Retevmo Drug Information

Patient Selection

Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC, thyroid cancer, or other solid tumors) or specific RET gene mutation (MTC) in tumor specimens. 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.

Important Administration Instructions RETEVMO may be taken with or without food unless coadministered with a proton pump inhibitor (PPI). 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 a feeding tube, prepare and administer RETEVMO as a dispersion; only RETEVMO 40 mg tablets may be used to create the dispersion.

Recommended Dosage

The recommended dosage of RETEVMO administered as recommended and given until disease progression or unacceptable toxicity is shown in Table 1: Table 1: Missed Dose Do not take a missed dose unless it is more than 6 hours until next scheduled dose. Vomiting If vomiting occurs after RETEVMO administration, do not take an additional dose and continue to the next scheduled time for the next dose.

Dosage Modifications for Concomitant Use of Acid-Reducing Agents Avoid concomitant use of a PPI, a histamine-2 (H2) receptor antagonist, or a locally-acting antacid with RETEVMO. If concomitant use cannot be avoided: Take RETEVMO with food when coadministered with a PPI. Take RETEVMO 2 hours before or 10 hours after administration of an H2 receptor antagonist.

Table 2: Recommended RETEVMO The recommended dosage modifications for adverse reactions are provided in Table 3. Table 3: s Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the RETEVMO dose as recommended in Table 4.

After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume RETEVMO at the dose taken prior to initiating the CYP3A inhibitor. Table 4: for Severe Hepatic Impairment Reduce the recommended dosage of RETEVMO for patients with severe hepatic impairment as recommended in Table 5. Table 5:

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 Administration To prepare RETEVMO tablet as a dispersion: In a glass or medicine cup, add the correct number of 40 mg RETEVMO tablets required for the prescribed dose tablets, to approximately 1 tablespoon (15 mL) of room temperature or chilled water or 100% carrot puree.

Stir intermittently until tablet(s) have dispersed (approximately 7 to 10 minutes). Some settling may occur and the dispersion may appear cloudy if water is used. Administer the entire dispersion immediately.

Add 1 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 2 hours. RETEVMO 40 mg tablets for Feeding Tubes (Gastrostomy or Nasogastric Tube) Administration Use only polyurethane (French size 8 or larger) or vinyl chloride (French size 10 or larger) nasogastric tube or silicone (French size 14 or larger) gastrostomy tube.

In a glass or medicine cup, add the correct number of 40 mg RETEVMO tablet(s) required for the prescribed dose tablets, to a minimum of 10 mL of room temperature water. Flush the feeding tube according to manufacturer's instructions. Draw the dispersion into an enteral syringe and administer the dispersion via the feeding tube immediately.

Add 5 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 857 patients with advanced solid tumors in LIBRETTO-001. Among these patients, 97% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily.

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.

Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. 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 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), decreased sodium, increased aspartate aminotransferase (AST), decreased calcium, and decreased phosphate. Table 6 summarizes the adverse reactions in LIBRETTO-001. Table 7 summarizes the laboratory abnormalities in LIBRETTO-001.

Table 7: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received The safety population described below reflects exposure to RETEVMO as a single agent at 92 mg/m 2 orally twice daily evaluated in 36 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121. The median age was % 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 occurring in more than 1 patient were vomiting and fracture (2 patients each). Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, ascites, increased bilirubin, decreased neutrophils, and pyrexia. 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 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, decreased calcium, decreased hemoglobin, decreased neutrophils, increased ALT, decreased magnesium, and decreased potassium. Table 9 summarizes the laboratory abnormalities in LIBRETTO-121.

Table 9: Select Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients Who Received Treatment-naïve RET Fusion-Positive Non-Small Cell Lung Cancer LIBRETTO-431 The safety population described below reflects exposure to RETEVMO as a 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-.9 months; 87% were exposed for 6 months or longer and 70% were exposed for one year or longer. The median age was % were American Indian or Alaska Native, and 3.2% were missing. 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). Adverse reactions resulting in permanent discontinuation in ≥1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%). 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 3 or 4 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 11 summarizes the laboratory abnormalities in LIBRETTO-431. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed. RET-Mutant Medullary Thyroid Cancer LIBRETTO-531 The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg (adults) or at 92 mg/m 2 (adolescent, not to exceed 160 mg) orally twice daily, in patients with progressive, advanced, kinase inhibitor naïve, RET -mutant medullary thyroid cancer in LIBRETTO-531.

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). 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).

Adverse reactions requiring dosage omission in ≥5% of patients included ALT increased (9%) and hypertension (7%). One adverse reaction, increased ALT (7%), required a dose reduction in ≥5% of patients. Table 13 summarizes the laboratory abnormalities in LIBRETTO-531.

Postmarketing Experience

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

Effects of Other Drugs on RETEVMO Acid-Reducing Agents

Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations, 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 a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid).

Strong and Moderate CYP3A Inhibitors Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations, which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation. 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. Strong and Moderate CYP3A Inducers Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations, which may reduce RETEVMO anti-tumor activity.

Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.

Effects of RETEVMO on Other Drugs CYP2C8 and CYP3A Substrates RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations, which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions.

If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling. Certain P-gp and BCRP Substrates RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations, 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.

Drugs that Prolong QT Interval RETEVMO is associated with QTc interval prolongation. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

Pregnancy Risk Summary Based on findings from animal studies, and its mechanism of action, RETEVMO can cause fetal harm when administered to a 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 a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data Selpercatinib administration to pregnant rats during the period of organogenesis at oral doses ≥100 mg/kg resulted in 100% post-implantation loss.

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).

Pediatric Use The safety and effectiveness of RETEVMO have been established in pediatric patients aged 2 years and older for the treatment of: advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation who require systemic therapy advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate) locally advanced or metastatic solid tumors with a 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 2 years and older. 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.

The safety and effectiveness of RETEVMO have not been established in these indications in patients aged less than 2 years. The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications. Juvenile Animal Toxicity Data In a juvenile rat toxicity study, animals were dosed daily with selpercatinib from post-natal day 21 to day 70 (approximately equivalent to a 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 3 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 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Females exhibited delay in attainment of vaginal patency, a marker of sexual maturity, at 125 mg/kg (approximately 4 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.