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.

TAGRISSO (NDA-208065)

(OSIMERTINIB MESYLATE)

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

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09/25/2024 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

Additions and/or revisions underlined:

TAGRISSO can cause severe and fatal ILD/pneumonitis.

Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 4% of the 1813 patients treated with TAGRISSO monotherapy who had not received recent definitive chemoradiation therapy; 0.4% of cases were fatal.

ILD/Pneumonitis with TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy

In the FLAURA2 study, ILD/pneumonitis occurred in 3.3% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 0.4% of cases were fatal.

ILD/Pneumonitis Following Definitive Platinum-based Chemoradiation Therapy

In the LAURA study, following definitive platinum-based chemoradiation therapy, ILD/pneumonitis, including radiation pneumonitis, occurred in 80 of the 143 patients (56%) who received TAGRISSO monotherapy and 28 of the 73 patients (38%) who received placebo. There was one fatal case (0.7%), 3.5% Grade 3, 34% Grade 2, and 18% Grade 1 adverse reactions of ILD/pneumonitis in TAGRISSO- treated patients. For TAGRISSO-treated patients, ILD/pneumonitis led to permanent discontinuation of TAGRISSO in 7% of patients and dosage interruptions of TAGRISSO in 35% of patients. Among the 46 patients who were rechallenged with TAGRISSO, 11% had recurrence of ILD/pneumonitis. In the 80 TAGRISSO-treated patients, ILD/pneumonitis resolved in 40%, resolved with sequelae in 1.3%, were resolving in 16%, did not resolve in 41%, and resulted in death in 1.3%.

For patients receiving TAGRISSO who have not received recent definitive platinum-based chemoradiation therapy, withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening or respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue TAGRISSO if ILD/pneumonitis is confirmed [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

For patients who have received recent definitive platinum-based chemoradiation therapy with Grade 1 ILD/pneumonitis continue TAGRISSO or interrupt and restart, as appropriate. Permanently discontinue

TAGRISSO in patients diagnosed with Grade ?2 ILD/pneumonitis [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

5.2 QTc Interval Prolongation

Additions and/or revisions underlined:

TAGRISSO can cause heart rate-corrected QT (QTc) interval prolongation. Of the 1813 patients treated with TAGRISSO monotherapy in clinical trials, 1.1% were found to have a QTc >500 msec, and 4.3% of patients had an increase from baseline QTc >60 msec [see Clinical Pharmacology (12.2)].

Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study, 1.8% were found to have a QTc >500 msec, and 10.5% of patients had an increase from baseline QTc >60 msec.

No QTc-related arrhythmias were reported.

Clinical trials of TAGRISSO did not enroll patients with baseline QTc of >470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.5)].

5.3 Cardiomyopathy

Additions and/or revisions underlined:

TAGRISSO can cause cardiomyopathy, including cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction.

Across clinical trials, cardiomyopathy occurred in 3.8% of the 1813 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal.

In the FLAURA2 study, cardiomyopathy occurred in 9% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 1.1% of cardiomyopathy cases were fatal.

A decline in left ventricular ejection fraction (LVEF) ?10 percentage points from baseline and to less than 50% LVEF occurred in 4.2% of 1557 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of patients treated with TAGRISSO experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In the LAURA study, following platinum-based chemoradiation therapy, 3% (4/135) of patients treated with TAGRISSO and no patients treated with placebo experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In the FLAURA2 study, 8% (21/262) of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%.

For patients who will be receiving TAGRISSO monotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors.

For patients who will be receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in all patients.

Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO [see Dosage and Administration (2.5)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

Additions and/or revisions underlined:

Monotherapy

Of the 1813 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive NSCLC who were treated with TAGRISSO monotherapy, 770 patients were ?65 years and 207 patients were ?75 years of age [see Adverse Reactions (6.1)]. Exploratory analysis suggests a higher incidence of Grade 3 or higher adverse reactions (43% vs 33%) and more frequent dosage modifications for adverse reactions (34% vs 23%) in patients 65 years or older as compared to those younger than 65 years. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients.

TAGRISSO Following Definitive Platinum-based Chemoradiation Therapy

Of the 142 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced unresectable (Stage III) NSCLC treated with TAGRISSO following definitive platinum-based chemoradiation therapy, 62 patients were ?65 years and 13 patients were ?75 years of age [see Adverse Reactions (6.1)]. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients.

TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy

Of the 276 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced or metastatic NSCLC treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, 104 patients were ?65 years and 23 patients were ?75 years of age [see Adverse Reactions (6.1)]. Exploratory analysis suggests a higher incidence of Grade 3 or higher adverse reactions (68% vs 61%) and more frequent dosage modifications for adverse reactions (55% vs 43%) in patients 65 years or older as compared to those younger than 65 years. Clinical studies of TAGRISSO in combination with pemetrexed and platinum-based chemotherapy did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients.

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

PATIENT INFORMATION

Extensive changes; please refer to label for complete information

04/29/2024 (SUPPL-31)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

…

Clinically relevant adverse reactions in FLAURA in <10% of patients receiving TAGRISSO were alopecia (7%), epistaxis (6%), interstitial lung disease (3.9%), urticaria (2.2%), palmar-plantar erythrodysesthesia syndrome (1.4%), QTc interval prolongation (1.1%), keratitis (0.4%), and skin hyperpigmentation (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

…

Clinically relevant adverse reactions in FLAURA2 in <10% of patients receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy were alopecia (9%), epistaxis (7%), palmar-plantar erythrodysesthesia syndrome (5%), interstitial lung disease (3.3%), skin hyperpigmentation (2.5%), QTc interval prolongation (1.8%), erythema multiforme (1.4%), urticaria (1.4%), and keratitis (0.7%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

…

Clinically relevant adverse reactions in AURA3 in <10% of patients receiving TAGRISSO were epistaxis (5%), interstitial lung disease (3.9%), alopecia (3.6%), urticaria (2.9%), palmar-plantar erythrodysesthesia syndrome (1.8%), QTc interval prolongation (1.4%), keratitis (1.1%), erythema multiforme (0.7%), and skin hyperpigmentation (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of TAGRISSO. Because these 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: Erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), cutaneous vasculitis, erythema dyschromicum perstans
Blood and lymphatic system disorders: Aplastic anemia

02/16/2024 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

Additions and/or revisions underlined:

Interstitial lung disease (ILD)/pneumonitis occurred in 4% of the 1813 TAGRISSO-treated patients; 0.4% of cases were fatal.

In the FLAURA2 study, ILD/pneumonitis occurred in 3.3% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 0.4% of cases were fatal.

…

5.2 QTc Interval Prolongation

Additions and/or revisions underlined:

Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1813 patients treated with TAGRISSO monotherapy in clinical trials, 1.1% were found to have a QTc>500 msec, and 4.3% of patients had an increase from baseline QTc >60 msec [see Clinical Pharmacology (12.2)].

…

5.3 Cardiomyopathy

Additions and/or revisions underlined:

Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 3.8% of the 1813 TAGRISSO- treated patients; 0.1% of cardiomyopathy cases were fatal.

In the FLAURA2 study, cardiomyopathy occurred in 9% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 1.1% of cardiomyopathy cases were fatal.

A decline in left ventricular ejection fraction (LVEF) ?10 percentage points from baseline and to less than 50% LVEF occurred in 4.2% of 1557 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of patients treated with TAGRISSO experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In the FLAURA2 study, 8% (21/262) of patients treated with TAGRISSO in combination with pemetrexed and platinum- based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%.

For patients who will be receiving TAGRISSO monotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors.

…

5.4 Keratitis

Additions and/or revisions underlined:

Keratitis was reported in 0.6% of 1813 patients treated with TAGRISSO monotherapy in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.

5.7 Aplastic Anemia

Additions and/or revisions underlined:

Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.06% of 1813) and postmarketing [see Postmarketing (6.2)].

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Monotherapy

Of the 1813 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive NSCLC who were treated with TAGRISSO monotherapy, 770 patients were greater than or equal to 65 years and 207 patients were greater than or equal to 75 years of age [see Adverse Reactions (6.1)]. Exploratory analysis suggests a higher incidence of Grade 3 or higher adverse reactions (43% vs 33%) and more frequent dosage modifications for adverse reactions (34% vs 23%) in patients 65 years or older as compared to those younger than 65 years. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients.

TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy

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

PATIENT INFORMATION

Additions and/or revisions underlined:

TAGRISSO may cause serious side effects, including:

…

Heart problems, including heart failure. TAGRISSO may cause heart problems that may lead to death. Your healthcare provider should check your heart function before you start taking TAGRISSO and during treatment as needed. Tell your healthcare provider right away if you have any of the following signs and symptoms of a heart problem: feeling like your heart is pounding or racing, shortness of breath, swelling of your ankles and feet, dizziness, feeling lightheaded, or feeling faint.

What is TAGRISSO?

…

in combination with pemetrexed and platinum-based chemotherapy, as your first treatment when your lung cancer has spread to nearby tissues (locally advanced) or to other parts of the body (metastatic).
Before taking TAGRISSO, tell your healthcare provider about all of your medical conditions, including if you:

have lung or breathing problems other than your lung cancer.
…

Females who are able to become pregnant should have a pregnancy test before starting treatment with TAGRISSO. You should use effective birth control (contraception) during treatment with TAGRISSO and for 6 weeks after the final dose of TAGRISSO.

…

How should I take TAGRISSO?

…

If you have a nasogastric (NG) tube:

Follow the same instructions for mixing TAGRISSO tablets in a container that contains 15 mL of water. Do not use carbonated water or any other liquids.
Stir the TAGRISSO tablets and water until the TAGRISSO tablets are in small pieces (the tablets will not completely dissolve). Do not crush, heat, or use ultrasound to prepare the mixture.
Add another 15 mL of water into the container to make sure no pieces of TAGRISSO tablet remain.
Give the TAGRISSO tablet and water mixture using the NG tube manufacturer instructions within 30 minutes.
Add another 30 mL of water into the syringe and give the water and any remaining TAGRISSO through the NG tube to make sure that all of the medicine is given. Repeat this step until no pieces remain in the syringe. This will help to ensure that the full prescribed dose of the TAGRISSO is given.

What are the possible side effects of TAGRISSO?

…

The most common side effects of TAGRISSO when given alone include:

low white blood cell counts
muscle, bone, or joint pain
dry skin
low platelet counts
changes in your nails,including: redness, tenderness, pain, inflammation, brittleness, separation from the nailbed, and shedding of nail
mouth sores
low red blood cell counts
tiredness (anemia)
diarrhea

rash

The most common side effects of TAGRISSO in combination with pemetrexed and platinum- based chemotherapy include:

low white blood cell counts
changes in your nails, including: redness, tenderness, pain, inflammation, brittleness, separation from the nailbed, and shedding of nail
dry skin
low platelet counts
increase of a substance in the blood called creatinine
rash
diarrhea
mouth sores

06/21/2023 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

(Additions and/or revisions underlined)

Interstitial lung disease (ILD)/pneumonitis occurred in 3.8% of the 1479 TAGRISSO-treated patients; 0.3% of cases were fatal.

Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD/pneumonitis is confirmed [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].

5.5 Erythema Multiforme Major, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis

(Additions and/or revisions underlined)

Postmarketing cases consistent with erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving TAGRISSO [see Postmarketing (6.2)]. Withhold TAGRISSO if EMM, SJS, or TEN is suspected and permanently discontinue if confirmed.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
QTc Interval Prolongation [see Warnings and Precautions (5.2)]
Cardiomyopathy [see Warnings and Precautions (5.3)]
Keratitis [see Warnings and Precautions (5.4)]
Erythema multiforme, Stevens-Johnson syndrome, and Toxic epidermal necrolysis [see Warnings and Precautions (5.5)]
Cutaneous Vasculitis [see Warnings and Precautions (5.6)]
Aplastic Anemia [see Warnings and Precautions (5.7)

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.

…

Other Clinical Trials Experience

The following adverse reaction has been reported following administration of TAGRISSO: increased blood creatine phosphokinase.

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

Skin and subcutaneous tissue: Erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), cutaneous vasculitis
Blood and lymphatic system disorders: Aplastic anemia

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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

…

Erythema Multiforme Major, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis

Inform patients of signs and symptoms that may be indicative of EMM, SJS, or TEN. Advise patients to contact their healthcare provider immediately if they develop target lesions or severe blistering or peeling of skin. [see Warnings and Precautions (5.5)].

09/30/2022 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Aplastic Anemia

New subsection added

Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.07% of 1479) and postmarketing [see Postmarketing (6.2)]. Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO [see Dosage and Administration (2.4)].

Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated.

6 Adverse Reactions

Additions and/or revisions underlined

…

Aplastic Anemia [see Warnings and Precautions (5.7)]
6.2 Postmarketing Experience
Additions and/or revisions underlined
…

Blood and lymphatic system disorders: Aplastic anemia

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

…

Aplastic Anemia

Inform patients of signs and symptoms of aplastic anemia including but not limited to new or persistent fevers, bruising, bleeding, pallor, infection, tiredness or weakness. Advise patients to contact their healthcare provider immediately if signs and symptoms suggestive of aplastic anemia [see Warnings and Precautions (5.7)].
…
PATIENT INFORMATION
Additions and/or revisions underlined
What is the most important information I should know about TAGRISSO?
TAGRISSO may cause serious side effects, including:
…

Blood and bone marrow problems. TAGRISSO may cause a condition where your bone marrow cannot make enough new blood cells (aplastic anemia), and which may lead to death. Your healthcare provider will monitor your blood cell counts before you start and during treatment with TAGRISSO. Tell your healthcare provider right away if you develop any signs or symptoms of blood and bone marrow problems, including:

a new fever or fever that does not go away (temperature 100.4 F or higher)
easy bruising or bleeding that will not stop
unusually pale skin
infection
tiredness
weakness

…

07/26/2021 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

Clinically relevant adverse reactions in ADAURA in <10% of patients receiving TAGRISSO were alopecia (6%), epistaxis (6%), interstitial lung disease (3%), palmar-plantar erythrodysesthesia syndrome (1.8%), urticaria (1.5%), keratitis (0.6%), QTc interval prolongation (0.6%), and erythema multiform (0.3%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation>500msec.

…

Clinically relevant adverse reactions in FLAURA in <10% of patients receiving TAGRISSO were alopecia (7%), epistaxis (6%), interstitial lung disease (3.9%), urticaria (2.2%), palmar-plantar erythrodysesthesia syndrome (1.4%), QTc interval prolongation (1.1%), and keratitis (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500msec.

…

Clinically relevant adverse reactions in AURA3 in <10% of patients receiving TAGRISSO were epistaxis (5%), interstitial lung disease (3.9%), alopecia (3.6%), urticaria (2.9%), palmar-plantar erythrodysesthesia syndrome (1.8%), QTc interval prolongation (1.4%), keratitis (1.1%), and erythema multiform (0.7%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500msec.

…

12/18/2020 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

(Additions and/or revisions underlined)

Interstitial lung disease (ILD)/pneumonitis occurred in 3.7% of the 1479 TAGRISSO-treated patients; 0.3% of cases were fatal.

Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed [see Dosage and Administration (2.4) and Adverse Reactions (6)].

5.2 QTc Interval Prolongation

(Additions and/or revisions underlined)

Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1479 patients treated with TAGRISSO in clinical trials, 0.8% were found to have a QTc > 500 msec, and 3.1% of patients had an increase from baseline QTc > 60 msec [see Clinical Pharmacology (12.2)]. No QTc-related arrhythmias were reported.

Clinical trials of TAGRISSO did not enroll patients with baseline QTc of > 470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.4)].

5.3 Cardiomyopathy

(Additions and/or revisions underlined)

Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 3% of the 1479 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal.

A decline in left ventricular ejection fraction (LVEF) ?10 percentage points from baseline and to less than 50% LVEF occurred in 3.2% of 1233 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of patients treated with TAGRISSO experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%.

Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO [see Dosage and Administration (2.4)].

5.4 Keratitis

(Additions and/or revisions underlined)

Keratitis was reported in 0.7% of 1479 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Based on animal data, TAGRISSO can cause malformations, embryo lethality, and postnatal death at doses resulting in exposures 1.5 times or less the human exposure at the clinical dose of 80 mg daily[see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose [see Use in Specific Populations (8.1)].

Males

Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of TAGRISSO [see Nonclinical Toxicology (13.1)].

Infertility

Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are reversible [see Nonclinical Toxicology (13.1)].

8.5 Geriatric Use

(Additions and/or revisions underlined)

Forty-three percent (43%) of the 1479 patients in ADAURA (n=337), FLAURA (n=279), AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and AURA1, (n=173) were 65 years of age and older. No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of Grade 3 and 4 adverse reactions (35% vs 27%) and more frequent dose modifications for adverse reactions (32% vs 21%) in patients 65 years or older as compared to those younger than 65 years.

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

PATIENT INFORMATION

(Extensive changes; please refer to label)

12/11/2020 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.6 Cutaneous Vasculitis

Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity.

6 Adverse Reactions

Newly added to the bulleted line listing:

Cutaneous vasculitis [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

Following Table 4, additions and/or revisions underlined:

¶ Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, paronychia.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Skin and subcutaneous tissue: Stevens-Johnson syndrome, erythema multiforme, cutaneous vasculitis

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

PATIENT COUNSELING INFORMATION

Newly added information:

Cutaneous Vasculitis

Inform patients of signs and symptoms that may be indicative of cutaneous vasculitis. Advise patients to contact their healthcare provider immediately if they develop multiple, non-blanching red papules on their forearms, lower legs, or buttocks or large hives on their trunk that do not go away within 24 hours and develop a bruised appearance [see Warnings and Precautions (5.6)].

PATIENT INFORMATION

What is the most important information I should know about TAGRISSO?

TAGRISSO may cause serious side effects, including:

Newly added information:

inflammation of the blood vessels in your skin. TAGRISSO may cause blood vessel problems in your skin. Tell your healthcare provider right away if you develop purple spots or redness of the skin that does not fade in color when pressed (non-blanching) on your lower arms, lower legs, or buttocks or large hives on the main part of your body (trunk) that do not go away within 24 hours and look bruised.

05/23/2020 (SUPPL-16)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.6 Renal Impairment

(Additions and/or revisions underlined)

No dose adjustment is recommended in patients with creatinine clearance (CLcr) 15 - 89 mL/min, as estimated by Cockcroft-Gault. There is no recommended dose of TAGRISSO for patients with end-stage renal disease (CLcr < 15 mL/min).

12/19/2019 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

Erythema Multiforme and Stevens-Johnson Syndrome

(Newly added subsection)

Postmarketing cases consistent with Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if SJS or EMM is suspected and permanently discontinue if confirmed.

Postmarketing Experience

(Newly added subsection)

Cutaneous: Stevens-Johnson syndrome, erythema multiforme

6 Adverse Reactions

(Newly added information)

Erythema multiforme and Stevens-Johnson syndrome [see Warnings and Precautions (5.5)]

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

PATIENT COUNSELING INFORMATION

(Newly added information)

Erythema multiforme and Stevens-Johnson syndrome

- Inform patients of signs and symptoms that may be indicative of EM or SJS. Advise patients to

contact their healthcare provider immediately if they develop target lesions or severe blistering or

peeling of skin. [see Warnings and Precautions (5.5)].

Patient Information

(Additions underlined)

TAGRISSO may cause serious side effects, including:

skin problems. TAGRISSO may cause skin problems. Tell your doctor right away if you develop target

lesions (skin reactions that look like rings), severe blistering or peeling of the skin.

What are the possible side effects of TAGRISSO?

TAGRISSO may cause serious side effects, including:

· See “What is the most important information I should know about TAGRISSO?”

· Severe blistering or peeling of skin – seek medical attention right away if you develop these symptoms.

· Target lesions, which are skin reactions that look like rings – seek medical attention right away if you

develop these symptoms.

08/28/2018 (SUPPL-11)

Approved Drug Label (PDF)

7 Drug Interactions

7.2 Effect of Osimertinib on Other Drugs

Additions and/or revisions underlined:

Co-administering TAGRISSO with a breast cancer resistant protein (BCRP) or P-glycoprotein (P-gp) substrate increased the exposure of the substrate compared to administering it alone. Increased BCRP or P-gp substrate exposure may increase the risk of exposure- related toxicity.

Monitor for adverse reactions of the BCRP or P-gp substrate, unless otherwise instructed in its approved labeling, when co-administered with TAGRISSO.

8 Use in Specific Populations

8.6 Renal Impairment

Additions and/or revisions underlined:

8.7 Hepatic Impairment

Additions and/or revisions underlined:

No dose adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh A and B or total bilirubin ? ULN and AST > ULN or total bilirubin 1 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment (total bilirubin between 3 to 10 times ULN and any AST).

04/18/2018 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Interstitial Lung Disease/Pneumonitis

(additions and revisions underlined)

Interstitial lung disease (ILD)/pneumonitis occurred in 3. 9% of the 1142 TAGRISSO-treated patients; 0. 4% of cases were fatal.

5.2 QTc Interval Prolongation

(additions and revisions underlined)

Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1142 patients treated with TAGRISSO in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported.

…

5.3 Cardiomyopathy

(additions and revisions underlined)

Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 2.6% of the 1142 TAGRISSO- treated patients; 0.1% of cardiomyopathy cases were fatal.

A decline in left ventricular ejection fraction (LVEF) greater than or equal to 10% from baseline and to less than 50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment.

5.4 Keratitis

(revision underlined)

Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.

5.5 Embryo-Fetal Toxicity

(additions underlined)

Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose.

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive additions and revisions, please refer to label)

7 Drug Interactions

7.3 Drugs That Prolong the QTc Interval

(new subsection added)

The effect of coadministering medicinal products known to prolong the QTc interval with TAGRISSO is unknown. When feasible, avoid concomitant administration of drugs known to prolong the QTc interval with known risk of Torsades de pointes. If not feasible to avoid concomitant administration of such drugs, conduct periodic ECG monitoring.

8 Use in Specific Populations

8.1 Pregnancy

(addition underlined)

…

Data

Animal Data

When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1 times the AUC observed at the recommended clinical dose of 80 mg once daily),...

8.2 Lactation

(additions underlined)

Risk Summary

There are no data on the presence of osimertinib or its active metabolites in human milk, the effects of osimertinib on the breastfed infant or on milk production. Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death.

Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential

(additions underlined)

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating TAGRISSO.

TAGRISSO can cause fetal harm when administered to pregnant women.

...

8.5 Geriatric Use

(revisions underlined)

Fourty-three percent (43%) of the 1142 patients in FLAURA (n=279), AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and AURA1, (n=173) were 65 years of age and older. No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of Grade 3 and 4 adverse reactions (13.4% versus 9.3%) and more frequent dose modifications for adverse reactions (13.4% versus 7.6%) in patients 65 years or older as compared to those younger than 65 years.

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

Patient Information

(additions, please refer to label).

03/30/2017 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

The following information for ILD/ Pneumonitis, QTc Interval Prolongation, Cardiomyopathy and Keratitis reflects exposure to TAGRISSO in 833 patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who received TAGRISSO at the recommended dose of 80 mg once daily in AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and an expansion cohort in the first-in- human trial of osimertinib (AURA1, n=143).

5.1 Interstitial Lung Disease/Pneumonitis

Across Interstitial lung disease (ILD)/pneumonitis occurred in 3.5% (n=29) of TAGRISSO-treated patients

(n=833); 0.6% (n=5) of cases were fatal.

Withhold TAGRISSO and promptly investigate for ILD …

5.2 QTc Interval Prolongation

Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the

833 patients treated with TAGRISSO in clinical trials, 0.7% (n=6) were found to have a QTc greater than

500 msec, and 2.9% of patients (n=24) had an increase from baseline QTc greater than 60 msec. No QTc-related arrhythmias were reported.

In Clinical trials of TAGRISSO did not enroll patients with baseline QTc of greater than 470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia.

5.3 Cardiomyopathy

Across clinical trials, cardiomyopathy (defined as cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 1.9% (n=16) of 833 TAGRISSO-treated patients: 0.1% (n=1) of cases were fatal.

Left Ventricular Ejection Fraction (LVEF) decline greater than or equal to 10% and a drop to less than

50% occurred in 4.0% (26/655) of patients who had baseline and at least one follow-up LVEF assessment.

Conduct cardiac monitoring, including an assessment of LVEF at baseline and during treatment in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure …

5.4 Keratitis

Keratitis was reported in 0.7% (n=6) of 833 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Addition of the following:

Cardiomyopathy

Keratitis

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

The data described below reflect exposure to TAGRISSO (80 mg daily) in patients with EGFR T790M mutation-positive metastatic NSCLC in an open-label, randomized, active-controlled trial (AURA3, n=279) and in two single arm trials, AURA Extension (n=201) and AURA2 (n=210). Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required: steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from trial enrollment.

AURA3 Trial

The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized (2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation- positive NSCLC who had progressive disease following first line EGFR TKI treatment. A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapy-treated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%).

The most common adverse reactions (?20%) in patients treated with TAGRISSO were diarrhea (41%), rash (34%), dry skin ( 23%), nail toxicity (22%), and fatigue (22%). Serious adverse reactions were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis).

Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%).

Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3. AURA3 was not designed to demonstrate a statistically significant reduction in adverse reaction rates for TAGRISSO, or for the control arm, for any adverse reaction listed in Tables 2 and 3.

Table 2. Adverse Reactions Occurring in greater than or equal to 10% of Patients Receiving TAGRISSO in AURA 3 Data in table has changed; please refer to label.

d Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychoclasis, onycholysis, onychomadesis,

e Includes pruritus, pruritus generalized, eyelid pruritus.

f Includes fatigue, asthenia

Table 3. Common Laboratory Abnormalities (greater than 20% for all NCI CTCAE Grades) in AURA3

Data in table has changed; please refer to label.

a Based on the number of patients with available follow-up laboratory data.

AURA Extension and AURA2 Trials

The safety of TAGRISSO was evaluated in two single arm trials, AURA Extension (n=201) and AURA2 (n equal 210). A total of 411 patients with EGFR 790M mutation-positive NSLC who received one or more prior EGFR therapies including an EGFR TKI were treated with TAGRISSO (80 mg daily). The majority of patients were heavily pretreated. Prior to enrollment, 68% of patients had received at least 2 prior treatment regimens, 46% had received 3 or more prior lines of therapy, and 63% had received prior platinum-based chemotherapy.

Median duration of exposure to TAGRISSO was 7.7 months (range: less than 0.1 to 11.6 months). The toxicity profile of TAGRISSO observed in the AURA Extension and AURA2 trials was generally consistent with the toxicity profile observed in the AURA3 trial. Four patients (1%) treated with TAGRISSO developed fatal adverse reactions of ILD/pneumonitis. Discontinuation of therapy …

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Three hundred and forty-six (42%) of the 833 patients in AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and an expansion cohort in the first-in-human trial of osimertinib (AURA1, n=143) were 65 years of age and older. No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of Grade 3 and 4 adverse reactions ( 9.8% versus 6.8%) and more frequent dose modifications for adverse reactions (10.1% versus 6.0%) in patients 65 years or older as compared to those younger than 65 years.

8.6 Renal Impairment

Additions and/or revisions underlined:

No dose adjustment is recommended in patients with mild, [creatinine clearance (CLcr) 60-89 mL/min, as estimated by the Cockcroft Gault method (C-G)] moderate, (CLcr 30-59 mL/min, as estimated by C-G) or severe (CLcr 15-29 mL/min) renal impairment. There is no recommended dose of TAGRISSO for patients with end-stage renal disease.

8.7 Hepatic Impairment

Additions and/or revisions underlined:

No dose adjustment is recommended in patients with mild hepatic impairment [total bilirubin less than or equal to upper limit of normal (ULN) and AST greater than ULN or total bilirubin between 1.0 to 1.5 times ULN and any AST] or moderate hepatic impairment (total bilirubin between 1.5 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment.

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

PATIENT COUNSELING INFORMATION

Addition of the following:

Keratitis

Advise patients to contact their healthcare provider immediately if they develop eye symptoms (eye inflammation, lacrimation, light sensitivity, eye pain, red eye or changes in vision).

08/12/2016 (SUPPL-2)

Approved Drug Label (PDF)

7 Drug Interactions

Effect of Osimertinib on Other Drugs

Coadministering TAGRISSO with a BCRP substrate increased the exposure of the BCRP substrate compared to administering the BCRP substrate alone. Increased BCRP substrate exposure may increase the risk of exposure-related toxicity.

Monitor for adverse reactions of the BCRP substrate (e.g., rosuvastatin, sulfasalazine, topotecan), unless otherwise instructed in its approved labeling, when coadministered with TAGRISSO.

Effect of Other Drugs on Osimertinib

Strong CYP3A Inducers (revised)

Coadministering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone. Decreased osimertinib exposure may lead to reduced efficacy.

Avoid coadministering TAGRISSO with strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, St. John’s Wort) [note: effect of St. John’s Wort varies widely and is preparation dependent]. Increase the TAGRISSO dosage when coadministering with a strong CYP3A4 inducer if concurrent use is unavoidable. No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers.

8 Use in Specific Populations

Females and Males of Reproductive Potential

Infertility

Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential.

The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are reversible.

Hepatic Impairment (updated)

No dose adjustment is recommended in patients with mild hepatic impairment [total bilirubin less than or equal to upper limit of normal (ULN) and AST greater than ULN or total bilirubin between 1.0 to 1.5 times ULN and any AST]. There is no recommended dose for TAGRISSO for patients with moderate or severe hepatic impairment.

Renal Impairment (updated)

No dose adjustment is recommended in patients with mild [creatinine clearance (CLcr) 60-89 mL/min, as estimated by the Cockcroft Gault method (C-G)] or moderate (CLcr 30-59 mL/min, as estimated by C-G) renal impairment. There is no recommended dose of TAGRISSO for patients with severe renal impairment (CLcr <30 mL/min) or end-stage renal disease.