Drug Safety-related Labeling Changes (SrLC)

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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.

LUMAKRAS (NDA-214665)

(SOTORASIB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/16/2025 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hepatotoxicity

Additions and/or revisions underlined:

LUMAKRAS can cause hepatotoxicity and increased alanine aminotransferase (ALT) or increased aspartate aminotransferase (AST) which may lead to drug-induced liver injury and hepatitis.

In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg [see Adverse Reactions (6.1)], hepatotoxicity occurred in 27% of patients, of which 16% were Grade greater than or equal to 3. Among patients with hepatotoxicity who required dosage modifications, 64% required treatment with corticosteroids.

In this pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, 17% of patients who received LUMAKRAS had increased ALT/increased AST; of which 9% were Grade greater than or equal to 3. The median time to first onset of increased ALT/AST was 6.3 weeks (range: 0.4 to 42). Increased ALT/AST leading to dose interruption or reduction occurred in 9% of patients treated with LUMAKRAS. LUMAKRAS was permanently discontinued due to increased ALT/AST in 2.7% of patients. Drug-induced liver injury occurred in 1.6% (all grades) including 1.3% (Grade greater than or equal to 3).

In this pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, a total of 40% patients with recent (less than or equal to 3 months) immunotherapy prior to starting LUMAKRAS had an event of hepatotoxicity. An event of hepatotoxicity was observed in 18% of patients who started LUMAKRAS more than 3 months after last dose of immunotherapy and in 17% of those who never received immunotherapy. Regardless of time from prior immunotherapy, 94% of hepatotoxicity events improved or resolved with dosage modification of LUMAKRAS, with or without corticosteroid treatment.

In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab [see Adverse Reactions (6.1)], hepatotoxicity occurred in 15% of patients, of which 4.8% were Grade 3. A total of 7% of patients who received LUMAKRAS had increased ALT or increased AST, of which 0.8% were Grade 3. The median time to first onset of increased ALT or increased AST was 10 weeks (range: 2 to 22). Increased ALT or increased AST leading to dose interruption occurred in 2.4% of patients. A total of 3.2% of patients who received LUMAKRAS had hyperbilirubinemia, of which 2.4% were Grade 3. The median time to first onset of hyperbilirubinemia was 12 weeks (range: 0, 29). Hyperbilirubinemia leading to dose interruption occurred in 1.6% of patients. Among patients with hepatotoxicity, 21% received corticosteroids.

Monitor liver function tests (ALT, AST, alkaline phosphatase and total bilirubin) prior to the start of LUMAKRAS, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations. Withhold, reduce the dose or permanently discontinue LUMAKRAS based on severity of the adverse reaction [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. Consider administering systemic corticosteroids for the management of hepatotoxicity.

5.2 Interstitial Lung Disease (ILD)/Pneumonitis

Additions and/or revisions underlined:

LUMAKRAS can cause ILD/pneumonitis that can be fatal.

In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 2.2% of patients, of which 1.1% were Grade greater than or equal to 3, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 8.6 weeks (range: 2.1 to 36.7 weeks). LUMAKRAS was permanently discontinued due to ILD/pneumonitis in 1.3% of LUMAKRAS-treated patients. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab, 1 patient experienced a Grade 1 event of ILD/pneumonitis [see Adverse Reactions (6.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Refer to the Full Prescribing Information of panitumumab for pregnancy risk information and contraception recommendations when LUMAKRAS is administered in combination with panitumumab.

…

8.2 Lactation

Additions and/or revisions underlined:

…

Refer to the Full Prescribing Information of panitumumab for lactation recommendations when LUMAKRAS is administered in combination with panitumumab.

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 357 patients with any tumor type who received LUMAKRAS 960 mg orally once daily in CodeBreaK 100, 46% were 65 and over, and 10% were 75 and over. No overall differences in safety or effectiveness were observed between older patients and younger patients treated with LUMAKRAS as a single agent.

In a pooled analysis of 132 patients who received LUMAKRAS 960 mg in combination with panitumumab for KRAS G12C-mutated mCRC, 30% were 65 and over while 9% were 75 and over. No overall differences in safety or efficacy were observed between older patients (greater than or equal to 65 years of age) compared to younger patients, treated with LUMAKRAS 960 mg in combination with panitumumab.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Lactation

Advise women not to breastfeed during treatment with LUMAKRAS and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Refer to the Full Prescribing Information of panitumumab for lactation information, when LUMAKRAS is used in combination with panitumumab.

…

Missed Dose

If a dose of LUMAKRAS is missed by greater than 6 hours, resume treatment as prescribed the next day [see Dosage and Administration (2.2)].

LUMAKRAS in combination with panitumumab

Advise patients taking LUMAKRAS in combination with panitumumab to:

take the first dose of LUMAKRAS prior to the first panitumumab infusion [see Dosage and Administration (2.2)].

stop taking panitumumab whenever LUMAKRAS is withheld or discontinued [see Dosage and Administration (2.3)].

PATIENT INFORMATION

Additions and/or revisions underlined:

What is LUMAKRAS?

LUMAKRAS is a prescription medicine used in adults:

alone to treat non-small cell lung cancer (NSCLC):

that has spread to other parts of the body or cannot be removed by surgery, and
whose tumor has an abnormal KRAS G12C gene, and
who have received at least one prior treatment for their cancer.

in combination with a prescription medicine called panitumumab to treat colon or rectal cancer (CRC):

that has spread to other parts of the body and
whose tumor has an abnormal KRAS G12C gene, and
who have previously received certain chemotherapy medicines.

Your healthcare provider will perform a test to make sure that LUMAKRAS is right for you. It is not known if LUMAKRAS is safe and effective in children.

…

How should I take LUMAKRAS?

Take LUMAKRAS exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking LUMAKRAS unless your healthcare provider tells you to.
Take your prescribed dose of LUMAKRAS 1 time each day, at the same time each day.
For colon or rectal cancer, you will also receive panitumumab through a vein in your arm (intravenously) given by your healthcare provider. You will first take LUMAKRAS before you receive your first dose of panitumumab. Your healthcare provider will temporarily or permanently stop your treatment with panitumumab if your treatment with LUMAKRAS is temporarily or permanently stopped.

…

LUMAKRAS may cause serious side effects, including:

Liver problems. Abnormal liver blood tests are common with LUMAKRAS and can sometimes be severe. Your healthcare provider should do blood tests before starting and during treatment with LUMAKRAS to check your liver function. Tell your healthcare provider right away if you develop any signs or symptoms of liver problems, including:

…

Lung or breathing problems. LUMAKRAS may cause inflammation of the lungs that can lead to death. Tell your healthcare provider or get emergency medical help right away if you have new or worsening shortness of breath, cough, or fever.

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with LUMAKRAS if you develop side effects.

The most common side effects of LUMAKRAS when used alone for NSCLC include:

diarrhea
muscle or bone pain
nausea
tiredness
cough
changes in certain blood tests

The most common side effects of LUMAKRAS when used in combination with panitumumab for CRC include:

skin rash
dry skin
diarrhea
mouth sores
tiredness
muscle and bone pain
changes in certain blood tests

These are not all the possible side effects of LUMAKRAS.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Amgen at 1-800-772-6436 (1-800-77-AMGEN).

…

09/30/2024 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hepatotoxicity

Additions and/or revisions underlined:

LUMAKRAS can cause hepatotoxicity and increased ALT or AST which may lead to drug-induced liver injury and hepatitis.

In the pooled safety population of NSCLC patients who received single agent LUMAKRAS 960 mg [see Adverse Reactions (6.1)], hepatotoxicity occurred in 27% of patients, of which 16% were Grade greater than or equal to 3.

Among patients with hepatotoxicity who required dosage modifications, 64% required treatment with corticosteroids.

In this pooled safety population of NSCLC patients who received single agent LUMAKRAS 960 mg, 17% of patients who received LUMAKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); of which 9% were Grade greater than or equal to 3. The median time to first onset of increased ALT/AST was 6.3 weeks (range: 0.4 to 42). Increased ALT/AST leading to dose interruption or reduction occurred in 9% of patients treated with LUMAKRAS. LUMAKRAS was permanently discontinued due to increased ALT/AST in 2.7% of patients. Drug-induced liver injury occurred in 1.6% (all grades) including 1.3% (Grade greater than or equal to 3).

In this pooled safety population of NSCLC patients who received single agent LUMAKRAS 960 mg, a total of 40% patients with recent (less than or equal to 3 months) immunotherapy prior to starting LUMAKRAS had an event of hepatotoxicity. An event of hepatotoxicity was observed in 18% of patients who started LUMAKRAS more than 3 months after last dose of immunotherapy and in 17% of those who never received immunotherapy. Regardless of time from prior immunotherapy, 94% of hepatotoxicity events improved or resolved with dosage modification of LUMAKRAS, with or without corticosteroid treatment.

5.2 Interstitial Lung Disease (ILD)/Pneumonitis

Additions and/or revisions underlined:

LUMAKRAS can cause ILD/pneumonitis that can be fatal.In the pooled safety population of NSCLC patients who received single agent LUMAKRAS 960 mg [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 2.2% of patients, of which 1.1% were Grade greater than or equal to 3, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 8.6 weeks (range: 2.1 to 36.7 weeks). LUMAKRAS was permanently discontinued due to ILD/pneumonitis in 1.3% of LUMAKRAS-treated patients. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to LUMAKRAS as a single agent at 960 mg orally once daily until disease progression or unacceptable toxicity in 549 patients with NSCLC with KRAS G12C mutation in the following trials: CodeBreaK 200 (NCT04303780), CodeBreaK 100 (NCT03600883), and CodeBreaK 101 (NCT04185883) and CodeBreaK 105 (NCT04380753). Among these 549 patients who received LUMAKRAS, 44% were exposed for 6 months or longer and 21% were exposed for greater than one year.

04/24/2023 (SUPPL-4)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.6 Hepatic Impairment

Newly added subsection

No dosage modification is recommended in patients with mild to moderate hepatic impairment (Child Pugh A or B).

The effect of severe hepatic impairment (Child-Pugh C) on the safety of LUMAKRAS is unknown. Monitor for sotorasib adverse reactions in patients with hepatic impairment more frequently since these patients may be at increased risk for adverse reactions including hepatotoxicity [see Clinical Pharmacology (12.3)].

11/21/2022 (SUPPL-2)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effects of Other Drugs on LUMAKRAS

Additions and/or revisions underlined:

Acid-Reducing Agents

The solubility of sotorasib is pH-dependent. Coadministration of LUMAKRAS with gastric acid-reducing agents decreased sotorasib concentrations [see Clinical Pharmacology (12.3)], which may reduce the efficacy of sotorasib …

Strong CYP3A4 Inducers

Sotorasib is a CYP3A4 substrate. Coadministration of LUMAKRAS with a strong CYP3A4 inducer decreased sotorasib concentrations [see Clinical Pharmacology (12.3)], which may reduce the efficacy of sotorasib …

7.2 Effects of LUMAKRAS on Other Drugs

Additions and/or revisions underlined:

CYP3A4 Substrates

Sotorasib is a CYP3A4 inducer. Coadministration of LUMAKRAS with a CYP3A4 substrate decreased its plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce the efficacy of the substrate …

P-glycoprotein (P-gp) Substrates

Sotorasib is a P-gp inhibitor. Coadministration of LUMAKRAS with a P-gp substrate increased its plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the adverse reactions of the substrate. Avoid coadministration of LUMAKRAS with P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the P-gp substrate dosage in accordance with its Prescribing Information.

Newly added information:

Breast Cancer Resistance Protein (BCRP) Substrates

Sotorasib is a BCRP-inhibitor. Coadministration of LUMAKRAS with a BCRP substrate increased its plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions of the substrate. When coadministered with LUMAKRAS, monitor for adverse reactions of the BCRP substrate and decrease the BCRP substrate dosage in accordance with its Prescribing Information.