RETEVMO Capsule Ref.[10397] Active ingredients: Selpercatinib

5.1 Hepatotoxicity

Serious hepatic adverse reactions occurred in 2.6% of patients treated with RETEVMO. Increased AST occurred in 51% of patients, including Grade 3 or 4 events in 8% and increased ALT occurred in 45% of patients, including Grade 3 or 4 events in 9% [see Adverse Reactions (6.1)]. The median time to first onset for increased AST was 4.1 weeks (range: 5 days to 2 years) and increased ALT was 4.1 weeks (range: 6 days to 1.5 years).

Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)].

5.2 Hypertension

Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient [see Adverse Reactions (6.1)]. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.

Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)].

5.3 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 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% 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 dose reduce or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)].

5.4 Hemorrhagic Events

Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥ 3 hemorrhagic events occurred in 2.3% of patients treated with RETEVMO, including 3 (0.4%) patients with fatal hemorrhagic events, including one case each of cerebral hemorrhage, tracheostomy site hemorrhage, and hemoptysis.

Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.5)].

5.5 Hypersensitivity

Hypersensitivity occurred in 4.3% of patients receiving RETEVMO, including Grade 3 hypersensitivity in 1.6%. The median time to onset was 1.7 weeks (range: 6 days to 1.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis.

If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg. Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration (2.5)]. Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity.

5.6 Risk of Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, RETEVMO has the potential to adversely affect wound healing.

Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established.

5.7 Embryo-Fetal Toxicity

Based on data from animal reproduction studies and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for at least 1 week after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the final dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hepatotoxicity [see Warnings and Precautions (5.1)]
• Hypertension [see Warnings and Precautions (5.2)]
• QT Interval Prolongation [see Warnings and Precautions (5.3)]
• Hemorrhagic Events [see Warnings and Precautions (5.4)]
• Hypersensitivity [see Warnings and Precautions (5.5)]
• Risk of Impaired Wound Healing [see Warnings and Precautions (5.6)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

RET Gene Fusion or Gene Mutation Positive Solid Tumors

The pooled safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent at 160 mg orally twice daily evaluated in 702 patients in LIBRETTO-001 [see Clinical Studies (14)]. Among the 702 patients who received RETEVMO, 65% were exposed for 6 months or longer and 34% were exposed for greater than one year. Among these patients, 95% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily.

The median age was 59 years (range: 15 to 92 years); 0.3% were pediatric patients 12 to 16 years of age; 52% were male; and 69% were White, 22% were Asian, 5% were Hispanic/Latino, and 3% were Black. The most common tumors were NSCLC (47%), MTC (44%), and non-medullary thyroid carcinoma (5%).

Serious adverse reactions occurred in 33% of patients who received RETEVMO. The most frequent serious adverse reaction (in ≥2% of patients) was pneumonia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions which occurred in >1 patient included sepsis (n=3), cardiac arrest (n=3) and respiratory failure (n=3).

Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation included increased ALT (0.4%), sepsis (0.4%), increased AST (0.3%), drug hypersensitivity (0.3%), fatigue (0.3%), and thrombocytopenia (0.3%).

Dosage interruptions due to an adverse reaction occurred in 42% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥2% of patients included ALT increased, AST increased, hypertension, diarrhea, pyrexia, and QT prolongation.

Dose reductions due to an adverse reaction occurred in 31% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included ALT increased, AST increased, QT prolongation and fatigue.

The most common adverse reactions, including laboratory abnormalities, (≥25%) were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation.

Table 5 summarizes the adverse reactions in LIBRETTO-001.

Table 5. Adverse Reactions (≥15%) in Patients Who Received RETEVMO in LIBRETTO-001:

¹Diarrhea includes diarrhea, defecation urgency, frequent bowel movements, and anal incontinence
²Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain
³Fatigue includes fatigue, asthenia, malaise
⁴Edema includes edema, edema peripheral, face edema, eye edema, eyelid edema, generalized edema, localized edema, lymph edema, scrotal edema, peripheral swelling, scrotal swelling, swelling, swelling face, eye swelling, peripheral swelling
⁵Includes rash, rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash pruritic
⁶Headache includes headache, sinus headache, tension headache
⁷Includes cough, productive cough
⁸Includes dyspnea, dyspnea exertional, dyspnea at rest
⁹Hemorrhage includes epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, gastric hemorrhage, hemorrhage intracranial, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, diverticulum intestinal hemorrhagic, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic anemia, intraabdominal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, pelvic hematoma, periorbital hematoma, pharyngeal hemorrhage, pulmonary contusion, purpura, retroperitoneal hematoma, subarachnoid hemorrhage, subdural hemorrhage, upper gastrointestinal hemorrhage, vessel puncture site hematoma
^* Only includes a grade 3 adverse reaction.

Clinically relevant adverse reactions in ≤15% of patients who received RETEVMO include hypothyroidism (9%).

Table 6 summarizes the laboratory abnormalities in LIBRETTO-001.

Table 6. Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-001:

¹ Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 675 to 692 patients

Increased Creatinine

In 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)].

7.1 Effects of Other Drugs on RETEVMO

Acid-Reducing Agents

Concomitant 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 a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) [see Dosage and Administration (2.4)].

Strong and Moderate CYP3A Inhibitors

Concomitant use of RETEVMO with a 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), Warning and Precautions (5.3)].

Strong and Moderate CYP3A Inducers

Concomitant use of RETEVMO with a 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 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 [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.

7.3 Drugs that Prolong QT Interval

RETEVMO is associated with QTc interval prolongation [see Warnings and Precautions (5.3), 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.

Risk Summary

Based on findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], 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 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Selpercatinib 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], 6 of 8 females had 100% early resorptions; the remaining 2 females had high levels of early resorptions with only 3 viable fetuses across the 2 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).

Risk Summary

There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with RETEVMO and for 1 week after the final dose.

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 Testing

Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO [see Use in Specific Populations (8.1)].

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the final dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the final dose.

Infertility

RETEVMO may impair fertility in females and males of reproductive potential [See Nonclinical Toxicology (13.1)].

The safety and effectiveness of RETEVMO have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)]. The safety and effectiveness of RETEVMO have not been established in these indications in patients less than 12 years of age.

The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications [see Indications and Usage (1)].

Animal Toxicity Data

In 4-week general toxicology studies in rats, animals showed signs of physeal hypertrophy and tooth dysplasia at doses resulting in exposures ≥ approximately 3 times the human exposure at the 160 mg twice daily clinical dose. Minipigs also showed signs of minimal to marked increases in physeal thickness at the 15 mg/kg high dose level (approximately 0.3 times the human exposure at the 160 mg twice daily clinical dose). Rats in both the 4- and 13-week toxicology studies had malocclusion and tooth discoloration at the high dose levels (≥ 1.5 times the human exposure at the 160 mg twice daily clinical dose) that persisted during the recovery period.

Of 702 patients who received RETEVMO, 34% (239 patients) were ≥65 years of age and 10% (67 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.

No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] ≥30 mL/min, estimated by Cockcroft-Gault). The recommended dosage has not been established for patients with severe renal impairment (CLcr <30 mL/min) or end-stage renal disease [see Clinical Pharmacology (12.3)].

Reduce the dose when administering RETEVMO to patients with severe [total bilirubin greater than 3 to 10 times 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 less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment. Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)].