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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
RETEVMO (NDA-213246)
(SELPERCATINIB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
11/20/2025 (SUPPL-15)
5 Warnings and Precautions
5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients
Additions and/or revisions underlined:
Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in 1 adolescent (2.8% of 36 patients) receiving RETEVMO in LIBRETTO-121 and 1 adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 [see Adverse Reactions (6.1)]. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate [see Adverse Reactions (6.1)].
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined
. . .
LIBRETTO-121
The safety population described below reflects exposure to RETEVMO as a single agent at 92 mg/m2 orally twice daily evaluated in 36 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121 [see Clinical Studies (14)]. Among the 36 pediatric and adolescent patients who received RETEVMO, 86% were exposed for 6 months or longer and 72% were exposed for greater than one year.
The median age was 13 years (range: 2 to 20 years); 31% were pediatric patients 2 to 12 years of age; 53% were male; and 47% were White, 28% were Asian, and 8% were Black or African American; and 19% were Hispanic/Latino. The most common cancers were MTC (42%), and papillary thyroid cancer (42%).
Serious adverse reactions occurred in 42% of patients who received RETEVMO. Serious adverse reactions occurring in more than 1 patient were vomiting and fracture (2 patients each). Dosage interruptions due to an adverse reaction occurred in 42% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in greater than or equal to 5% of patients included increased ALT, increased AST, ascites, increased bilirubin, decreased neutrophils, and pyrexia.
Dose reductions due to an adverse reaction occurred in 22% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in greater than or equal to 2% of patients included increased ALT, decreased neutrophils, increased weight, and increased bilirubin.
The most common adverse reactions (greater than or equal to 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 (greater than or equal to 5%) were decreased lymphocytes, decreased calcium, decreased hemoglobin, decreased neutrophils, increased ALT, decreased magnesium, and decreased potassium.
Table 8 summarizes the adverse reactions in LIBRETTO-121.
Table 8: Adverse Reactions (greater than or equal to 15%) in Patients Who Received RETEVMO in LIBRETTO-121
Extensive changes in table; please refer to label for complete information.
Clinically relevant adverse reactions in <15% of patients who received RETEVMO include dizziness (14%), electrocardiogram QT prolonged (14%), hypersensitivity (11%), stomatitis (14%), proteinuria (11%), hypertension (8%), decreased appetite (8%), erectile dysfunction (6%), chylous ascites (2.8%), dry mouth (2.8%), epiphysiolysis (2.8%), and pneumonia (2.8%).
Table 9 summarizes the laboratory abnormalities in LIBRETTO-121.
Table 9: Select Laboratory Abnormalities (greater than or equal to 15%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-121
Extensive changes in table; please refer to label for complete information.
. . .
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
How should I take RETEVMO?
. . .
- Do not take or give RETEVMO capsules or tablets if you or your child are unable to swallow.
- If you or your child are unable to swallow RETEVMO whole or if you or your child has a feeding tube, RETEVMO can be prepared and taken or given as a dispersion using only the RETEVMO 40 mg tablets. See the Instructions for Use that comes with RETEVMO for information about the right way to prepare and take or give a dose of RETEVMO 40 mg tablets.
. . .
The most common side effects of RETEVMO in children 2 years and older with solid tumors include:
- muscle and bone pain
- vomiting
- diarrhea
- tiredness
- nausea
- cough
- bleeding
- rash
- fever
- coronavirus infection
- stomach-area (abdominal) pain
- upper respiratory tract infection
- headache
- swelling
. . .
The most common severe abnormal laboratory test results with RETEVMO in children 2 years and older with solid tumors include decreased white blood cell count, decreased levels of calcium in the blood, decreased red blood cell count, increased liver enzymes, decreased levels of magnesium in the blood, and decreased levels of potassium in the blood.
. . .
11/20/2025 (SUPPL-16)
5 Warnings and Precautions
5.6 Hypersensitivity
Additions and/or revisions underlined:
RETEVMO can cause hypersensitivity, including severe skin reactions such as Stevens Johnson Syndrome. All grade hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 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. Stevens Johnsons Syndrome has been observed in the post-marketing setting [see Adverse Reactions (6.2)]. Discontinue RETEVMO in patients with Stevens Johnson Syndrome.
If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at 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 Dosage and Administration (2.5)]. Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity.
6 Adverse Reactions
6.2 Postmarketing Experience
Newly added subsection:
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
12/18/2024 (SUPPL-14)
7 Drug Interactions
7.2 Effects of RETEVMO on Other Drugs
Additions and/or revisions underlined:
…
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 [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P- gp and BCRP substrates provided in their approved product labeling.
09/27/2024 (SUPPL-11)
5 Warnings and Precautions
5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients
Additions and/or revisions underlined:
Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in 1 adolescent (3.7% of 27 patients) receiving RETEVMO in LIBRETTO-121 and 1 adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 [see Adverse Reactions (6.1)]. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate [see Adverse Reactions (6.1)].
6 Adverse Reactions
6.1 Clinical Trials Experience
Extensive changes; please refer to label
06/12/2024 (SUPPL-9)
6 Adverse Reactions
6.1 Clinical Trials ExperienceExtensive changes to table; please refer to label
Additions and revisions underlined:
Clinically relevant adverse reactions in ?15% of patients who received RETEVMO include hypothyroidism (13%); pneumonia (11%), hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all < 2%).
09/21/2022 (SUPPL-7)
5 Warnings and Precautions
5.1 Hepatoxicity
Additions and/or revisions underlined:
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% [see Adverse Reactions (6.1)]. 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 Dosage and Administration (2.5)].
Newly added subsection:
5.2 Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 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 Dosage and Administration (2.5)].
5.3 Hypertension
Additions and/or revisions underlined:
Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Adverse Reactions (6.1)]. Overall, 6.3% had their dose interrupted and 1.3% had their dose reduced for hypertension …
5.4 QT Interval Prolongation
Additions and/or revisions underlined:
RETEVMO can cause concentration-dependent QT interval prolongation [see Clinical Pharmacology (12.2)]. 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 Adverse Reactions (6.1)] …
5.5 Hemorrhagic Events
Additions and/or revisions underlined:
Serious including fatal hemorrhagic events can occur with RETEVMO. Grade greater than or equal to 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) …
5.6 Hypersensitivity
Additions and/or revisions underlined:
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 …
5.7 Tumor Lysis Syndrome
Additions and/or revisions underlined:
Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO [see Adverse Reactions (6.1)] …
Newly added subsection:
5.9 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 Adverse Reactions (6.1)].
Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity [see Dosage and Administration (2.5)].
5.10 Embryo-Fetal Toxicity
Additions and/or revisions underlined:
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 Use in Specific Populations (8.1, 8.3)].
6 Adverse Reactions
Newly added to bulleted line listing:
Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.2)]
Hypothyroidism [see Warnings and Precautions (5.9)]
6.1 Clinical Trials Experience
Extensively changed; please refer to label for complete information.
7 Drug Interactions
7.2 Effects of RETEVMO on Other DrugsNewly added information:
Certain P-gp Substrates
RETEVMO is a P-gp inhibitor. Concomitant use of RETEVMO with P-gp substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp 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.
8 Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined:
… The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications [see Indications and Usage (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 physical 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 greater than or equal to 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 greater than or equal to 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 greater than or equal to 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.
8.5 Geriatric Use
Additions and/or revisions underlined:
Of 796 patients who received RETEVMO, 34% (268 patients) were greater than or equal to 65 years of age and 9% (74 patients) were greater than or equal to 75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were greater than or equal to 65 years of age and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONNewly added information:
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 Warnings and Precautions (5.2)].
Hypothyroidism
Advise patients that RETEVMO can cause hypothyroidism and to immediately contact their healthcare provider for signs or symptoms of hypothyroidism [see Warnings and Precautions (5.9)].
What is RETEVMO?
Newly added bullet point:
adults with locally advanced solid tumors (cancers) or solid tumors that have spread, and have gotten worse (progressed) on or after other treatment or there are no satisfactory treatment options.
Additions and/or revisions underlined:
It is not known if RETEVMO is safe and effective when used:
in children younger than 12 years of age for the treatment of MTC who require systemic therapy, and advanced thyroid cancer who require systemic therapy and who have received radioactive iodine and it did not work or is no longer working, or
in children for the treatment of any other cancers.
Before taking RETEVMO, tell your healthcare provider about all your medical conditions, including if you:
Additions and/or revisions underlined:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RETEVMO may affect the way other medicines work, and other medicines may affect how RETEVMO works, and may increase your risk of side effects.
What are the possible side effects of RETEVMO?
RETEVMO may cause serious side effects, including:
Newly added information:
Lung problems. RETEVMO may cause severe or life-threatening inflammation of the lungs during treatment, that can lead to death. Tell your healthcare provider right away if you have any new or worsening lung symptoms, including:
shortness of breath
cough
fever
Additions and/or revisions underlined:
High blood pressure (hypertension). High blood pressure is common with RETEVMO and may sometimes be severe. You should check your blood pressure regularly during treatment with RETEVMO. If you develop blood pressure problems, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you have increased blood pressure readings or get any symptoms of high blood pressure, including: …
Heart rhythm changes (QT prolongation). RETEVMO may cause very slow, very fast or irregular heartbeats. Your healthcare provider may perform tests before and during treatment with RETEVMO to check the activity of your heart and the levels of body salts (electrolytes) and thyroid-stimulating hormone (TSH) in your blood. Tell your healthcare provider right away if you get any of the following symptoms: …
Newly added information:
Low thyroid hormone levels in your blood (hypothyroidism). Your healthcare provider will do blood tests to check your thyroid function before and during treatment with RETEVMO. Tell your healthcare provider right away if you develop signs or symptoms of low thyroid hormone levels, including:
weight gain
tiredness that worsens or that does not go away
feeling cold
constipation
Additions and/or revisions underlined:
The most common side effects of RETEVMO include:
swelling of your arms, legs, hands, and feet (edema)
stomach-area (abdominal) pain
diarrhea
constipation
tiredness
rash
dry mouth
nausea
high blood pressure
headache
Newly added information:
The most common severe abnormal laboratory test results with RETEVMO include decreased white blood cell count, decreased levels of sodium in the blood, and decreased levels of calcium in the blood.
09/21/2022 (SUPPL-8)
5 Warnings and Precautions
5.1 Hepatoxicity
Additions and/or revisions underlined:
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% [see Adverse Reactions (6.1)]. 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 Dosage and Administration (2.5)].
Newly added subsection:
5.2 Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 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 Dosage and Administration (2.5)].
5.3 Hypertension
Additions and/or revisions underlined:
Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Adverse Reactions (6.1)]. Overall, 6.3% had their dose interrupted and 1.3% had their dose reduced for hypertension …
5.4 QT Interval Prolongation
Additions and/or revisions underlined:
RETEVMO can cause concentration-dependent QT interval prolongation [see Clinical Pharmacology (12.2)]. 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 Adverse Reactions (6.1)] …
5.5 Hemorrhagic Events
Additions and/or revisions underlined:
Serious including fatal hemorrhagic events can occur with RETEVMO. Grade greater than or equal to 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) …
5.6 Hypersensitivity
Additions and/or revisions underlined:
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 …
5.7 Tumor Lysis Syndrome
Additions and/or revisions underlined:
Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO [see Adverse Reactions (6.1)] …
Newly added subsection:
5.9 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 Adverse Reactions (6.1)].
Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity [see Dosage and Administration (2.5)].
5.10 Embryo-Fetal Toxicity
Additions and/or revisions underlined:
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 Use in Specific Populations (8.1, 8.3)].
6 Adverse Reactions
Newly added to bulleted line listing:
Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.2)]
Hypothyroidism [see Warnings and Precautions (5.9)]
6.1 Clinical Trials Experience
Extensively changed; please refer to label for complete information.
7 Drug Interactions
7.2 Effects of RETEVMO on Other DrugsNewly added information:
Certain P-gp Substrates
RETEVMO is a P-gp inhibitor. Concomitant use of RETEVMO with P-gp substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp 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.
8 Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined:
… The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications [see Indications and Usage (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 physical 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 greater than or equal to 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 greater than or equal to 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 greater than or equal to 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.
8.5 Geriatric Use
Additions and/or revisions underlined:
Of 796 patients who received RETEVMO, 34% (268 patients) were greater than or equal to 65 years of age and 9% (74 patients) were greater than or equal to 75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were greater than or equal to 65 years of age and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONNewly added information:
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 Warnings and Precautions (5.2)].
Hypothyroidism
Advise patients that RETEVMO can cause hypothyroidism and to immediately contact their healthcare provider for signs or symptoms of hypothyroidism [see Warnings and Precautions (5.9)].
What is RETEVMO?
Newly added bullet point:
adults with locally advanced solid tumors (cancers) or solid tumors that have spread, and have gotten worse (progressed) on or after other treatment or there are no satisfactory treatment options.
Additions and/or revisions underlined:
It is not known if RETEVMO is safe and effective when used:
in children younger than 12 years of age for the treatment of MTC who require systemic therapy, and advanced thyroid cancer who require systemic therapy and who have received radioactive iodine and it did not work or is no longer working, or
in children for the treatment of any other cancers.
Before taking RETEVMO, tell your healthcare provider about all your medical conditions, including if you:
Additions and/or revisions underlined:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RETEVMO may affect the way other medicines work, and other medicines may affect how RETEVMO works, and may increase your risk of side effects.
What are the possible side effects of RETEVMO?
RETEVMO may cause serious side effects, including:
Newly added information:
Lung problems. RETEVMO may cause severe or life-threatening inflammation of the lungs during treatment, that can lead to death. Tell your healthcare provider right away if you have any new or worsening lung symptoms, including:
shortness of breath
cough
fever
Additions and/or revisions underlined:
High blood pressure (hypertension). High blood pressure is common with RETEVMO and may sometimes be severe. You should check your blood pressure regularly during treatment with RETEVMO. If you develop blood pressure problems, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you have increased blood pressure readings or get any symptoms of high blood pressure, including: …
Heart rhythm changes (QT prolongation). RETEVMO may cause very slow, very fast or irregular heartbeats. Your healthcare provider may perform tests before and during treatment with RETEVMO to check the activity of your heart and the levels of body salts (electrolytes) and thyroid-stimulating hormone (TSH) in your blood. Tell your healthcare provider right away if you get any of the following symptoms: …
Newly added information:
Low thyroid hormone levels in your blood (hypothyroidism). Your healthcare provider will do blood tests to check your thyroid function before and during treatment with RETEVMO. Tell your healthcare provider right away if you develop signs or symptoms of low thyroid hormone levels, including:
weight gain
tiredness that worsens or that does not go away
feeling cold
constipation
Additions and/or revisions underlined:
The most common side effects of RETEVMO include:
swelling of your arms, legs, hands, and feet (edema)
stomach-area (abdominal) pain
diarrhea
constipation
tiredness
rash
dry mouth
nausea
high blood pressure
headache
Newly added information:
The most common severe abnormal laboratory test results with RETEVMO include decreased white blood cell count, decreased levels of sodium in the blood, and decreased levels of calcium in the blood.
01/28/2021 (SUPPL-2)
5 Warnings and Precautions
5.5 Hypersensitivity(Additions and/or revisions underlined)
If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent).
(Newly added section)
Tumor lysis syndrome (TLS) occurred in 1% 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.
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions underlined)
Animal Toxicity Data
In a 4-week general toxicology study, rats 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. In a 13-week general toxicology study, minipigs 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.
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.
(Additions and/or revisions underlined)
No dosage modification is recommended for patients with mild to severe renal impairment [estimated Glomerular Filtration Rate (eGFR) ?15 to 89 mL/min, estimated by Modification of Diet in Renal Disease (MDRD) equation]. The recommended dosage has not been established for patients with end-stage renal disease (ESRD) [see Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Newly added information)
Tumor Lysis Syndrome
Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS [see Warnings and Precautions (5.6)].
(Additions and/or revisions underlined)
Tell your healthcare provider if you have any signs of bleeding during treatment with RETEVMO,
including:
• Tumor lysis syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. TLS can cause
kidney failure, the need for dialysis treatment, and an abnormal heartbeat. TLS can lead to
hospitalization. Your healthcare provider may do blood tests to check you for TLS. You should stay
well hydrated during treatment with RETEVMO. Call your healthcare provider or get emergency
medical help right away if you develop any of these symptoms during treatment with RETEVMO:
- nausea
- shortness of breath
- vomiting
- muscle cramps
- weakness
- seizures
- swelling