RET Fusion-Positive Non-Small Cell Lung Cancer 

RETEVMO^® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an approved test.

RET-Mutant Medullary Thyroid Cancer 

RETEVMO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an approved test, who require systemic therapy.

RET Fusion-Positive Thyroid Cancer 

RETEVMO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

Other RET Fusion-Positive Solid Tumors

RETEVMO is indicated for the treatment of adult patients with 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.

Posology

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 [see Pharmacodynamic Properties (5.1)].

Important Administration Instructions 

RETEVMO may be taken with or without food unless coadministered with a proton pump inhibitor (PPI) [see Pharmacodynamic Properties (5.1)].

Recommended Dosage 

The recommended dosage of RETEVMO based on body weight is:

·   Less than 50 kg: 120 mg

·   50 kg or greater: 160 mg

The recommended starting dose for patients with severe hepatic impairment is 80 mg orally, twice daily.

Take RETEVMO orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity.

Swallow the capsules whole. Do not crush or chew the capsules.

Do not take a missed dose unless it is more than 6 hours until next scheduled dose.

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 [see Interaction with other medicinal products and other forms of interaction (4.5)]. 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.

·       Take RETEVMO 2 hours before or 2 hours after administration of a locally-acting antacid.

Dosage Modifications for Adverse Reactions 

Management of some adverse reactions may require dose interruption and/or dose reduction. Generally, dose reductions should be in 40-mg decrements.

The recommended dose reductions for adverse reactions are provided in Table 1.

Table 1: Recommended RETEVMO Dose Reductions for Adverse Reactions 

Permanently discontinue RETEVMO in patients unable to tolerate three dose reductions.

The recommended dosage modifications for adverse reactions are provided in Table 2.

Table 2: Recommended RETEVMO Dosage Modifications for Adverse Reactions 

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 a strong or moderate CYP3A inhibitor cannot be avoided, reduce the RETEVMO dose as recommended in Table 3. 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 [see Interaction with other medicinal products and other forms of interaction (4.5)].

Table 3: Recommended RETEVMO Dosage for Concomitant Use of Strong and Moderate CYP3A Inhibitors 

Dosage Modification for Severe Hepatic Impairment 

Reduce the recommended dosage of RETEVMO for patients with severe hepatic impairment as recommended in Table 4  [see Undesirable effects (4.8)].

Table 4: Recommended RETEVMO Dosage for Severe Hepatic Impairment 

Method of administration

Oral use

• Hepatotoxicity 

  Serious hepatic adverse reactions occurred in 3% of patients treated with RETEVMO. Increased AST occurred in 59% of patients, including Grade 3 or 4 events in 11% and increased ALT occurred in 55% of patients, including Grade 3 or 4 events in 12% [Undesirable effects (4.8)]. The median time to first onset for increased AST was 6 weeks (range: 1 day to 3.4 years) and increased ALT was 5.8 weeks (range: 1 day to 2.5 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 Posology and method of administration (4.2)].

  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 1.8% of patients who received RETEVMO, including 0.3% with Grade 3 or 4 events, and 0.3% 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 dose or permanently discontinue RETEVMO based on severity of confirmed ILD [see Posology and method of administration (4.2)].

   

  Hypertension 

  Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Undesirable effects (4.8)]. Overall, 6.3% 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 Posology and method of administration (4.2)].

  QT Interval Prolongation 

  RETEVMO can cause concentration-dependent QT interval prolongation [see Pharmacological properties (5)]. An increase in QTcF interval to >500 ms was measured in 7% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 20% of patients [see Undesirable effects (4.8)]. 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 Posology and method of administration (4.2)].

  Hemorrhagic Events 

  Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥ 3 hemorrhagic events occurred in 3.1% of patients treated with RETEVMO, including 4 (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n = 2), tracheostomy site hemorrhage (n = 1), and hemoptysis (n=1).

  Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage [see Posology and method of administration (4.2)]. 

  Hypersensitivity 

  Hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 hypersensitivity in 1.9%. The median time to onset was 1.9 weeks (range: 5 days to 2 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis.    

  If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Posology and method of administration (4.2)]. Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity. 

  Tumor Lysis Syndrome

  Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

   

  Risk of Impaired Wound Healing 

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

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

   

  Hypothyroidism

  RETEVMO can cause hypothyroidism. Hypothyroidism occurred in 13% of patients treated with RETEVMO; all reactions were Grade 1 or 2. Hypothyroidism occurred in 13% of patients (50/373) with thyroid cancer and 13% of patients (53/423) with other solid tumors including NSCLC [see Posology and method of administration (4.2)].

  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 Posology and method of administration (4.2)].

   

  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 and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Fertility, pregnancy and lactation (4.6)].

Effects of Other Drugs on RETEVMO 

Acid-Reducing Agents

Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations [see Pharmacological properties (5)], 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 Posology and method of administration (4.2)].

Strong and Moderate CYP3A Inhibitors

Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations [see Pharmacological properties (5)], 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 Posology and method of administration (4.2), Special Warnings and precautions for use (4.4)].

Strong and Moderate CYP3A Inducers

Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations [see Pharmacological properties (5)], 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 [see Pharmacological properties (5)], 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 Substrates

RETEVMO is a P-gp inhibitor. Concomitant use of RETEVMO with P-gp substrates increases their plasma concentrations [see Pharmacological properties (5)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp substrates provided in their approved product labeling.

Drugs that Prolong QT Interval 

RETEVMO is associated with QTc interval prolongation [see Special warnings and precautions for use (4.4), Pharmacological properties (5)]. 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 [see Pharmacological properties (5)], 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 and fetal loss 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).

Lactation 

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 last dose.

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 Undesirable effects (4.8)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO [see Undesirable effects (4.8)].

Contraception

Females

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

Males

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

Infertility

RETEVMO may impair fertility in females and males of reproductive potential [see Fertility, pregnancy and lactation (4.1), Preclinical safety data (5.3)].

Results of fertility studies conducted in rats, and results of general toxicology studies in rats and minipigs, indicated injury to reproductive tissues, suggesting that selpercatinib could impair fertility in males and females.

No studies have been conducted to determine the effects of selpercatinib on the ability to drive or use machines.

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

·       Hepatotoxicity [see Special warnings and precautions for use (4.4)]

·      Interstitial Lung Disease / Pneumonitis [see Special warnings and precautions for use (4.4)]

·       Hypertension [see Special warnings and precautions for use (4.4)]

·       QT Interval Prolongation [see Special warnings and precautions for use (4.4)]

·       Hemorrhagic Events [see Special warnings and precautions for use (4.4)]

·       Hypersensitivity [see Special warnings and precautions for use (4.4)]

·       Tumor Lysis Syndrome [see Special warnings and precautions for use (4.4)]

·       Risk of Impaired Wound Healing [see Special warnings and precautions for use (4.4)]

·      Hypothyroidism [see Special warnings and precautions for use (4.4)]

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.

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 796 patients with advanced solid tumors in LIBRETTO-001 [see Pharmacodynamic properties (5.1)]. Among the 796 patients who received RETEVMO, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. Among these patients, 96% 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; 51% were male; and 69% were White, 23% were Asian, 5% were Hispanic/Latino, and 3% were Black. The most common tumors were NSCLC (45%), MTC (40%), and non-medullary thyroid carcinoma (7%).

Serious adverse reactions occurred in 44% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n = 6), respiratory failure (n = 5), hemorrhage (n = 4), pneumonia (n = 3), pneumonitis (n = 2), cardiac arrest (n=2), sudden death (n = 1), and cardiac failure (n = 1). 

Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥0.5% of patients included increased ALT (0. 6%), fatigue (0.6%), sepsis (0.5%), and  increased AST (0.5%).

Dosage interruptions due to an adverse reaction occurred in 64% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in > 5% of patients included increased ALT, increased AST, diarrhea, and hypertension.

Dose reductions due to an adverse reaction occurred in 41% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in > 2% of patients included increased ALT, increased AST, QT prolongation, fatigue, diarrhea, drug hypersensitivity, and edema.

The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium.

Table 5 summarizes the adverse reactions in LIBRETTO-001.

Table 5: Adverse Reactions (≥ 20%) in Patients Who Received RETEVMO in LIBRETTO-001 

¹Diarrhea includes diarrhea, defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence.

²Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain.

3Edema includes edema, 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.

4      Fatigue includes fatigue, asthenia, malaise.

⁵Rash includes  rash, rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular. 

⁶Headache includes headache, sinus headache, tension headache.

⁷Includes cough, productive cough, upper airway cough syndrome.

⁸Includes dyspnea, dyspnea exertional, dyspnea at rest.
⁹Hemorrhage includes hemorrhage, 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, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemorrhoidal hemorrhage, hepatic hemorrhage, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, post procedural hemorrhage, postmenopausal hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma.

^*Only includes a grade 3 adverse reaction.

^#    Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03

Clinically relevant adverse reactions in ≤ 15% of patients who received RETEVMO include hypothyroidism (13%); hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all < 2%).

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 765 to 791 patients.

^#    Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03

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 Pharmacological properties (5)].

Pediatric Use 

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 Undesirable effects (4.8), Pharmacological properties (5), Pharmacodynamic properties (5.1)].  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 Therapeutic indications (4.1)].

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 affect 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 adolescent 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.

Geriatric Use 

Of 796 patients who received RETEVMO, 34% (268 patients) were ≥ 65 years of age and 9% (74 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. 

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 Pharmacological properties (5)].

No clinically significant changes were observed across the spectrum of renal impairment as assessed by estimating glomerular filtration rates. No data are available for patients with end-stage renal disease regardless of whether dialysis is used.

Hepatic Impairment 

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 Posology and method of administration (4.2)]. 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 Pharmacological properties (5)].

Selpercatinib is metabolized in the liver. In adults with severe hepatic impairment (Child-Pugh class C), unbound C_max increased 132% and unbound AUC₀-∞ increased 228% for plasma unbound selpercatinib. The recommended dose for patients with severe hepatic impairment is 80 mg orally, twice daily.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed here.

In case of overdose, use supportive therapy. There is no known antidote for selpercatinib overdose.

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents, protein kinase inhibitors, ATC code: L01EX22  

Mechanism of Action 

Selpercatinib is a 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 3 at higher concentrations that were still clinically achievable. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 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 a patient-derived RET fusion positive tumor.

Pharmacodynamics 

Exposure-Response Relationship

Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology

The effect of RETEVMO on the QTc interval was evaluated in a 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 (C_max) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.

CLINICAL STUDIES 

RET Fusion-Positive Non-Small Cell Lung Cancer 

The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive NSCLC enrolled in a 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 a 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 a blinded independent review committee (BIRC) according to RECIST v1.1.

RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy

Efficacy was evaluated in 247 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy enrolled into a 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, and 2.8% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3%) and 97% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1–15); 58% had prior anti‑PD‑1/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 7.

Table 7: 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 estimable

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 2 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-naïve RET Fusion-Positive NSCLC 

Efficacy was evaluated in 69 patients with treatment-naïve RET fusion-positive NSCLC enrolled into a 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. ECOG performance status was 0-1 (94%) or 2 (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 naïve RET fusion-positive NSCLC are summarized in Table 8.

Table 8: Efficacy Results in LIBRETTO-001 (Treatment-Naïve RET Fusion-Positive NSCLC) 

¹ Confirmed overall response rate assessed by BIRC.

² Based on observed duration of response.

NE = not estimable

Among the 69 patients with treatment-naïve RET fusion-positive NSCLC, 5 had measurable CNS metastases at baseline as assessed by BIRC. Two patients received RT to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 4 of these 5 patients; 38% of responders had an intracranial DOR of ≥ 12 months.

RET-Mutant Medullary Thyroid Cancer 

The efficacy of RETEVMO was evaluated in patients with RET-mutant MTC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, 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 naïve to cabozantinib and vandetanib in separate cohorts.

RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib

Efficacy was evaluated in 55 patients with RET-mutant advanced MTC who had previously treated with cabozantinib or vandetanib enrolled into a 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 2 (5%) and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 – 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 9.

Table 9: Mutations used to Identify and Enroll Patients with RET-Mutant MTC in LIBRETTO-001 

¹ 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), D631_L633delinsV (2), D631_L633delinsE (5), D378_G385delinsE (1), D898_E901del (2), A883F (4), E632_L633del (4), L790F (2), T636_V637insCRT(1), D898_E901del + D903_S904delinsEP (1).

⁴ One patient also had a M918T mutation.

Efficacy results for RET-mutant MTC are summarized in Table 10.

Table 10: 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 estimable

Cabozantinib and Vandetanib-naïve RET-Mutant MTC

Efficacy was evaluated in 88 patients with RET-mutant MTC who were cabozantinib and vandetanib treatment-naïve enrolled into a 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 2 (3.4%). All patients (100%) had metastatic disease and 18% had received 1 or 2 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 9.

Efficacy results for cabozantinib and vandetanib-naïve RET-mutant MTC are summarized in Table 11.

Table 11: Efficacy Results in LIBRETTO-001 (Cabozantinib and Vandetanib-naïve RET-Mutant MTC) 

¹ Confirmed overall response rate assessed by BIRC.

² Based on observed duration of response.

NE = not estimable

RET Fusion-Positive Thyroid Cancer 

The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive thyroid cancer enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 27 patients with RET fusion-positive thyroid cancer who were radioactive iodine (RAI)-refractory (if RAI was an appropriate treatment option) and were systemic therapy naïve and patients with RET fusion-positive thyroid cancer who were RAI-refractory and had received sorafenib, lenvatinib, or both, in separate cohorts.

The median age was 54 years (range 20 to 88); 52% were male; 74% were White, 11% were Hispanic/Latino, 7.4% were Asian, and 3.7% were Black. ECOG performance status was 0‑1 (89%) or 2 (11%). All (100%) patients had metastatic disease with primary tumor histologies including papillary thyroid cancer (78%), poorly differentiated thyroid cancer (11%), anaplastic thyroid cancer (7%) and Hurthle cell thyroid cancer (4%). Patients had received a median of 3 prior therapies (range 1–7).  RET fusion-positive status was detected in 93% of patients using NGS tumor samples and in 7% using blood samples.

Efficacy results for RET fusion-positive thyroid cancer are summarized in Table 12.

Table 12: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive Thyroid Cancer) 

¹Confirmed overall response rate assessed by BIRC.

² Based on observed duration of response.

NE = not estimable

14.4    Other RET Fusion-Positive Solid Tumors

The efficacy of RETEVMO was evaluated in patients with locally advanced or metastatic RET fusion-positive solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 41 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 50 years (range 21 to 85), 54% were female, 68% were White, 24% were Asian, and 4.9% were Black; 7% were Hispanic/Latino. ECOG performance status was 0-1 (95%) or 2 (5%) and 95% of patients had metastatic disease. Thirty-seven patients (90%) received prior systemic therapy (median 2 [range 0 – 9]; 32% received 3 or more). The most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%) and unknown primary (7%). RET fusion-positive status was detected in 97.6% of patients using NGS and 2.4% using FISH.

Efficacy results for RET fusion-positive solid tumors other than NSCLC and thyroid cancer are summarized in Table 14 and Table 15.

Table 14: 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.

NE = not estimable

Table 15: 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.

The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. Steady state selpercatinib AUC and C_max increased in a 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 7 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%)] C_max was 2,980 (53%) ng/mL and AUC_0-24h was 51,600 (58%) ng*h/mL.

Absorption

The median t_max of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects.

Effect of Food

No clinically significant differences in selpercatinib AUC or C_max were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects.

Distribution

The apparent volume of distribution (V_ss/F) of selpercatinib is 191 L.

Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7.

Elimination

The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects.

Metabolism

Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma.

Excretion

Following oral administration of a 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 Populations

The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (27 kg to 179 kg).

No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (15 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.

Patients with Hepatic Impairment

The selpercatinib AUC_0-INF increased by 7%, 32%, and 77% in subjects 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), moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, respectively, compared to subjects with normal hepatic function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC_0-INF and C_max when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC_0-INF and C_max when RETEVMO was administered with food (Table 15).

Table 15: Change in Selpercatinib Exposure After Coadministration with PPI 

¹ 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 g of fat.

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 2 hours after the RETEVMO dose (administered fasting).

Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC_0-INF by 133% and C_max by 30%.

Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC by 60‑99% and C_max by 46-76%.

Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC_0-INF by 87% and C_max 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 C_max 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 C_max by 26%.

CYP2C8 Substrates: Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC_0-INF by 188% and C_max by 91%.

CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A substrate) increased the midazolam AUC_0-INF by 54% and C_max by 39%.

P-glycoprotein (P-gp) Substrates: Coadministration of RETEVMO with dabigatran (P-gp substrate) increased the dabigatran AUC_0-INF by 38% and C_max by 43%.

P-gp Inhibitors: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a 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 Studies

CYP Enzymes: Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.

Transporter Systems: Selpercatinib inhibits MATE1 and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Undesirable effects (4.8)]. Selpercatinib is a substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.

Locally acting antacids

Administer selpercatinib 2 hours before or 2 hours after locally acting antacids.

Carcinogenesis, Mutagenesis, Impairment of Fertility 

Carcinogenicity studies have not been conducted with selpercatinib. 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 C_max 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 recommended human dose.  In a 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 dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display a 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 dose) accompanied by altered sperm morphology at 30 mg/kg.

In a 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 a 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 a 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea at a 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).

40 mg

Capsule Fill Excipients

·       colloidal silicon dioxide

·       microcrystalline cellulose
 

Capsule Shell Ingredients

·       gelatin

·       titanium dioxide

·       iron oxide, black

Black Ink Ingredients

·       shellac

·       dehydrated alcohol

·       Isopropyl alcohol

·       butyl alcohol

·       propylene glycol

·       purified water

·       strong ammonia solution

·       potassium hydroxide

·       iron oxide black

80 mg

Capsule Fill Excipients

·       colloidal silicon dioxide

·       microcrystalline cellulose
 

Capsule Shell Ingredients

·       gelatin

·       titanium dioxide

·       FD&C Blue No. 1

Black Ink Ingredients

·       Shellac

·       dehydrated alcohol

·       Isopropyl alcohol

·       butyl alcohol

·       propylene glycol

·       purified water

·       strong ammonia solution

·       potassium hydroxide

·       iron oxide black

Not applicable

Do not store above 30°C.

RETEVMO (selpercatinib) capsules are supplied as follows:
40 mg: Gray opaque, imprinted with “Lilly”, “3977” and “40 mg” in black ink
• 60 count bottle
80 mg: Blue opaque, imprinted with “Lilly”, “2980” and “80 mg” in black ink
• 60 count bottle
• 120 count bottle

Not all pack sizes may be marketed.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Patient Counseling Information 

Advise the patient to read the approved patient labeling (Patient Information).

Hepatotoxicity

Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity [see Special warnings and precautions for use (4.4)].

Interstitial Lung Disease (ILD)/Pneumonitis

Advise 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 Special warnings and precautions for use (4.4)].

Hypertension

Advise 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 Special warnings and precautions for use (4.4)].

QT Prolongation

Advise 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 Special warnings and precautions for use (4.4)].

Hemorrhagic Events

Advise 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 Special warnings and precautions for use (4.4)].

Hypersensitivity Reactions

Advise patients to monitor for signs and symptoms of hypersensitivity reactions, particularly during the first month of treatment [see Special warnings and precautions for use (4.4)].

Tumor Lysis Syndrome

Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS [see Special warnings and precautions for use (4.4)].

Risk of Impaired Wound Healing

Advise patients that RETEVMO may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Special warnings and precautions for use (4.4)].

Hypothyroidism

Advise patients that RETEVMO can cause hypothyroidism and to immediately contact their healthcare provider for signs or symptoms of hypothyroidism [see Special warnings and precautions for use (4.4)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the possible risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Special warnings and precautions for use (4.4), Fertility, pregnancy and lactation (4.6)].

Advise females of reproductive potential to use effective contraception during the treatment with RETEVMO and for 1 week after the last dose [see Fertility, pregnancy and lactation (4.6)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Fertility, pregnancy and lactation (4.6)].

Lactation

Advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose [see Fertility, pregnancy and lactation (4.6)].

Infertility

Advise males and females of reproductive potential that RETEVMO may impair fertility [see Fertility, pregnancy and lactation (4.6), Preclinical safety data (5.3)].

Drug Interactions

Advise 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. John’s 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 2 hours before or 10 hours after the H2 receptor antagonist. If locally-acting antacids are required, instruct patients to take RETEVMO 2 hours before or 2 hours after the locally-acting antacid [see Interaction with other medicinal products and other forms of interaction (4.4)].