO-431Laboratory Abnormality1RETEVMOChemotherapywith or without pembrolizumabGrades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)1 Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available: RETEVMO (range: 154 to 157 patients) and chemotherapy with or without pembrolizumab (range: 96 to 97 patients). Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.ChemistryALT increased8121634.1AST increased7710460Alkaline phosphatase Increased351.3220Total bilirubin Increased521.390Blood creatinine Increased230210Magnesium decreased160.680Albumin decreased25050Calcium decreased531.9241.0Sodium decreased313.2412.1Potassium decreased171.3151.0HematologyPlatelets decreased533.2395Lymphocyte count decreased5386415Hemoglobin decreased210915Neutrophil count decreased532.05811. Increased CreatinineIn healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].. RET-Mutant Medullary Thyroid Cancer. LIBRETTO-531The safety population described below reflects exposure to RETEVMO as single agent administered at 160 mg (adults) or at 92 mg/m2 (adolescent, not to exceed 160 mg) orally twice daily, in patients with progressive, advanced, kinase inhibitor naive, RET-mutant medullary thyroid cancer in LIBRETTO-531 [see Clinical Studies (14.2)]. Among the 193 patients who received RETEVMO, the observed median duration of exposure was 14.5 months (range: 25 days to 36 months); 80% were exposed for months or longer and 59% were exposed for one year or longer.The median age was 55 years (range: 12 to 84 years); 63% were male; and 69% were White, 28% were Asian, 2.9% were Black or African American and ethnicity was not routinely collected.Serious adverse reactions occurred in 22% of patients who received RETEVMO. The most frequent serious adverse reactions were pneumonia and pyrexia (n 3, each) and hypertension and urinary tract infection (n 2, each). Fatal adverse reactions occurred in 2.1% of patients; fatal adverse reactions included COVID-19, diabetic ketoacidosis, multiple organ dysfunction syndrome, and sudden death (n=1 each).Permanent discontinuation due to an adverse reaction occurred in 4.7% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation were edema, multiple organ dysfunction syndrome, sudden death, AST increased, diabetic ketoacidosis, chronic kidney disease, retinopathy, COVID-19, and somatic symptom disorder (n 1, each).Dosage interruptions due to an adverse reaction occurred in 49% of patients who received RETEVMO. Adverse reactions requiring dosage omission in >=5% of patients included ALT increased (9%) and hypertension (7%).Dose reductions due to an adverse reaction occurred in 39% of patients who received RETEVMO. One adverse reaction, increased ALT (7%), required dose reduction in >=5% of patients.The most common adverse reactions (>=25%) in patients who received RETEVMO were hypertension, edema, dry mouth, fatigue, and diarrhea.The most common Grade or laboratory abnormalities (>=5%) in patients who received RETEVMO were decreased lymphocytes, increased ALT, decreased neutrophils, increased ALP, increased blood creatinine, decreased calcium, and increased AST.Table 12 summarizes the adverse reactions in LIBRETTO-531.Table 12: Adverse Reactions (>=10%) in Patients Who Received RETEVMO in LIBRETTO-5311 Hypertension includes hypertension, blood pressure increased.2 Edema includes edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, generalized edema, eye swelling, lymphoedema, orbital edema, eye edema, edema, edema genital, swelling, scrotal edema, scrotal swelling, angioedema, skin edema, testicular swelling, vulvovaginal swelling.3 Fatigue includes fatigue, asthenia, malaise.4 Dry mouth includes dry mouth, mucosal dryness.5 Diarrhea includes diarrhea, anal incontinence, defecation urgency, frequent bowel movements, gastrointestinal hypermotility.6 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain.7 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation.8 Headache includes headache, sinus headache, tension headache.9 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash pruritic, exfoliative rash, rash papular, dermatitis allergic, rash follicular, rash generalized, rash pustular, butterfly rash, rash morbilliform, rash vesicular.10 Electrocardiogram QT prolongation includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal.11 Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased. Only includes Grade adverse reaction Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.Adverse ReactionRETEVMON 193Cabozantinib or VandetanibN 97Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Vascular disordersHypertension1 43194118General disorders and administration-site conditionsEdema2 33050Fatigue3 284.1479Pyrexia121.02.10Gastrointestinal disordersDry mouth4 320.5101.0Diarrhea5 263.1618Abdominal pain6 180.5212.1Constipation160120Stomatitis7 140.54213Nausea101.0325Nervous system disordersHeadache8 230.5210Skin and subcutaneous tissue disordersRash9 191.6274.1Reproductive system and breast disordersErectile dysfunction16000InvestigationsElectrocardiogram QT prolonged10 144.7132.1Metabolism and nutrition disordersDecreased appetite120.5285Endocrine disordersHypothyroidism11 110210Clinically relevant adverse reactions in <=10% of patients who received RETEVMO include dizziness (8%); urinary tract infections (8%); vomiting (8%); pneumonia, interstitial lung disease/pneumonitis, chylous ascites, and hypersensitivity (all 2%).Table 13 summarizes the laboratory abnormalities in LIBRETTO-531.Table 13: Select Laboratory Abnormalities (>=5%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-531Laboratory AbnormalityRETEVMO1Cabozantinib or Vandetanib1Grades 1-4%Grades 3-4%Grades 1-4%Grades 3-4%1 Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available: RETEVMO (range: 183 to 191 patients) and chemotherapy with or without cabozantinib or vandetanib (range: 91 to 94 patients). Only includes Grade laboratory abnormality Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0ChemistryCalcium decreased5556211ALT increased5316727AST increased475683.2Alkaline phosphatase increased376285Total bilirubin increased321.1303.2Blood creatinine increased276168Sodium decreased203.2160Albumin decreased111.170Magnesium decreased93.3269Potassium decreased80224.4HematologyLymphocyte count decreased41183613Neutrophil count decreased33144219Platelets decreased281.1341.1Hemoglobin decreased182.1232.1. Increased CreatinineIn healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Hepatotoxicity [see Warnings and Precautions (5.1)] Interstitial Lung Disease Pneumonitis [see Warnings and Precautions (5.2)] Hypertension [see Warnings and Precautions (5.3)] QT Interval Prolongation [see Warnings and Precautions (5.4)] Hemorrhagic Events [see Warnings and Precautions (5.5)] Hypersensitivity [see Warnings and Precautions (5.6)] Tumor Lysis Syndrome [see Warnings and Precautions (5.7)] Risk of Impaired Wound Healing [see Warnings and Precautions (5.8)] Hypothyroidism [see Warnings and Precautions (5.9)] Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Adolescent Patients [see Warnings and Precautions (5.11)] Hepatotoxicity [see Warnings and Precautions (5.1)] Interstitial Lung Disease Pneumonitis [see Warnings and Precautions (5.2)] Hypertension [see Warnings and Precautions (5.3)] QT Interval Prolongation [see Warnings and Precautions (5.4)] Hemorrhagic Events [see Warnings and Precautions (5.5)] Hypersensitivity [see Warnings and Precautions (5.6)] Tumor Lysis Syndrome [see Warnings and Precautions (5.7)] Risk of Impaired Wound Healing [see Warnings and Precautions (5.8)] Hypothyroidism [see Warnings and Precautions (5.9)] Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Adolescent Patients [see Warnings and Precautions (5.11)] The most common adverse reactions (>=25%) include:Adult patients with solid tumors: musculoskeletal pain, edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, rash, nausea, constipation, cough, headache, vomiting, dyspnea, and hemorrhage. (6)Pediatric patients with solid tumors: musculoskeletal pain, diarrhea, nausea, hemorrhage, pyrexia, abdominal pain, headache, vomiting, fatigue, cough, rash, coronavirus infection, upper respiratory tract infection, and edema. (6)The most common Grade or laboratory abnormalities (>=5%) include:Adult patients with solid tumors: decreased lymphocytes, increased alanine aminotransferase (ALT), decreased sodium, increased aspartate aminotransferase (AST), decreased calcium, and decreased phosphate. (6)Pediatric patients with solid tumors: decreased lymphocytes, decreased calcium, decreased hemoglobin, decreased neutrophils, increased alanine aminotransferase, decreased magnesium, and decreased potassium. (6)To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Adult patients with solid tumors: musculoskeletal pain, edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, rash, nausea, constipation, cough, headache, vomiting, dyspnea, and hemorrhage. (6). Pediatric patients with solid tumors: musculoskeletal pain, diarrhea, nausea, hemorrhage, pyrexia, abdominal pain, headache, vomiting, fatigue, cough, rash, coronavirus infection, upper respiratory tract infection, and edema. (6). Adult patients with solid tumors: decreased lymphocytes, increased alanine aminotransferase (ALT), decreased sodium, increased aspartate aminotransferase (AST), decreased calcium, and decreased phosphate. (6). Pediatric patients with solid tumors: decreased lymphocytes, decreased calcium, decreased hemoglobin, decreased neutrophils, increased alanine aminotransferase, decreased magnesium, and decreased potassium. (6). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as single agent administered at 160 mg orally twice daily evaluated in 857 patients with advanced solid tumors in LIBRETTO-001 [see Clinical Studies (14)].. RETGene Fusion or Gene Mutation Positive Solid Tumors. LIBRETTO-001Among the 857 patients who received RETEVMO, 74% were exposed for 12 months or longer and 57% were exposed for 24 months or longer. Among these patients, 97% 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); 0.2% were pediatric patients 12 to 16 years of age; 51% were male; and 68% were White, 24% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino. The most common tumors were NSCLC (43%), MTC (39%), and non-medullary thyroid carcinoma (8%).Serious adverse reactions occurred in 58% of patients who received RETEVMO. The most frequent serious adverse reactions (>=2% of patients) were pneumonia, hemorrhage, abdominal pain, dyspnea, pleural effusion, sepsis, musculoskeletal pain, hyponatremia, vomiting, diarrhea, and increased blood creatinine. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n 6), respiratory failure (n 5), hemorrhage (n 4), pneumonia (n 4), cardiac arrest (n=3), pneumonitis, cardiac failure (n=2 each), sudden death, cerebral infarction and dyspnea (n 1 each).Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in >=0.5% of patients included increased ALT (0.7%), fatigue (0.6%), sepsis (0.5%), pneumonia (0.5%), and increased AST (0.5%).Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in >=5% of patients included increased ALT, increased AST, diarrhea, hypertension, and QT prolongation.Dose reductions due to an adverse reaction occurred in 45% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in >=2% of patients included increased ALT, increased AST, fatigue, QT prolongation, diarrhea, drug hypersensitivity, and ascites.The most common adverse reactions (>=25%) were musculoskeletal pain, edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, rash, nausea, constipation, headache, vomiting, cough, dyspnea, and hemorrhage.The most common Grade or laboratory abnormalities (>=5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), decreased sodium, increased aspartate aminotransferase (AST), decreased calcium, and decreased phosphate.Table summarizes the adverse reactions in LIBRETTO-001.Table 6: Adverse Reactions (>=20%) in Patients Who Received RETEVMO in LIBRETTO-001Adverse ReactionRETEVMO(n 857)Grades 1-4(%)Grades 3-4(%)1 Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal pain, neck pain, musculoskeletal chest pain, non-cardiac chest pain, bone pain, musculoskeletal stiffness, spinal pain.2 Edema includes edema peripheral, face edema, periorbital edema, eye edema, eyelid edema, orbital edema, localized edema, lymphedema, scrotal edema, peripheral swelling, scrotal swelling, swelling, swelling face, eye swelling, generalized edema, genital edema, angioedema, penile edema, skin edema, testicular swelling, vulvovaginal swelling3 Fatigue includes asthenia, malaise.4 Diarrhea includes defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence.5 Dry mouth includes mucosal dryness6 Abdominal pain includes abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain.7 Vomiting includes regurgitation, retching.8 Hypertension includes blood pressure increased9 Rash includes skin exfoliation, rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular, dermatitis, urticaria, dermatitis allergic, rash pustular.10 Cough includes productive cough, upper airway cough syndrome11 Dyspnea includes dyspnea exertional, dyspnea at rest12 Headache includes sinus headache, tension headache.13 Dizziness includes vertigo, presyncope, dizziness postural.14 Hemorrhage includes epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, international normalized ratio increased, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, hematocrit decreased, gastric hemorrhage, hemorrhage intracranial, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, arterial hemorrhage, coagulopathy, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye contusion, eye hematoma, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemothorax, hemorrhoidal hemorrhage, hepatic hemorrhage, menorrhagia, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, esophageal hemorrhage, post procedural hemorrhage, postmenopausal hemorrhage, pulmonary hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, activated partial thromboplastin time prolonged, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, subdural hematoma, testicular hemorrhage, tracheal hemorrhage, traumatic hemothorax, tumor hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma.15 Prolonged QT interval includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal. Only includes grade adverse reaction. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain1 594.1General Disorders and Administration Site ConditionsEdema2 531.3Fatigue3 494.7Gastrointestinal DisordersDiarrhea4 526.2Dry mouth5 440Abdominal pain6 393.5Nausea361.9Constipation350.8Vomiting7 292.9Vascular DisordersHypertension8 4320Skin and Subcutaneous Tissue DisordersRash9 380.8Respiratory, Thoracic and Mediastinal DisordersCough10 300Dyspnea11 284.1Nervous System DisordersHeadache12 301.8Dizziness13 220.5Blood and Lymphatic System DisordersHemorrhage14 263.9Metabolism and Nutrition DisordersDecreased appetite230.9InvestigationsProlonged QT interval15 215Infections and InfestationsUrinary tract infection202.2 Clinically relevant adverse reactions in <=15% of patients who received RETEVMO include hypothyroidism (15%); pneumonia (14%), hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all 3%).Table summarizes the laboratory abnormalities in LIBRETTO-001.Table 7: Select Laboratory Abnormalities (>=20%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-0011 Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available, which ranged from 823 to 855 patients. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03Laboratory AbnormalityRETEVMO1Grades 1-4(%)Grades 3-4(%)ChemistryIncreased AST6211Decreased calcium617Decreased albumin613.6Increased ALT5813Increased glucose564.0Increased creatinine513.6Decreased sodium4913Increased alkaline phosphatase434.4Increased potassium393.5Decreased glucose391.5Increased total cholesterol371.7Decreased magnesium370.7Increased bilirubin322.9Decreased phosphate255HematologyDecreased lymphocytes5622Decreased platelets414.0Decreased hemoglobin364.1Decreased neutrophils273.8. LIBRETTO-121The safety population described below reflects exposure to RETEVMO as single agent at 92 mg/m2 orally twice daily evaluated in 36 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121 [see Clinical Studies (14)]. Among the 36 pediatric and adolescent patients who received RETEVMO, 86% were exposed for months or longer and 72% were exposed for greater than one year.The median age was 13 years (range: to 20 years); 31% were pediatric patients to 12 years of age; 53% were male; and 47% were White, 28% were Asian, and 8% were Black or African American; and 19% were Hispanic/Latino. The most common cancers were MTC (42%), and papillary thyroid cancer (42%).Serious adverse reactions occurred in 42% of patients who received RETEVMO. Serious adverse reactions occurring in more than patient were vomiting and fracture (2 patients each).Dosage interruptions due to an adverse reaction occurred in 42% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in >=5% of patients included increased ALT, increased AST, ascites, increased bilirubin, decreased neutrophils, and pyrexia.Dose reductions due to an adverse reaction occurred in 22% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in >=2% of patients included increased ALT, decreased neutrophils, increased weight, and increased bilirubin.The most common adverse reactions (>=25%) were musculoskeletal pain, diarrhea, nausea, hemorrhage, pyrexia, abdominal pain, headache, vomiting, fatigue, cough, rash, coronavirus infection, upper respiratory tract infection, and edema.The most common Grade or laboratory abnormalities (>=5%) were decreased lymphocytes, decreased calcium, decreased hemoglobin, decreased neutrophils, increased ALT, decreased magnesium, and decreased potassium.Table summarizes the adverse reactions in LIBRETTO-121.Table 8: Adverse Reactions (>=15%) in Patients Who Received RETEVMO in LIBRETTO-121Adverse ReactionsRETEVMON= 36Grades 1-4%Grades 3-4%1 Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, non-cardiac chest pain, neck pain, pain in extremity2 Diarrhea includes anal incontinence3 Abdominal pain includes abdominal pain upper, abdominal discomfort4 Hemorrhage includes epistaxis, hematuria, anal hemorrhage, blood urine present, hemoptysis, menorrhagia, mouth hemorrhage5 Fatigue includes asthenia, malaise6 Edema includes face edema, edema peripheral, periorbital edema, localized edema, generalized edema, gastrointestinal edema, swelling7 Rash includes rash maculopapular, rash erythematous, urticaria8 Urinary tract infection includes cystitis9 Hypothyroidism includes blood thyroid stimulating hormone increased, thyroglobulin increased No Grade events were reported. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain1 580Gastrointestinal DisordersDiarrhea2 472.8Nausea422.8Abdominal pain3 360Vomiting318Constipation226 Blood and Lymphatic System DisordersHemorrhage4 390General Disorders and Administration Site ConditionsPyrexia390Fatigue5 310Edema6 250Nervous System DisordersHeadache330Respiratory, Thoracic and Mediastinal DisordersCough310Oropharyngeal pain220Skin and Subcutaneous Tissue DisordersRash7 280Infections and InfestationsCoronavirus infection280Upper respiratory tract infection282.8Urinary tract infection8 192.8Endocrine DisordersHypothyroidism9 220InvestigationsIncreased weight1911Clinically relevant adverse reactions in <15% of patients who received RETEVMO include dizziness (14%), electrocardiogram QT prolonged (14%), hypersensitivity (11%), stomatitis (14%), proteinuria (11%), hypertension (8%), decreased appetite (8%), erectile dysfunction (6%), chylous ascites (2.8%), dry mouth (2.8%), epiphysiolysis (2.8%), and pneumonia (2.8%).Table summarizes the laboratory abnormalities in LIBRETTO-121.Table 9: Select Laboratory Abnormalities (>=15%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-1211 Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available, which ranged from 18 to 36 patients. No Grade abnormalities were reported. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.Laboratory AbnormalityRETEVMO1Grades 1-4(%)Grades 3-4(%)ChemistryDecreased calcium6111Increased ALT588Decreased albumin530Increased alkaline phosphatase500Increased AST502.8Increased bilirubin312.8Increased cholesterol280Decreased magnesium286Increased potassium282.8Increased creatinine192.8Decreased potassium196Decreased sodium170HematologyDecreased neutrophils408Decreased hemoglobin3611Increased hemoglobin332.8Decreased platelets282.8Decreased lymphocytes2814. Treatment-naive RET Fusion-Positive Non-Small Cell Lung Cancer. LIBRETTO-431The safety population described below reflects exposure to RETEVMO as single agent administered at 160 mg orally twice daily evaluated in 158 patients with unresectable locally advanced or metastatic RET fusion-positive NSCLC in LIBRETTO-431 [see Clinical Studies (14)]. Among the 158 patients who received RETEVMO, the median duration of exposure was 16.7 months (range: days to 37.9 months); 87% were exposed for months or longer and 70% were exposed for one year or longer.The median age was 61 years (range: 31 to 87 years); 46% were male; and 36% were White, 58% were Asian, 1.3% were Black or African American, 1.3% were American Indian or Alaska Native, and 3.2% were missing.Serious adverse reactions occurred in 35% of patients who received RETEVMO. The most frequent serious adverse reactions (>=2% of patients) were pleural effusion, and abnormal hepatic function. Fatal adverse reactions occurred in 4.4% of patients who received RETEVMO; fatal adverse reactions included myocardial infarction (n 2), respiratory failure (n 2), cardiac arrest, malnutrition, and sudden death (n 1, each).Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in >=1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%).Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in >=5% of patients included increased ALT, hypertension, increased AST, QT prolongation, diarrhea, and COVID-19 infection.Dose reductions due to an adverse reaction occurred in 51% of patients who received RETEVMO. Adverse reactions requiring dose reductions in >=5% of patients included increased ALT, increased AST, QT prolongation.The most common adverse reactions (>=25%) in patients who received RETEVMO were hypertension, diarrhea, edema, dry mouth, rash, fatigue, abdominal pain, and musculoskeletal pain.The most common Grade or laboratory abnormalities (>=5%) in patients who received RETEVMO were increased ALT, increased AST, and decreased lymphocytes.Table 10 summarizes the adverse reactions in LIBRETTO-431.Table 10: Adverse Reactions (>=15%) in Patients on Either Arm in LIBRETTO-4311 Diarrhea includes diarrhea, anal incontinence.2 Dry mouth includes dry mouth, mucosal dryness.3 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain.4 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation.5 Vomiting includes vomiting, retching, regurgitation.6 Edema includes edema, edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, orbital edema, eye edema, scrotal edema, penile edema, orbital swelling, periorbital swelling.7 Fatigue includes fatigue, asthenia, malaise.8 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash papular, dermatitis allergic, rash pustular, rash vesicular, genital rash.9 Musculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, musculoskeletal chest pain, non-cardiac chest pain, neck pain, pain in extremity. No Grade abnormalities were reported. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.Adverse ReactionRETEVMO(n=158)Chemotherapywith or without pembrolizumab(n=98)Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Vascular disordersHypertension482073.1Gastrointestinal disordersDiarrhea1 441.3242.0Dry mouth2 39060Abdominal pain3 250.6192.0Constipation220401.0Stomatitis4 180160Nausea130441.0Vomiting5 130231.0General disorders and administration site conditionsEdema6 412.5280Fatigue7 323.2505Pyrexia130.6230Skin and subcutaneous tissue disordersRash8 331.9301.0Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain9 250280InvestigationsElectrocardiogram QT prolonged2091.00Infections and infestationsCOVID-19 infection190.6180Metabolism and nutrition disordersDecreased appetite170342.0Clinically relevant adverse reactions in <15% of patients who received RETEVMO include headache (14%); hemorrhage (13%); urinary tract infections (12%); hypothyroidism (9%); pneumonia (9%); dizziness (8%); interstitial lung disease/pneumonitis (4.4%); hypersensitivity, chylous ascites, and chylothorax (all 2%).Table 11 summarizes the laboratory abnormalities in LIBRETTO-431.Table 11: Select Laboratory Abnormalities (>=20%) Worsening from Baseline in Patients on Either Arm in LIBRETTO-431Laboratory Abnormality1RETEVMOChemotherapywith or without pembrolizumabGrades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)1 Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available: RETEVMO (range: 154 to 157 patients) and chemotherapy with or without pembrolizumab (range: 96 to 97 patients). Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.ChemistryALT increased8121634.1AST increased7710460Alkaline phosphatase Increased351.3220Total bilirubin Increased521.390Blood creatinine Increased230210Magnesium decreased160.680Albumin decreased25050Calcium decreased531.9241.0Sodium decreased313.2412.1Potassium decreased171.3151.0HematologyPlatelets decreased533.2395Lymphocyte count decreased5386415Hemoglobin decreased210915Neutrophil count decreased532.05811. Increased CreatinineIn healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].. RET-Mutant Medullary Thyroid Cancer. LIBRETTO-531The safety population described below reflects exposure to RETEVMO as single agent administered at 160 mg (adults) or at 92 mg/m2 (adolescent, not to exceed 160 mg) orally twice daily, in patients with progressive, advanced, kinase inhibitor naive, RET-mutant medullary thyroid cancer in LIBRETTO-531 [see Clinical Studies (14.2)]. Among the 193 patients who received RETEVMO, the observed median duration of exposure was 14.5 months (range: 25 days to 36 months); 80% were exposed for months or longer and 59% were exposed for one year or longer.The median age was 55 years (range: 12 to 84 years); 63% were male; and 69% were White, 28% were Asian, 2.9% were Black or African American and ethnicity was not routinely collected.Serious adverse reactions occurred in 22% of patients who received RETEVMO. The most frequent serious adverse reactions were pneumonia and pyrexia (n 3, each) and hypertension and urinary tract infection (n 2, each). Fatal adverse reactions occurred in 2.1% of patients; fatal adverse reactions included COVID-19, diabetic ketoacidosis, multiple organ dysfunction syndrome, and sudden death (n=1 each).Permanent discontinuation due to an adverse reaction occurred in 4.7% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation were edema, multiple organ dysfunction syndrome, sudden death, AST increased, diabetic ketoacidosis, chronic kidney disease, retinopathy, COVID-19, and somatic symptom disorder (n 1, each).Dosage interruptions due to an adverse reaction occurred in 49% of patients who received RETEVMO. Adverse reactions requiring dosage omission in >=5% of patients included ALT increased (9%) and hypertension (7%).Dose reductions due to an adverse reaction occurred in 39% of patients who received RETEVMO. One adverse reaction, increased ALT (7%), required dose reduction in >=5% of patients.The most common adverse reactions (>=25%) in patients who received RETEVMO were hypertension, edema, dry mouth, fatigue, and diarrhea.The most common Grade or laboratory abnormalities (>=5%) in patients who received RETEVMO were decreased lymphocytes, increased ALT, decreased neutrophils, increased ALP, increased blood creatinine, decreased calcium, and increased AST.Table 12 summarizes the adverse reactions in LIBRETTO-531.Table 12: Adverse Reactions (>=10%) in Patients Who Received RETEVMO in LIBRETTO-5311 Hypertension includes hypertension, blood pressure increased.2 Edema includes edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, generalized edema, eye swelling, lymphoedema, orbital edema, eye edema, edema, edema genital, swelling, scrotal edema, scrotal swelling, angioedema, skin edema, testicular swelling, vulvovaginal swelling.3 Fatigue includes fatigue, asthenia, malaise.4 Dry mouth includes dry mouth, mucosal dryness.5 Diarrhea includes diarrhea, anal incontinence, defecation urgency, frequent bowel movements, gastrointestinal hypermotility.6 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain.7 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation.8 Headache includes headache, sinus headache, tension headache.9 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash pruritic, exfoliative rash, rash papular, dermatitis allergic, rash follicular, rash generalized, rash pustular, butterfly rash, rash morbilliform, rash vesicular.10 Electrocardiogram QT prolongation includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal.11 Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased. Only includes Grade adverse reaction Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.Adverse ReactionRETEVMON 193Cabozantinib or VandetanibN 97Grades 1-4(%)Grades 3-4(%)Grades 1-4(%)Grades 3-4(%)Vascular disordersHypertension1 43194118General disorders and administration-site conditionsEdema2 33050Fatigue3 284.1479Pyrexia121.02.10Gastrointestinal disordersDry mouth4 320.5101.0Diarrhea5 263.1618Abdominal pain6 180.5212.1Constipation160120Stomatitis7 140.54213Nausea101.0325Nervous system disordersHeadache8 230.5210Skin and subcutaneous tissue disordersRash9 191.6274.1Reproductive system and breast disordersErectile dysfunction16000InvestigationsElectrocardiogram QT prolonged10 144.7132.1Metabolism and nutrition disordersDecreased appetite120.5285Endocrine disordersHypothyroidism11 110210Clinically relevant adverse reactions in <=10% of patients who received RETEVMO include dizziness (8%); urinary tract infections (8%); vomiting (8%); pneumonia, interstitial lung disease/pneumonitis, chylous ascites, and hypersensitivity (all 2%).Table 13 summarizes the laboratory abnormalities in LIBRETTO-531.Table 13: Select Laboratory Abnormalities (>=5%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-531Laboratory AbnormalityRETEVMO1Cabozantinib or Vandetanib1Grades 1-4%Grades 3-4%Grades 1-4%Grades 3-4%1 Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available: RETEVMO (range: 183 to 191 patients) and chemotherapy with or without cabozantinib or vandetanib (range: 91 to 94 patients). Only includes Grade laboratory abnormality Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0ChemistryCalcium decreased5556211ALT increased5316727AST increased475683.2Alkaline phosphatase increased376285Total bilirubin increased321.1303.2Blood creatinine increased276168Sodium decreased203.2160Albumin decreased111.170Magnesium decreased93.3269Potassium decreased80224.4HematologyLymphocyte count decreased41183613Neutrophil count decreased33144219Platelets decreased281.1341.1Hemoglobin decreased182.1232.1. Increased CreatinineIn healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].. 6.2 Postmarketing Experience. The following adverse reaction has been identified during post-approval use of RETEVMO. Because such reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Selpercatinib was not carcinogenic in 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in 6-month study in rasH2 transgenic mice when administered by daily oral gavage at doses of up to 60 mg/kg.Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation. Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the Cmax at the human dose of 160 mg twice daily.In general toxicology studies, male rats and minipigs exhibited testicular degeneration which was associated with luminal cell debris and/or reduced luminal sperm in the epididymis at selpercatinib exposures approximately 0.4 (rat) and 0.1 (minipig) times the clinical exposure by AUC at the 160 mg twice daily clinical dose. In dedicated fertility study in male rats, administration of selpercatinib at doses up to 30 mg/kg/day (approximately twice the clinical exposure by AUC at the 160 twice daily clinical dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display dose-dependent increase in testicular germ cell depletion and spermatid retention at doses >=3 mg/kg (~0.2 times the clinical exposure by AUC at the 160 twice daily clinical dose) accompanied by altered sperm morphology at 30 mg/kg.In dedicated fertility study in female rats treated with selpercatinib for 15 days before mating to Gestational Day 7, there were decreases in the number of estrous cycles at dose of 75 mg/kg (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). While selpercatinib did not have clear effects on mating performance or ability to become pregnant at any dose level, half of females at the 75 mg/kg dose level had 100% nonviable embryos. At the same dose level in females with some viable embryos there were increases in post-implantation loss. In 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea at selpercatinib dose of 15 mg/kg (approximately 0.3 times to the human exposure by AUC at the 160 mg twice daily clinical dose). Corpora luteal cysts were present in the minipig at selpercatinib doses >=2 mg/kg (approximately 0.07 times the human exposure by AUC at the 160 mg twice daily clinical dose).

DESCRIPTION SECTION.

11 DESCRIPTION. RETEVMO contains selpercatinib, kinase inhibitor. The molecular formula for selpercatinib is C29H31N7O3 and the molecular weight is 525.61 g/mol. The chemical name is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Selpercatinib has the following chemical structure:Selpercatinib is white to light yellow powder that is slightly hygroscopic. The aqueous solubility of selpercatinib is pH dependent, from sparingly soluble at low pH to practically insoluble at neutral pH.RETEVMO capsules contain either 40 mg or 80 mg of selpercatinib in hard gelatin capsules for oral use. Each capsule contains inactive ingredients of colloidal silicon dioxide and microcrystalline cellulose. The 40 mg capsule shell is composed of gelatin, titanium dioxide, ferric oxide black and black ink. The 80 mg capsule shell is composed of gelatin, titanium dioxide, FD&C blue and black ink. The black ink is composed of shellac, potassium hydroxide and ferric oxide black.RETEVMO tablets contain 40 mg, 80 mg, 120 mg, or 160 mg of selpercatinib as film coated, debossed tablets for oral use. Each tablet contains inactive ingredients of croscarmellose sodium, hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The tablet film coating material contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Additionally, the film coating of the 40 mg, 80 mg, and 120 mg tablets contains ferrosoferric oxide and the film coating of the 80 mg, 120 mg, and 160 mg tablets contain ferric oxide.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Select patients for treatment with RETEVMO based on the presence of RET gene fusion (NSCLC, thyroid, or other solid tumors) or specific RET gene mutation (MTC). (2.1, 14)Adult and adolescent patients 12 years of age or older: the recommended dosage is based on weight (2.3):Less than 50 kg: 120 mg orally twice daily50 kg or greater: 160 mg orally twice dailyPediatric patients to less than 12 years of age: the recommended dosage is based on body surface area (2.3):0.33 m2 to 0.65 m2: 40 mg orally three times daily0.66 m2 to 1.08 m2: 80 mg orally twice daily1.09 m2 to 1.52 m2: 120 mg orally twice daily>=1.53 m2: 160 mg orally twice daily For patients who cannot swallow, disperse 40 mg RETEVMO tablets and administer orally or via gastrostomy or nasogastric tube (2.8)Only RETEVMO 40 mg tablets may be used to create the dispersion (2.2)Reduce RETEVMO dose in patients with severe hepatic impairment. (2.7, 8.7). Select patients for treatment with RETEVMO based on the presence of RET gene fusion (NSCLC, thyroid, or other solid tumors) or specific RET gene mutation (MTC). (2.1, 14). Adult and adolescent patients 12 years of age or older: the recommended dosage is based on weight (2.3):Less than 50 kg: 120 mg orally twice daily50 kg or greater: 160 mg orally twice daily. Less than 50 kg: 120 mg orally twice daily. 50 kg or greater: 160 mg orally twice daily. Pediatric patients to less than 12 years of age: the recommended dosage is based on body surface area (2.3):0.33 m2 to 0.65 m2: 40 mg orally three times daily0.66 m2 to 1.08 m2: 80 mg orally twice daily1.09 m2 to 1.52 m2: 120 mg orally twice daily>=1.53 m2: 160 mg orally twice daily. 0.33 m2 to 0.65 m2: 40 mg orally three times daily. 0.66 m2 to 1.08 m2: 80 mg orally twice daily. 1.09 m2 to 1.52 m2: 120 mg orally twice daily. >=1.53 m2: 160 mg orally twice daily. For patients who cannot swallow, disperse 40 mg RETEVMO tablets and administer orally or via gastrostomy or nasogastric tube (2.8). Only RETEVMO 40 mg tablets may be used to create the dispersion (2.2). Reduce RETEVMO dose in patients with severe hepatic impairment. (2.7, 8.7). 2.1 Patient Selection. Select patients for treatment with RETEVMO based on the presence of RET gene fusion (NSCLC, thyroid cancer, or other solid tumors) or specific RET gene mutation (MTC) in tumor specimens [see Clinical Studies (14)]. Information on FDA-approved test(s) for the detection of RET gene fusions and RET gene mutations is available at: http://www.fda.gov/CompanionDiagnostics. An FDA-approved companion diagnostic test for the detection of RET gene fusions and RET gene mutations in plasma is not available.. 2.2 Important Administration Instructions. RETEVMO may be taken with or without food unless coadministered with proton pump inhibitor (PPI) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].Swallow the capsule or tablet whole. Do not crush or chew the capsules or tablets.For patients unable to swallow capsules or tablets or who are using feeding tube, prepare and administer RETEVMO as dispersion; only RETEVMO 40 mg tablets may be used to create the dispersion [see Dosage and Administration (2.8)].. RETEVMO may be taken with or without food unless coadministered with proton pump inhibitor (PPI) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].. Swallow the capsule or tablet whole. Do not crush or chew the capsules or tablets.. For patients unable to swallow capsules or tablets or who are using feeding tube, prepare and administer RETEVMO as dispersion; only RETEVMO 40 mg tablets may be used to create the dispersion [see Dosage and Administration (2.8)].. 2.3 Recommended Dosage. The recommended dosage of RETEVMO administered as recommended [see Dosage and Administration (2.2)] and given until disease progression or unacceptable toxicity is shown in Table 1:Table 1: Recommended RETEVMO DosagePopulationRETEVMO DosageAdult and adolescent patients 12 years of age or older based on body weightLess than 50 kg120 mg twice daily50 kg or greater160 mg twice dailyPediatric patients to less than 12 years of age based on body surface area0.33 to 0.65 m2 40 mg three times daily0.66 to 1.08 m2 80 mg twice daily1.09 to 1.52 m2 120 mg twice daily>=1.53 m2 160 mg twice dailyDosing pediatric patients with body surface area less than 0.33 m2 is not recommended. Less than 50 kg. 50 kg or greater. 0.33 to 0.65 m2 0.66 to 1.08 m2 1.09 to 1.52 m2 >=1.53 m2 Missed DoseDo not take missed dose unless it is more than hours until next scheduled dose.. VomitingIf vomiting occurs after RETEVMO administration, do not take an additional dose and continue to the next scheduled time for the next dose.. 2.4 Dosage Modifications for Concomitant Use of Acid-Reducing Agents. Avoid concomitant use of PPI, histamine-2 (H2) receptor antagonist, or locally-acting antacid with RETEVMO [see Drug Interactions (7.1)]. If concomitant use cannot be avoided:Take RETEVMO with food when coadministered with PPI.Take RETEVMO hours before or 10 hours after administration of an H2 receptor antagonist.Take RETEVMO hours before or hours after administration of locally-acting antacid.. Take RETEVMO with food when coadministered with PPI.. Take RETEVMO hours before or 10 hours after administration of an H2 receptor antagonist.. Take RETEVMO hours before or hours after administration of locally-acting antacid.. 2.5 Dosage Modifications for Adverse Reactions. The recommended dose reductions for adverse reactions are provided in Table 2.Table 2: Recommended RETEVMO Dose Reductions for Adverse ReactionsCurrentRETEVMO DosageDose ReductionFirstSecondThird40 mg three times daily40 mg twice daily40 mg once dailypermanently discontinue80 mg twice daily40 mg twice daily40 mg once dailypermanently discontinue120 mg twice daily80 mg twice daily40 mg twice daily40 mg once daily160 mg twice daily120 mg twice daily80 mg twice daily40 mg twice dailyPermanently discontinue RETEVMO in patients unable to tolerate three dose reductions.The recommended dosage modifications for adverse reactions are provided in Table 3.Table 3: Recommended RETEVMO Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityDosage ModificationHepatotoxicity [see Warnings and Precautions (5.1)] Grade 3orGrade 4Withhold RETEVMO and monitor AST/ALT once weekly until resolution to Grade or baseline.Resume at reduced dose by dose levels and monitor AST and ALT once weekly until weeks after reaching dose taken prior to the onset of Grade or increased AST or ALT.Increase dose by dose level after minimum of weeks without recurrence and then increase to dose taken prior to the onset of Grade or increased AST or ALT after minimum of weeks without recurrence.Interstitial Lung Disease/ Pneumonitis [see Warnings and Precautions (5.2)] Grade 2Withhold RETEVMO until resolution.Resume at reduced dose.Discontinue RETEVMO for recurrent ILD/pneumonitis.Grade orGrade 4Discontinue RETEVMO for confirmed ILD/pneumonitis.Hypertension [see Warnings and Precautions (5.3)] Grade 3Withhold RETEVMO for Grade hypertension that persists despite optimal antihypertensive therapy. Resume at reduced dose when hypertension is controlled.Grade 4Discontinue RETEVMO.QT Interval Prolongation [see Warnings and Precautions (5.4)] Grade 3Withhold RETEVMO until recovery to baseline or Grade or 1.Resume at reduced dose or permanently discontinue RETEVMO.Grade 4Discontinue RETEVMO.Hemorrhagic Events [see Warnings and Precautions (5.5)] Grade 3orGrade 4Withhold RETEVMO until recovery to baseline or Grade or 1.Discontinue RETEVMO for severe or life-threatening hemorrhagic events.Hypersensitivity Reactions [see Warnings and Precautions (5.6)] Grades 1-3Withhold RETEVMO until resolution of the event. Initiate corticosteroids.Resume at reduced dose by dose levels while continuing corticosteroids.Increase dose by dose level each week until the dose taken prior to the onset of hypersensitivity is reached, then taper corticosteroids.Discontinue RETEVMO for any severe skin reaction including Stevens-Johnson Syndrome.Recurrent Grade or Grade 4Discontinue RETEVMO.Hypothyroidism [see Warnings and Precautions (5.9)] Grade orGrade 4Withhold RETEVMO until resolution to Grade or baseline.Discontinue RETEVMO based on severity.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3orGrade 4Withhold RETEVMO until recovery to baseline or Grade or 1.Resume at reduced dose.. Withhold RETEVMO and monitor AST/ALT once weekly until resolution to Grade or baseline.. Resume at reduced dose by dose levels and monitor AST and ALT once weekly until weeks after reaching dose taken prior to the onset of Grade or increased AST or ALT.. Increase dose by dose level after minimum of weeks without recurrence and then increase to dose taken prior to the onset of Grade or increased AST or ALT after minimum of weeks without recurrence.. Withhold RETEVMO until resolution.. Resume at reduced dose.. Discontinue RETEVMO for recurrent ILD/pneumonitis.. Discontinue RETEVMO for confirmed ILD/pneumonitis.. Withhold RETEVMO for Grade hypertension that persists despite optimal antihypertensive therapy. Resume at reduced dose when hypertension is controlled.. Discontinue RETEVMO.. Withhold RETEVMO until recovery to baseline or Grade or 1.. Resume at reduced dose or permanently discontinue RETEVMO.. Discontinue RETEVMO.. Withhold RETEVMO until recovery to baseline or Grade or 1.. Discontinue RETEVMO for severe or life-threatening hemorrhagic events.. Withhold RETEVMO until resolution of the event. Initiate corticosteroids.. Resume at reduced dose by dose levels while continuing corticosteroids.. Increase dose by dose level each week until the dose taken prior to the onset of hypersensitivity is reached, then taper corticosteroids.. Discontinue RETEVMO for any severe skin reaction including Stevens-Johnson Syndrome.. Discontinue RETEVMO.. Withhold RETEVMO until resolution to Grade or baseline.. Discontinue RETEVMO based on severity.. Withhold RETEVMO until recovery to baseline or Grade or 1.. Resume at reduced dose.. 2.6 Dosage Modifications for Concomitant Use of Strong and Moderate CYP3A Inhibitors. Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong or moderate CYP3A inhibitor cannot be avoided, reduce the RETEVMO dose as recommended in Table 4. After the inhibitor has been discontinued for to elimination half-lives, resume RETEVMO at the dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions (7.1)].Table 4: Recommended RETEVMO Dosage for Concomitant Use of Strong and Moderate CYP3A InhibitorsCurrent RETEVMO DosageRecommended RETEVMO DosageModerate CYP3A InhibitorStrong CYP3A Inhibitor40 mg orally three times daily40 mg orally once daily40 mg orally once daily80 mg orally twice daily40 mg orally twice daily40 mg orally twice daily120 mg orally twice daily80 mg orally twice daily40 mg orally twice daily160 mg orally twice daily120 mg orally twice daily80 mg orally twice daily. 2.7 Dosage Modification for Severe Hepatic Impairment. Reduce the recommended dosage of RETEVMO for patients with severe hepatic impairment as recommended in Table [see Use in Specific Populations (8.7)].Table 5: Recommended RETEVMO Dosage for Severe Hepatic ImpairmentCurrent RETEVMO DosageRecommended RETEVMO Dosage40 mg orally three times daily40 mg orally twice daily80 mg orally twice daily40 mg orally twice daily120 mg orally twice daily80 mg orally twice daily160 mg orally twice daily80 mg orally twice daily. 2.8 Alternative Administration for Patients Unable to Swallow Tablets or Capsules. For patients unable to swallow whole capsules or tablets, the 40 mg tablet may be dispersed and administered orally or via gastrostomy or nasogastric tube. Use only the 40 mg tablet to make the dispersion.RETEVMO 40 mg tablets for Oral AdministrationTo prepare RETEVMO tablet as dispersion:In glass or medicine cup, add the correct number of 40 mg RETEVMO tablets required for the prescribed dose (1, 2, 3, or tablets), to approximately tablespoon (15 mL) of room temperature or chilled water or 100% carrot puree.Stir intermittently until tablet(s) have dispersed (approximately to 10 minutes). Some settling may occur and the dispersion may appear cloudy if water is used.Administer the entire dispersion immediately.Add tablespoon (15 mL) of water to the glass or medicine cup, swirl or stir to collect any remaining medicine and administer immediately.Discard RETEVMO dispersion if not taken within hours.RETEVMO 40 mg tablets for Feeding Tubes (Gastrostomy or Nasogastric Tube) AdministrationUse only polyurethane (French size or larger) or vinyl chloride (French size 10 or larger) nasogastric tube or silicone (French size 14 or larger) gastrostomy tube.In glass or medicine cup, add the correct number of 40 mg RETEVMO tablet(s) required for the prescribed dose (1, 2, 3, or tablets), to minimum of 10 mL of room temperature water.Stir intermittently until tablet(s) have dispersed (approximately to 10 minutes). Some settling may occur and the dispersion may appear cloudy.Flush the feeding tube according to manufacturers instructions.Draw the dispersion into an enteral syringe and administer the dispersion via the feeding tube immediately.Add mL of water to the glass or medicine cup, swirl or stir to collect any remaining medicine, and deliver this rinse via the feeding tube using the same syringe.Repeat rinse as necessary to ensure full dose is delivered.Flush the feeding tube according to manufacturers instructions.Discard RETEVMO dispersion if not taken within hours.. In glass or medicine cup, add the correct number of 40 mg RETEVMO tablets required for the prescribed dose (1, 2, 3, or tablets), to approximately tablespoon (15 mL) of room temperature or chilled water or 100% carrot puree.. Stir intermittently until tablet(s) have dispersed (approximately to 10 minutes). Some settling may occur and the dispersion may appear cloudy if water is used.. Administer the entire dispersion immediately.. Add tablespoon (15 mL) of water to the glass or medicine cup, swirl or stir to collect any remaining medicine and administer immediately.. Discard RETEVMO dispersion if not taken within hours.. In glass or medicine cup, add the correct number of 40 mg RETEVMO tablet(s) required for the prescribed dose (1, 2, 3, or tablets), to minimum of 10 mL of room temperature water.. Stir intermittently until tablet(s) have dispersed (approximately to 10 minutes). Some settling may occur and the dispersion may appear cloudy.. Flush the feeding tube according to manufacturers instructions.. Draw the dispersion into an enteral syringe and administer the dispersion via the feeding tube immediately.. Add mL of water to the glass or medicine cup, swirl or stir to collect any remaining medicine, and deliver this rinse via the feeding tube using the same syringe.. Repeat rinse as necessary to ensure full dose is delivered.. Flush the feeding tube according to manufacturers instructions.. Discard RETEVMO dispersion if not taken within hours.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capsules:40 mg: gray opaque capsule imprinted with Lilly, 3977 and 40 mg in black ink.80 mg: blue opaque capsule imprinted with Lilly, 2980 and 80 mg in black ink.Tablets:40 mg: light gray, film coated, round tablet debossed with Ret 40 on one side and 5340 on the other side.80 mg: dark red-purple, film coated, round tablet debossed with Ret 80 on one side and 6082 on the other side.120 mg: light purple, film coated, round tablet debossed with Ret 120 on one side and 6120 on the other side.160 mg: light pink, film coated, round tablet debossed with Ret 160 on one side and 5562 on the other side.. 40 mg: gray opaque capsule imprinted with Lilly, 3977 and 40 mg in black ink.. 80 mg: blue opaque capsule imprinted with Lilly, 2980 and 80 mg in black ink.. 40 mg: light gray, film coated, round tablet debossed with Ret 40 on one side and 5340 on the other side.. 80 mg: dark red-purple, film coated, round tablet debossed with Ret 80 on one side and 6082 on the other side.. 120 mg: light purple, film coated, round tablet debossed with Ret 120 on one side and 6120 on the other side.. 160 mg: light pink, film coated, round tablet debossed with Ret 160 on one side and 5562 on the other side.. Capsules: 40 mg, 80 mg. (3)Tablets: 40 mg, 80 mg, 120 mg, 160 mg. (3). Capsules: 40 mg, 80 mg. (3). Tablets: 40 mg, 80 mg, 120 mg, 160 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Acid-Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid). (2.4, 7.1)Strong and Moderate CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the RETEVMO dose. (2.6, 7.1)Strong and Moderate CYP3A Inducers: Avoid coadministration. (7.1)CYP2C8 and CYP3A Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. (7.2)Certain P-gp and BCRP Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. (7.2). Acid-Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid). (2.4, 7.1). Strong and Moderate CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the RETEVMO dose. (2.6, 7.1). Strong and Moderate CYP3A Inducers: Avoid coadministration. (7.1). CYP2C8 and CYP3A Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. (7.2). Certain P-gp and BCRP Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. (7.2). 7.1 Effects of Other Drugs on RETEVMO. Acid-Reducing AgentsConcomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce RETEVMO anti-tumor activity.Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid) [see Dosage and Administration (2.4)].. Strong and Moderate CYP3A InhibitorsConcomitant use of RETEVMO with strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], 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 strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently [see Dosage and Administration (2.6), Warnings and Precautions (5.4)].. Strong and Moderate CYP3A InducersConcomitant use of RETEVMO with strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce RETEVMO anti-tumor activity.Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.. 7.2 Effects of RETEVMO on Other Drugs. CYP2C8 and CYP3A SubstratesRETEVMO is moderate CYP2C8 inhibitor and weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], 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.. Certain P-gp and BCRP SubstratesRETEVMO is P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling.. 7.3 Drugs that Prolong QT Interval. RETEVMO is associated with QTc interval prolongation [see Warnings and Precautions (5.4), Clinical Pharmacology (12.2)]. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Based on animal data, RETEVMO can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating RETEVMO [see Use in Specific Populations (8.1)].. Contraception. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for week after the last dose.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for week after the last dose.. InfertilityRETEVMO may impair fertility in females and males of reproductive potential [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of 857 patients who received RETEVMO, 35% (298 patients) were >=65 years of age and 10% (85 patients) were >=75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were >=65 years of age and younger patients.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. Reduce the dose when administering RETEVMO to patients with severe [total bilirubin 3 to 10 upper limit of normal (ULN) and any AST] hepatic impairment [see Dosage and Administration (2.7)].No dosage modification is recommended for patients with mild (total bilirubin <= ULN with AST ULN or total bilirubin 1 to 1.5 ULN with any AST) or moderate (total bilirubin 1.5 to x ULN and any AST) hepatic impairment.Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedRETEVMO capsules are supplied as follows:Capsule StrengthDescriptionPackage ConfigurationNDC Number40 mgGray opaque, imprinted with Lilly, 3977 and 40 mg in black ink60 count bottleNDC 0002-3977-6080 mgBlue opaque, imprinted with Lilly, 2980 and 80 mg in black ink60 count bottleNDC 0002-2980-60120 count bottleNDC 0002-2980-26RETEVMO tablets are supplied in bottles with desiccant in the following configurations:Tablet StrengthDescriptionPackage ConfigurationNDC Number40 mgLight gray, film coated, round tablets debossed with Ret 40 on one side and 5340 on the other side60 count bottleNDC 0002-5340-6080 mgDark red-purple, film coated, round tablets debossed with Ret 80 on one side and 6082 on the other side60 count bottleNDC 0002-6082-60120 mgLight purple, film coated, round tablets debossed with Ret 120 on one side and 6120 on the other side60 count bottleNDC 0002-6120-60160 mgLight pink, film coated, round tablets debossed with Ret 160 on one side and 5562 on the other side60 count bottleNDC 0002-5562-60. Storage and HandlingStore at 20C to 25C (68F to 77F); excursions between 15C and 30C (59F to 86F) are permitted [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. RETEVMO(R) is kinase inhibitor indicated for the treatment of:Adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test (1.1)Adult and pediatric patients years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with RET mutation, as detected by an FDA-approved test, who require systemic therapy (1.2)Adult and pediatric patients years of age and older with advanced or metastatic thyroid cancer with RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) (1.3)Adult and pediatric patients years of age and older with locally advanced or metastatic solid tumors with RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options (1.4). Adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test (1.1). Adult and pediatric patients years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with RET mutation, as detected by an FDA-approved test, who require systemic therapy (1.2). Adult and pediatric patients years of age and older with advanced or metastatic thyroid cancer with RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) (1.3). Adult and pediatric patients years of age and older with locally advanced or metastatic solid tumors with RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options (1.4). 1.1 RET Fusion-Positive Non-Small Cell Lung Cancer. RETEVMO(R) is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test.. 1.2 RET-Mutant Medullary Thyroid Cancer. RETEVMO is indicated for the treatment of adult and pediatric patients years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with RET mutation, as detected by an FDA-approved test, who require systemic therapy.. 1.3 RET Fusion-Positive Thyroid Cancer. RETEVMO is indicated for the treatment of adult and pediatric patients years of age and older with advanced or metastatic thyroid cancer with RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).. 1.4 Other RET Fusion-Positive Solid Tumors. RETEVMO is indicated for the treatment of adult and pediatric patients years of age and older with locally advanced or metastatic solid tumors with RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. HepatotoxicityAdvise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.1)].. Interstitial Lung Disease (ILD)/PneumonitisAdvise patients that ILD/ pneumonitis can occur and to contact their healthcare provider immediately for signs or symptoms of ILD including new or worsening cough or shortness of breath [see Warnings and Precautions (5.2)]. HypertensionAdvise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings [see Warnings and Precautions (5.3)].. QT ProlongationAdvise patients that RETEVMO can cause QTc interval prolongation and to inform their healthcare provider if they have any QTc interval prolongation symptoms, such as syncope [see Warnings and Precautions (5.4)].. Hemorrhagic EventsAdvise patients that RETEVMO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding [see Warnings and Precautions (5.5)].. Hypersensitivity ReactionsAdvise patients to monitor for signs and symptoms of hypersensitivity reactions, particularly during the first month of treatment [see Warnings and Precautions (5.6)].. Tumor Lysis SyndromeAdvise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS [see Warnings and Precautions (5.7)].. Risk of Impaired Wound HealingAdvise patients that RETEVMO may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.8)].. HypothyroidismAdvise patients that RETEVMO can cause hypothyroidism and to immediately contact their healthcare provider for signs or symptoms of hypothyroidism [see Warnings and Precautions (5.9)].. Slipped Capital Femoral Epiphysis/Slipped Upper Femoral EpiphysisAdvise pediatric patients and caregivers to contact their healthcare provider promptly to report any signs and symptoms indicative of slipped capital femoral epiphysis/slipped upper femoral epiphysis [see Warnings and Precautions (5.11)].. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the possible risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during the treatment with RETEVMO and for week after the last dose [see Use in Specific Populations (8.3)].Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for week after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment with RETEVMO and for week after the last dose [see Use in Specific Populations (8.2)].. InfertilityAdvise males and females of reproductive potential that RETEVMO may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].. Drug InteractionsAdvise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. Johns wort, proton pump inhibitors, H2 receptor antagonists, and antacids while taking RETEVMO.If PPIs are required, instruct patients to take RETEVMO with food. If H2 receptor antagonists are required, instruct patients to take RETEVMO hours before or 10 hours after the H2 receptor antagonist. If locally-acting antacids are required, instruct patients to take RETEVMO hours before or hours after the locally-acting antacid [see Drug Interactions (7.1, 7.2)].Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 2020, 2026, Eli Lilly and Company. All rights reserved.Pat.: www.lilly.com/patentsRET-0010-USPI-20260714.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 week after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Selpercatinib is kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and at higher concentrations that were still clinically achievable. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and and approximately 8-fold lower concentration than VEGFR3.Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with patient-derived RET fusion positive tumor.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Selpercatinib was not carcinogenic in 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in 6-month study in rasH2 transgenic mice when administered by daily oral gavage at doses of up to 60 mg/kg.Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation. Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the Cmax at the human dose of 160 mg twice daily.In general toxicology studies, male rats and minipigs exhibited testicular degeneration which was associated with luminal cell debris and/or reduced luminal sperm in the epididymis at selpercatinib exposures approximately 0.4 (rat) and 0.1 (minipig) times the clinical exposure by AUC at the 160 mg twice daily clinical dose. In dedicated fertility study in male rats, administration of selpercatinib at doses up to 30 mg/kg/day (approximately twice the clinical exposure by AUC at the 160 twice daily clinical dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display dose-dependent increase in testicular germ cell depletion and spermatid retention at doses >=3 mg/kg (~0.2 times the clinical exposure by AUC at the 160 twice daily clinical dose) accompanied by altered sperm morphology at 30 mg/kg.In dedicated fertility study in female rats treated with selpercatinib for 15 days before mating to Gestational Day 7, there were decreases in the number of estrous cycles at dose of 75 mg/kg (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). While selpercatinib did not have clear effects on mating performance or ability to become pregnant at any dose level, half of females at the 75 mg/kg dose level had 100% nonviable embryos. At the same dose level in females with some viable embryos there were increases in post-implantation loss. In 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea at selpercatinib dose of 15 mg/kg (approximately 0.3 times to the human exposure by AUC at the 160 mg twice daily clinical dose). Corpora luteal cysts were present in the minipig at selpercatinib doses >=2 mg/kg (approximately 0.07 times the human exposure by AUC at the 160 mg twice daily clinical dose).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL Retevmo 40 mg 60 Count BottleNDC-0002-3977-6060 capsulesRx onlyRetevmo(TM) (selpercatinib) capsules40 mgEach capsule contains 40 mg selpercatinibwww.retevmo.comLilly. Retevmo 40mg Capsules 60 Count Bottle.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of RETEVMO have been established in pediatric patients aged years and older for the treatment of:advanced or metastatic medullary thyroid cancer (MTC) with RET mutation who require systemic therapyadvanced or metastatic thyroid cancer with RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate)locally advanced or metastatic solid tumors with RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients aged years and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2, 14.3, 14.4)]. The predicted exposures of selpercatinib in pediatric patients at the recommended dosages were within the range of values observed in patients >= 12 years and >= 50 kg in body weight receiving the approved recommended dosage of 160 mg twice daily [see Clinical Pharmacology (12.3)].The safety and effectiveness of RETEVMO have not been established in these indications in patients aged less than years.The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications [see Indications and Usage (1)].. advanced or metastatic medullary thyroid cancer (MTC) with RET mutation who require systemic therapy. advanced or metastatic thyroid cancer with RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). locally advanced or metastatic solid tumors with RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.. Juvenile Animal Toxicity DataIn juvenile rat toxicity study, animals were dosed daily with selpercatinib from post-natal day 21 to day 70 (approximately equivalent to human child to late adolescent). Selpercatinib increased physeal thickness of multiple bones, extending into the metaphysis and associated with decreased trabecular bone, which was not reversible at doses approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily. Growth plate changes were associated with impairment of bone modeling, resulting in decreased femur length and with reduction in bone mineral density. Selpercatinib also induced reversible hypocellularity of bone marrow in males at >=30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily), and reversible alterations of dentin composition at >=50 mg/kg (approximately times the adult human exposure at the clinical dose of 160 mg twice daily). Irreversible, dose-dependent degeneration of testicular germinal epithelium, with vacuolation of Sertoli cells and corresponding depletion of spermatozoa in the epididymides, was also observed at >= 30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily) and affected male reproductive performance at 50 mg/kg (approximately times the adult human exposure at the clinical dose of 160 mg twice daily). Females exhibited delay in attainment of vaginal patency, marker of sexual maturity, at 125 mg/kg (approximately times the adult human exposure at the clinical dose of 160 mg twice daily); this effect was associated with lower mean body weight. Similar effects in irregular thickening of growth plates in adult rats and minipigs, and tooth dysplasia and malocclusion, resulting in tooth loss in adult rats were observed in repeat dose studies of up to 13-week duration with selpercatinib.Monitor growth plates in pediatric patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure-Response RelationshipSelpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.. Cardiac ElectrophysiologyThe effect of RETEVMO on the QTc interval was evaluated in thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of selpercatinib capsules were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. The capsule and tablet dosage forms of selpercatinib are bioequivalent. Steady state selpercatinib AUC and Cmax increased in slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily [0.06 to 1.5 times the maximum recommended total daily dosage].Steady-state was reached by approximately days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] Cmax was 2,980 (53%) ng/mL and AUC0-24h was 51,600 (58%) ngh/mL.. AbsorptionThe median tmax of selpercatinib is hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects.. Effect of FoodFor both the capsule and tablet dosage forms no clinically significant differences in selpercatinib AUC or Cmax were observed following administration of high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects.. DistributionThe apparent volume of distribution (Vss/F) of selpercatinib is 203 L.Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7.. EliminationThe apparent clearance (CL/F) of selpercatinib is L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects.. MetabolismSelpercatinib is metabolized predominantly by CYP3A4. Following oral administration of single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma.. ExcretionFollowing oral administration of single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged).. Specific PopulationsThe apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (9.6 kg to 179 kg).No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (2 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR >=15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied.. Pediatric patientsThe exposures of selpercatinib in pediatric patients are comparable to those in adult patients administered at the recommended dosages.. Patients with Hepatic ImpairmentThe selpercatinib AUC0-INF increased 1.1-fold in subjects with mild (total bilirubin <= ULN with AST ULN or total bilirubin 1 to 1.5 ULN with any AST), 1.3-fold in subjects with moderate (total bilirubin 1.5 to x ULN and any AST), and 1.8-fold in subjects with severe (total bilirubin 3 to 10 ULN and any AST) hepatic impairment, compared to subjects with normal hepatic function.. Drug Interaction Studies. Clinical Studies and Model-Informed ApproachesProton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when RETEVMO was administered with food (Table 14).Table 14: Change in Selpercatinib Exposure After Coadministration with PPI1 High-fat meal: approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; approximately 800 to 1,000 calories total.2 Low-fat meal: approximately 390 calories and 10 of fat.SelpercatinibAUC0-INFSelpercatinibCmaxRETEVMO fastingReferenceReferenceRETEVMO fasting PPI 69% 88%RETEVMO with high-fat meal1 PPI 2% 49%RETEVMO with low-fat meal2 PPINo change 22%H2 Receptor Antagonists: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and hours after the RETEVMO dose (administered fasting).Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC0-INF 2.3-fold and Cmax 1.3-fold.Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC 1.6 to 2-fold and Cmax 1.5 to 1.8-fold.Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC0-INF by 87% and Cmax by 70%.Moderate CYP3A Inducers: Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the selpercatinib AUC by 40-70% and Cmax by 34-57%.Weak CYP3A Inducers: Coadministration of multiple doses of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and Cmax by 26%.CYP2C8 Substrates: Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC0-INF 2.9-fold and Cmax 1.9-fold.CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A substrate) increased the midazolam AUC0-INF 1.5-fold and Cmax 1.4-fold.P-glycoprotein (P-gp) Substrates: Coadministration of RETEVMO with dabigatran (P-gp substrate) increased the dabigatran AUC0-INF 1.4-fold and Cmax 1.4-fold.BCRP Substrates: Coadministration of RETEVMO with rosuvastatin (BCRP substrate) increased the rosuvastatin AUC0-INF by 1.9-fold and Cmax by 1.7-fold.P-gp Inhibitors: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with single dose of rifampin (P-gp inhibitor).MATE1 Substrates: No clinically significant differences in glucose levels were observed when metformin (MATE1 substrate) was coadministered with selpercatinib.. In Vitro StudiesCYP Enzymes: Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.Transporter Systems: Selpercatinib inhibits MATE1. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Adverse Reactions (6.1)].Selpercatinib does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations.Selpercatinib is substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reaction has been identified during post-approval use of RETEVMO. Because such reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], RETEVMO can cause fetal harm when administered to pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to 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.. Data. Animal DataSelpercatinib administration to pregnant rats during the period of organogenesis at oral doses >=100 mg/kg [approximately 3.6 times the human exposure based on the area under the curve (AUC) at the clinical dose of 160 mg twice daily] resulted in 100% post-implantation loss. At the dose of 50 mg/kg [approximately equal to the human exposure (AUC) at the clinical dose of 160 mg twice daily], of females had 100% early resorptions; the remaining females had high levels of early resorptions with only viable fetuses across the litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax).

RECENT MAJOR CHANGES SECTION.

Indications and Usage Other RET Fusion-Positive Solid Tumors (1.4)07/2026Dosage and Administration (2.8)11/2025Warnings and Precautions (5.6)11/2025Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.7, 5.9)07/2026.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. 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].The recommended dosage has not been established for patients with end-stage renal disease (ESRD) [see Clinical Pharmacology (12.3)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised:07/2026PATIENT INFORMATIONRETEVMO(R)(reh-TEHV-moh)(selpercatinib)capsulesRETEVMO(R)(reh-TEHV-moh)(selpercatinib)tabletsWhat is RETEVMORETEVMO is prescription medicine that is used to treat certain cancers caused by abnormal RET genes in: adults with locally advanced non-small cell lung cancer (NSCLC) or NSCLC that has spread.adults and children years of age and older with advanced medullary thyroid cancer (MTC) or MTC that has spread, who require medicine by mouth or injection (systemic therapy).adults and children years of age and older with advanced thyroid cancer or thyroid cancer that has spread who require medicine by mouth or injection (systemic therapy), and who have received radioactive iodine and it did not work or is no longer working.adults and children years of age and older with locally advanced solid tumors (cancers) or solid tumors that have spread, and have gotten worse (progressed) on or after other treatment or there are no satisfactory treatment options.Your healthcare provider will perform test to make sure that RETEVMO is right for you.It is not known if RETEVMO is safe and effective when used: in children younger than years of age for the treatment of:advanced MTC or MTC that has spread who require medicine by mouth or injection.advanced thyroid cancer or thyroid cancer that has spread who require medicine by mouth or injection, and have received radioactive iodine and it did not work or is no longer working.locally advanced solid tumors or solid tumors that have spread, and have gotten worse on or after other treatment or there are no satisfactory treatment options. in children for other conditions. Before taking RETEVMO, tell your healthcare provider about all your medical conditions, including if you:have liver problemshave lung or breathing problems other than lung cancerhave high blood pressurehave heart problems including condition called QT prolongationhave bleeding problemsplan to have surgery. You should stop taking RETEVMO at least days before your planned surgery. See What are the possible side effects of RETEVMO are pregnant or plan to become pregnant. RETEVMO can harm your unborn baby. You should not become pregnant during treatment with RETEVMO.Females who are able to become pregnant:Your healthcare provider will do pregnancy test before you start treatment with RETEVMO.Use effective birth control (contraception) during treatment and for week after your last dose of RETEVMO. Talk to your healthcare provider about birth control methods that may be right for you.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with RETEVMO.Males with female partners who are able to become pregnant:Use effective birth control during treatment with RETEVMO and for week after your last dose of RETEVMO.Tell your healthcare provider right away if your female partner becomes pregnant during your treatment with RETEVMO.are breastfeeding or plan to breastfeed. It is not known if RETEVMO passes into your breast milk. Do not breastfeed during treatment with RETEVMO and for week after your last dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RETEVMO may affect the way other medicines work, and other medicines may affect how RETEVMO works, and may increase your risk of side effects. During treatment with RETEVMO, you should avoid taking: St. Johns wortproton pump inhibitors (PPIs), such as dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole sodium, and rabeprazoleH2 blockers, such as famotidine, nizatidine, and cimetidineantacids that contain aluminum, magnesium, calcium, simethicone, or buffered medicinesIf you cannot avoid taking PPIs, H2 blockers, or antacids, see How should take RETEVMO for more information on how to take RETEVMO with these medicines. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. How should take RETEVMOTake RETEVMO exactly as your healthcare provider tells you.Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with RETEVMO if you get side effects. Do not change your dose or stop taking RETEVMO unless your healthcare provider tells you.Swallow RETEVMO capsules and tablets whole. Do not crush or chew.Do not take or give RETEVMO capsules or tablets if you or your child are unable to swallow.If you or your child are unable to swallow RETEVMO whole or if you or your child has feeding tube, RETEVMO can be prepared and taken or given as dispersion using only the RETEVMO 40 mg tablets. See the Instructions for Use that comes with RETEVMO for information about the right way to prepare and take or give dose of RETEVMO 40 mg tablets.Take RETEVMO with or without food.If you take proton-pump inhibitor (PPIs), such as dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole sodium, and rabeprazole, take RETEVMO with food.If you take an H2 blocker (such as famotidine, nizatidine, and cimetidine), take RETEVMO hours before or 10 hours after taking the H2 blocker.If you take an antacid that contains aluminum, magnesium, calcium, simethicone, or buffered medicines, take RETEVMO hours before or hours after taking the antacid.If you vomit after taking dose of RETEVMO, do not take an extra dose. Take the next dose of RETEVMO at your scheduled time.Do not take missed dose of RETEVMO unless it is more than hours until your next scheduled dose.What are the possible side effects of RETEVMORETEVMO can cause serious side effects, including:Liver problems. Liver problems (increased liver enzymes) can happen during treatment with RETEVMO and may sometimes be severe. Your healthcare provider will do blood tests before and during treatment with RETEVMO to check for liver problems. Tell your healthcare provider right away if you get any of the following symptoms of liver problems during treatment:yellowing of your skin or the white part of your eyes (jaundice)dark tea-colored urinesleepinessbleeding or bruisingloss of appetitenausea or vomitingpain on the upper right side of your stomach area Lung problems. RETEVMO can cause severe or life-threatening inflammation of the lungs during treatment, that can lead to death. Tell your healthcare provider right away if you get any new or worsening lung symptoms, including:shortness of breathcoughfeverHigh blood pressure (hypertension). RETEVMO can cause high blood pressure, which can sometimes be severe. You should check your blood pressure regularly during treatment with RETEVMO. If you develop blood pressure problems, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you have increased blood pressure readings or get any symptoms of high blood pressure, including:confusionheadachesshortness of breathdizzinesschest painHeart rhythm changes (QT prolongation). RETEVMO can cause very slow, very fast or irregular heartbeats. Your healthcare provider may perform tests before and during treatment with RETEVMO to check the activity of your heart and the levels of body salts (electrolytes) and thyroid-stimulating hormone (TSH) in your blood. Tell your healthcare provider right away if you get any of the following symptoms:loss of consciousnessfaintingdizzinessa change in the way your heart beats (heart palpitations)Bleeding problems. RETEVMO can cause bleeding which can be serious and may lead to death. Tell your healthcare provider if you have any signs of bleeding during treatment with RETEVMO, including:vomiting blood or if your vomit looks like coffee-groundspink or brown urinered or black (looks like tar) stoolscoughing up blood or blood clotsunusual bleeding or bruising of your skinmenstrual bleeding that is heavier than normalunusual vaginal bleedingnose bleeds that happen oftendrowsiness or difficulty being awakenedconfusionheadachechange in speechAllergic reactions. RETEVMO can cause allergic reactions, including severe skin reactions, especially during the first month of treatment. Tell your healthcare provider right away if you get fever, rash, muscle or joint pain at any time during treatment with RETEVMO.Tumor lysis syndrome (TLS). TLS is caused by fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and an abnormal heartbeat. TLS can lead to hospitalization. Your healthcare provider may do blood tests to check you for TLS. You should stay well hydrated during treatment with RETEVMO. Tell your healthcare provider or get emergency medical help right away if you develop any of these symptoms during treatment with RETEVMO:nauseavomitingweaknessswellingshortness of breathmuscle crampsseizures Risk of wound healing problems. Wounds may not heal properly during treatment with RETEVMO. Tell your healthcare provider if you plan to have any surgery before or during treatment with RETEVMO.You should stop taking RETEVMO at least days before planned surgery.Your healthcare provider should tell you when you may start taking RETEVMO again after surgery. Low thyroid hormone levels in your blood (hypothyroidism). Your healthcare provider will do blood tests to check your thyroid function before and during treatment with RETEVMO. Tell your healthcare provider right away if you develop signs or symptoms of low thyroid hormone levels, including:weight gainfeeling coldtiredness that worsens or that does not go awayconstipation Hip joint problems (slipped capital femoral epiphysis or slipped upper femoral epiphysis) in children. Tell your healthcare provider right away if you develop signs and symptoms of hip problems, including hip or knee pain or painless limp.The most common side effects of RETEVMO in adults with solid tumors include:muscle and bone painswelling of your arms, legs, hands, and feet (edema)diarrheatirednessdry mouthhigh blood pressurestomach-area (abdominal) painrashnauseaconstipationcoughheadachevomitingshortness of breathbleedingThe most common side effects of RETEVMO in children years and older with solid tumors include:muscle and bone paindiarrheanauseableedingfeverstomach-area (abdominal) painheadachevomitingtirednesscoughrashcoronavirus infectionupper respiratory tract infectionswelling of your arms, legs, hands, and feet (edema)The most common severe abnormal laboratory test results with RETEVMO in adults with solid tumors include decreased white blood cell count, increased liver enzymes, decreased levels of sodium in the blood, decreased levels of calcium in the blood, and decreased levels of phosphate in the blood. The most common severe abnormal laboratory test results with RETEVMO in children years and older with solid tumors include decreased white blood cell count, decreased levels of calcium in the blood, decreased red blood cell count, increased liver enzymes, decreased levels of magnesium in the blood, and decreased levels of potassium in the blood.RETEVMO may affect fertility in females and males, which may affect your ability to have children. Talk to your healthcare provider if this is concern for you.These are not all the possible side effects with RETEVMO.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store RETEVMOStore RETEVMO at room temperature between 68F to 77F (20C to 25C).Keep RETEVMO and all medicines out of the reach of children.General information about the safe and effective use of RETEVMO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use RETEVMO for condition for which it was not prescribed. Do not give RETEVMO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about RETEVMO that is written for health professionals.What are the ingredients in RETEVMOActive ingredient: selpercatinib Inactive ingredients: Capsules: colloidal silicon dioxide and microcrystalline cellulose. The 40 mg capsule shell contains: gelatin, titanium dioxide, ferric oxide black and black ink. The 80 mg capsule shell contains: gelatin, titanium dioxide, FD&C blue and black ink. The black ink contains: shellac, potassium hydroxide and ferric oxide black.Tablets: croscarmellose sodium, hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The tablet film coating material contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Additionally, the film coating of the 40 mg, 80 mg, and 120 mg tablets contains ferrosoferric oxide and the film coating of the 80 mg, 120 mg, and 160 mg tablets contain ferric oxide. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 2020, 2026, Eli Lilly and Company. All rights reserved.RET-0009-PPI-20260714. adults with locally advanced non-small cell lung cancer (NSCLC) or NSCLC that has spread.. adults and children years of age and older with advanced medullary thyroid cancer (MTC) or MTC that has spread, who require medicine by mouth or injection (systemic therapy).. adults and children years of age and older with advanced thyroid cancer or thyroid cancer that has spread who require medicine by mouth or injection (systemic therapy), and who have received radioactive iodine and it did not work or is no longer working.. adults and children years of age and older with locally advanced solid tumors (cancers) or solid tumors that have spread, and have gotten worse (progressed) on or after other treatment or there are no satisfactory treatment options.. in children younger than years of age for the treatment of:advanced MTC or MTC that has spread who require medicine by mouth or injection.advanced thyroid cancer or thyroid cancer that has spread who require medicine by mouth or injection, and have received radioactive iodine and it did not work or is no longer working.locally advanced solid tumors or solid tumors that have spread, and have gotten worse on or after other treatment or there are no satisfactory treatment options. advanced MTC or MTC that has spread who require medicine by mouth or injection.. advanced thyroid cancer or thyroid cancer that has spread who require medicine by mouth or injection, and have received radioactive iodine and it did not work or is no longer working.. locally advanced solid tumors or solid tumors that have spread, and have gotten worse on or after other treatment or there are no satisfactory treatment options.. in children for other conditions.. have liver problems. have lung or breathing problems other than lung cancer. have high blood pressure. have heart problems including condition called QT prolongation. have bleeding problems. plan to have surgery. You should stop taking RETEVMO at least days before your planned surgery. See What are the possible side effects of RETEVMO are pregnant or plan to become pregnant. RETEVMO can harm your unborn baby. You should not become pregnant during treatment with RETEVMO.. Females who are able to become pregnant:Your healthcare provider will do pregnancy test before you start treatment with RETEVMO.Use effective birth control (contraception) during treatment and for week after your last dose of RETEVMO. Talk to your healthcare provider about birth control methods that may be right for you.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with RETEVMO.. Your healthcare provider will do pregnancy test before you start treatment with RETEVMO.. Use effective birth control (contraception) during treatment and for week after your last dose of RETEVMO. Talk to your healthcare provider about birth control methods that may be right for you.. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with RETEVMO.. Males with female partners who are able to become pregnant:Use effective birth control during treatment with RETEVMO and for week after your last dose of RETEVMO.Tell your healthcare provider right away if your female partner becomes pregnant during your treatment with RETEVMO.. Use effective birth control during treatment with RETEVMO and for week after your last dose of RETEVMO.. Tell your healthcare provider right away if your female partner becomes pregnant during your treatment with RETEVMO.. are breastfeeding or plan to breastfeed. It is not known if RETEVMO passes into your breast milk. Do not breastfeed during treatment with RETEVMO and for week after your last dose.. St. Johns wort. proton pump inhibitors (PPIs), such as dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole sodium, and rabeprazole. H2 blockers, such as famotidine, nizatidine, and cimetidine. antacids that contain aluminum, magnesium, calcium, simethicone, or buffered medicines. If you cannot avoid taking PPIs, H2 blockers, or antacids, see How should take RETEVMO for more information on how to take RETEVMO with these medicines. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. Take RETEVMO exactly as your healthcare provider tells you.. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with RETEVMO if you get side effects. Do not change your dose or stop taking RETEVMO unless your healthcare provider tells you.. Swallow RETEVMO capsules and tablets whole. Do not crush or chew.. Do not take or give RETEVMO capsules or tablets if you or your child are unable to swallow.. If you or your child are unable to swallow RETEVMO whole or if you or your child has feeding tube, RETEVMO can be prepared and taken or given as dispersion using only the RETEVMO 40 mg tablets. See the Instructions for Use that comes with RETEVMO for information about the right way to prepare and take or give dose of RETEVMO 40 mg tablets.. Take RETEVMO with or without food.. If you take proton-pump inhibitor (PPIs), such as dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole sodium, and rabeprazole, take RETEVMO with food.. If you take an H2 blocker (such as famotidine, nizatidine, and cimetidine), take RETEVMO hours before or 10 hours after taking the H2 blocker.. If you take an antacid that contains aluminum, magnesium, calcium, simethicone, or buffered medicines, take RETEVMO hours before or hours after taking the antacid.. If you vomit after taking dose of RETEVMO, do not take an extra dose. Take the next dose of RETEVMO at your scheduled time.. Do not take missed dose of RETEVMO unless it is more than hours until your next scheduled dose.. Liver problems. Liver problems (increased liver enzymes) can happen during treatment with RETEVMO and may sometimes be severe. Your healthcare provider will do blood tests before and during treatment with RETEVMO to check for liver problems. Tell your healthcare provider right away if you get any of the following symptoms of liver problems during treatment:. yellowing of your skin or the white part of your eyes (jaundice). dark tea-colored urine. sleepiness. bleeding or bruising. loss of appetite. nausea or vomiting. pain on the upper right side of your stomach area Lung problems. RETEVMO can cause severe or life-threatening inflammation of the lungs during treatment, that can lead to death. Tell your healthcare provider right away if you get any new or worsening lung symptoms, including:. shortness of breath. cough. fever. High blood pressure (hypertension). RETEVMO can cause high blood pressure, which can sometimes be severe. You should check your blood pressure regularly during treatment with RETEVMO. If you develop blood pressure problems, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you have increased blood pressure readings or get any symptoms of high blood pressure, including:. confusion. headaches. shortness of breath. dizziness. chest pain. Heart rhythm changes (QT prolongation). RETEVMO can cause very slow, very fast or irregular heartbeats. Your healthcare provider may perform tests before and during treatment with RETEVMO to check the activity of your heart and the levels of body salts (electrolytes) and thyroid-stimulating hormone (TSH) in your blood. Tell your healthcare provider right away if you get any of the following symptoms:. loss of consciousness. fainting. dizziness. change in the way your heart beats (heart palpitations). Bleeding problems. RETEVMO can cause bleeding which can be serious and may lead to death. Tell your healthcare provider if you have any signs of bleeding during treatment with RETEVMO, including:. vomiting blood or if your vomit looks like coffee-grounds. pink or brown urine. red or black (looks like tar) stools. coughing up blood or blood clots. unusual bleeding or bruising of your skin. menstrual bleeding that is heavier than normal. unusual vaginal bleeding. nose bleeds that happen often. drowsiness or difficulty being awakened. confusion. headache. change in speech. Allergic reactions. RETEVMO can cause allergic reactions, including severe skin reactions, especially during the first month of treatment. Tell your healthcare provider right away if you get fever, rash, muscle or joint pain at any time during treatment with RETEVMO.. Tumor lysis syndrome (TLS). TLS is caused by fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and an abnormal heartbeat. TLS can lead to hospitalization. Your healthcare provider may do blood tests to check you for TLS. You should stay well hydrated during treatment with RETEVMO. Tell your healthcare provider or get emergency medical help right away if you develop any of these symptoms during treatment with RETEVMO:. nausea. vomiting. weakness. swelling. shortness of breath. muscle cramps. seizures Risk of wound healing problems. Wounds may not heal properly during treatment with RETEVMO. Tell your healthcare provider if you plan to have any surgery before or during treatment with RETEVMO.You should stop taking RETEVMO at least days before planned surgery.Your healthcare provider should tell you when you may start taking RETEVMO again after surgery. You should stop taking RETEVMO at least days before planned surgery.. Your healthcare provider should tell you when you may start taking RETEVMO again after surgery.. Low thyroid hormone levels in your blood (hypothyroidism). Your healthcare provider will do blood tests to check your thyroid function before and during treatment with RETEVMO. Tell your healthcare provider right away if you develop signs or symptoms of low thyroid hormone levels, including:. weight gain. feeling cold. tiredness that worsens or that does not go away. constipation Hip joint problems (slipped capital femoral epiphysis or slipped upper femoral epiphysis) in children. Tell your healthcare provider right away if you develop signs and symptoms of hip problems, including hip or knee pain or painless limp.. muscle and bone pain. swelling of your arms, legs, hands, and feet (edema). diarrhea. tiredness. dry mouth. high blood pressure. stomach-area (abdominal) pain. rash. nausea. constipation. cough. headache. vomiting. shortness of breath. bleeding. muscle and bone pain. diarrhea. nausea. bleeding. fever. stomach-area (abdominal) pain. headache. vomiting. tiredness. cough. rash. coronavirus infection. upper respiratory tract infection. swelling of your arms, legs, hands, and feet (edema). Store RETEVMO at room temperature between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

1.1 RET Fusion-Positive Non-Small Cell Lung Cancer. RETEVMO(R) is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test.

STORAGE AND HANDLING SECTION.

Storage and HandlingStore at 20C to 25C (68F to 77F); excursions between 15C and 30C (59F to 86F) are permitted [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation:Advise not to breastfeed. (8.2)Pediatric Use: Monitor open growth plates in pediatric patients. Consider interrupting or discontinuing RETEVMO if abnormalities occur. (8.4). Lactation:Advise not to breastfeed. (8.2). Pediatric Use: Monitor open growth plates in pediatric patients. Consider interrupting or discontinuing RETEVMO if abnormalities occur. (8.4). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], RETEVMO can cause fetal harm when administered to pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to 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.. Data. Animal DataSelpercatinib administration to pregnant rats during the period of organogenesis at oral doses >=100 mg/kg [approximately 3.6 times the human exposure based on the area under the curve (AUC) at the clinical dose of 160 mg twice daily] resulted in 100% post-implantation loss. At the dose of 50 mg/kg [approximately equal to the human exposure (AUC) at the clinical dose of 160 mg twice daily], of females had 100% early resorptions; the remaining females had high levels of early resorptions with only viable fetuses across the litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax).. 8.2 Lactation. Risk SummaryThere 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 week after the last dose.. 8.3 Females and Males of Reproductive Potential. Based on animal data, RETEVMO can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating RETEVMO [see Use in Specific Populations (8.1)].. Contraception. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for week after the last dose.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for week after the last dose.. InfertilityRETEVMO may impair fertility in females and males of reproductive potential [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of RETEVMO have been established in pediatric patients aged years and older for the treatment of:advanced or metastatic medullary thyroid cancer (MTC) with RET mutation who require systemic therapyadvanced or metastatic thyroid cancer with RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate)locally advanced or metastatic solid tumors with RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients aged years and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2, 14.3, 14.4)]. The predicted exposures of selpercatinib in pediatric patients at the recommended dosages were within the range of values observed in patients >= 12 years and >= 50 kg in body weight receiving the approved recommended dosage of 160 mg twice daily [see Clinical Pharmacology (12.3)].The safety and effectiveness of RETEVMO have not been established in these indications in patients aged less than years.The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications [see Indications and Usage (1)].. advanced or metastatic medullary thyroid cancer (MTC) with RET mutation who require systemic therapy. advanced or metastatic thyroid cancer with RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). locally advanced or metastatic solid tumors with RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.. Juvenile Animal Toxicity DataIn juvenile rat toxicity study, animals were dosed daily with selpercatinib from post-natal day 21 to day 70 (approximately equivalent to human child to late adolescent). Selpercatinib increased physeal thickness of multiple bones, extending into the metaphysis and associated with decreased trabecular bone, which was not reversible at doses approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily. Growth plate changes were associated with impairment of bone modeling, resulting in decreased femur length and with reduction in bone mineral density. Selpercatinib also induced reversible hypocellularity of bone marrow in males at >=30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily), and reversible alterations of dentin composition at >=50 mg/kg (approximately times the adult human exposure at the clinical dose of 160 mg twice daily). Irreversible, dose-dependent degeneration of testicular germinal epithelium, with vacuolation of Sertoli cells and corresponding depletion of spermatozoa in the epididymides, was also observed at >= 30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily) and affected male reproductive performance at 50 mg/kg (approximately times the adult human exposure at the clinical dose of 160 mg twice daily). Females exhibited delay in attainment of vaginal patency, marker of sexual maturity, at 125 mg/kg (approximately times the adult human exposure at the clinical dose of 160 mg twice daily); this effect was associated with lower mean body weight. Similar effects in irregular thickening of growth plates in adult rats and minipigs, and tooth dysplasia and malocclusion, resulting in tooth loss in adult rats were observed in repeat dose studies of up to 13-week duration with selpercatinib.Monitor growth plates in pediatric patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment.. 8.5 Geriatric Use. Of 857 patients who received RETEVMO, 35% (298 patients) were >=65 years of age and 10% (85 patients) were >=75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were >=65 years of age and younger patients.. 8.6 Renal Impairment. 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].The recommended dosage has not been established for patients with end-stage renal disease (ESRD) [see Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. Reduce the dose when administering RETEVMO to patients with severe [total bilirubin 3 to 10 upper limit of normal (ULN) and any AST] hepatic impairment [see Dosage and Administration (2.7)].No dosage modification is recommended for patients with mild (total bilirubin <= ULN with AST ULN or total bilirubin 1 to 1.5 ULN with any AST) or moderate (total bilirubin 1.5 to x ULN and any AST) hepatic impairment.Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hepatotoxicity: Monitor ALT and AST prior to initiating RETEVMO, every weeks during the first months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. (2.5, 5.1)Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms. Withhold, reduce the dose or permanently discontinue RETEVMO based on severity. (2.5, 5.2)Hypertension: Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating RETEVMO. Monitor BP after week, at least monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. (2.5, 5.3)QT Interval Prolongation: Monitor patients who are at significant risk of developing QTc prolongation. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment. Monitor QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on severity. (2.5, 5.4)Hemorrhagic Events: Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage. (2.5, 5.5)Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon resolution, resume at reduced dose and increase dose by dose level each week until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. (2.5, 5.6)Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. (5.7)Risk of Impaired Wound Healing: Withhold RETEVMO for at least days prior to elective surgery. Do not administer for at least 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. (5.8)Hypothyroidism: Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Withhold until clinically stable or permanently discontinue based on severity. (5.9)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the possible risk to fetus and to use effective contraception. (5.10, 8.1, 8.3)Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis (SCFE/SUFE) in Pediatric Patients: Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate (5.11, 6.1). Hepatotoxicity: Monitor ALT and AST prior to initiating RETEVMO, every weeks during the first months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. (2.5, 5.1). Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms. Withhold, reduce the dose or permanently discontinue RETEVMO based on severity. (2.5, 5.2). Hypertension: Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating RETEVMO. Monitor BP after week, at least monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. (2.5, 5.3). QT Interval Prolongation: Monitor patients who are at significant risk of developing QTc prolongation. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment. Monitor QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on severity. (2.5, 5.4). Hemorrhagic Events: Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage. (2.5, 5.5). Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon resolution, resume at reduced dose and increase dose by dose level each week until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. (2.5, 5.6). Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. (5.7). Risk of Impaired Wound Healing: Withhold RETEVMO for at least days prior to elective surgery. Do not administer for at least 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. (5.8). Hypothyroidism: Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Withhold until clinically stable or permanently discontinue based on severity. (5.9). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the possible risk to fetus and to use effective contraception. (5.10, 8.1, 8.3). Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis (SCFE/SUFE) in Pediatric Patients: Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate (5.11, 6.1). 5.1 Hepatotoxicity. Serious hepatic adverse reactions occurred in 4.6% of patients treated with RETEVMO. Increased AST occurred in 62% of patients, including Grade or events in 11% and increased ALT occurred in 58% of patients, including Grade or events in 13% [see Adverse Reactions (6.1)]. The median time to first onset for increased AST was weeks (range: 4.9 days to years) and increased ALT was 4.9 weeks (range: days to years).Monitor ALT and AST prior to initiating RETEVMO, every weeks during the first months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)].. 5.2 Interstitial Lung Disease/Pneumonitis. Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 3% of patients who received RETEVMO, including 0.3% with Grade or events, and 0.2% with fatal reactions.Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold RETEVMO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce the dose or permanently discontinue RETEVMO based on severity of confirmed ILD [see Dosage and Administration (2.5)].. 5.3 Hypertension. Hypertension occurred in 43% of patients, including Grade hypertension in 20% and Grade in one (0.1%) patient [see Adverse Reactions (6.1)]. Overall, 6.4% had their dose interrupted, 1.5% had their dose reduced, and 0.2% discontinued RETEVMO 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 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce the dose, or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)].. 5.4 QT Interval Prolongation. RETEVMO can cause concentration-dependent QT interval prolongation [see Clinical Pharmacology (12.2)]. An increase in QTcF interval to >500 ms was measured in 8% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 22% of patients [see Adverse Reactions (6.1)]. 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 reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)].. 5.5 Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with RETEVMO. Grade >=3 hemorrhagic events occurred in 4.3% of patients treated with RETEVMO, including (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n 2), tracheostomy site hemorrhage, and hemoptysis (1 each).Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.5)].. 5.6 Hypersensitivity. RETEVMO can cause hypersensitivity, including severe skin reactions such as Stevens-Johnson Syndrome. All grade hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade in 2%. The median time to onset was 1.9 weeks (range: days to 6.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. Stevens Johnsons Syndrome has been observed in the post-marketing setting [see Adverse Reactions (6.2)]. Discontinue RETEVMO in patients with Stevens Johnson Syndrome.If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at dose of mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at reduced dose and increase the dose of RETEVMO by dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration (2.5)]. Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity.. 5.7 Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred in 0.9% of patients with medullary thyroid carcinoma and 0.3% of patients with non-small cell lung cancer receiving RETEVMO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.. 5.8 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 days prior to elective surgery. Do not administer for at least 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.. 5.9 Hypothyroidism. RETEVMO can cause hypothyroidism. Hypothyroidism occurred in 15% of patients treated with RETEVMO; all reactions were Grade or 2. Hypothyroidism occurred in 15% of patients (59/390) with thyroid cancer and 14% of patients (65/467) with other solid tumors including NSCLC [see Adverse Reactions (6.1)].Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity [see Dosage and Administration (2.5)].. 5.10 Embryo-Fetal Toxicity. Based on data from animal reproduction studies and its mechanism of action, RETEVMO can cause fetal harm when administered to 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 and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for week after the last dose [see Use in Specific Populations (8.1, 8.3)].. 5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients. Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in adolescent (2.8% of 36 patients) receiving RETEVMO in LIBRETTO-121 and adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 [see Adverse Reactions (6.1)]. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate.