Tagrisso
(osimertinib)Dosage & Administration
Adjuvant treatment of early-stage NSCLC: 80 mg orally once daily, with or without food, until disease recurrence, or unacceptable toxicity, or for up to 3 years.
Locally advanced, unresectable (stage III) NSCLC: Following platinum-based chemoradiation therapy, 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.
Metastatic NSCLC: 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.
Locally advanced or metastatic NSCLC: 80 mg orally once daily administered in combination with pemetrexed and platinum-based chemotherapy, with or without food, until disease progression or unacceptable toxicity due to TAGRISSO.
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Tagrisso Prescribing Information
Adjuvant Treatment of EGFR Mutation-Positive Non-Small Cell Lung Cancer (NSCLC)
TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)].
Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC
TAGRISSO is indicated for the treatment of adult patients with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)].
First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC
TAGRISSO is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)].
1.4 First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC
TAGRISSO in combination with pemetrexed and platinum-based chemotherapy is indicated for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)].
Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC
TAGRISSO is indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy [see Dosage and Administration (2.2)].
Recommended Evaluation and Testing Before Initiating TAGRISSO
TAGRISSO Monotherapy
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- Before initiating TAGRISSO monotherapy in patients with cardiac risk factors, conduct cardiac monitoring, including assessment of left ventricular ejection fraction (LVEF) [see Error! Hyperlink reference not valid.].
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- Before initiating TAGRISSO, perform complete blood count with differential [see Error! Hyperlink reference not valid.].
TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy
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- Before initiating TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring in all patients, including assessment of left ventricular ejection fraction (LVEF) [see Error! Hyperlink reference not valid.].
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- Before initiating TAGRISSO, perform complete blood count with differential [see Error! Hyperlink reference not valid.].
Patient Selection
Table 1 below presents the patient selection criteria for treatment with TAGRISSO.
Select patients for treatment with TAGRISSO based on the presence of a mutation as detected by an FDA-approved test. | |||
Indication | Treatment Regimen | Required Mutation | Source for Testing |
Adjuvant Treatment of EGFR Mutation-Positive NSCLC [see Indications and Usage (1.1)] | TAGRISSO monotherapy | EGFR exon 19 deletions or exon 21 L858R mutations | Tumor |
Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC [see Indications and Usage (1.2)] | Following completion of platinum-based chemoradiation therapy, TAGRISSO monotherapy | EGFR exon 19 deletions or exon 21 L858R mutations | Tumor |
First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC [see Indications and Usage (1.3)] | TAGRISSO monotherapy | EGFR exon 19 deletions or exon 21 L858R mutations | Plasma or tumor |
First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC [see Indications and Usage (1.4)] | TAGRISSO in combination with pemetrexed and platinum-based chemotherapy | EGFR exon 19 deletions or exon 21 L858R mutations | Plasma or tumor |
Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC [see Indications and Usage (1.5)] | TAGRISSO monotherapy | EGFR T790M Mutation | Plasma or tumor |
Information on FDA-approved tests for the detection of EGFR mutations is available at http://www.fda.gov/companiondiagnostics. | |||
Recommended Dosage and Administration
Recommended Dosage
Table 2 provides the recommended dosage of TAGRISSO by indication.
Indication | Recommended Dosage of TAGRISSO | Duration of Treatment |
Adjuvant Treatment of EGFR Mutation-Positive NSCLC | 80 mg tablet orally once daily with or without food | For a total of 3 years or until disease recurrence or unacceptable toxicity |
Locally Advanced, Unresectable (Stage III) EGFR Mutation-Positive NSCLC | Following platinum-based chemoradiation therapy, 80 mg tablet orally once daily with or without food | Until disease progression or unacceptable toxicity |
First-line Treatment of EGFR Mutation-Positive Metastatic NSCLC | 80 mg tablet orally once daily with or without food | Until disease progression or unacceptable toxicity |
First-line Treatment of EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC | 80 mg tablet orally once daily with or without food in combination with pemetrexed and platinum-based chemotherapy Refer to the Prescribing Information for pemetrexed and cisplatin or carboplatin for the respective dosing information. | Until disease progression or unacceptable toxicity due to TAGRISSO |
Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC | 80 mg tablet orally once daily with or without food | Until disease progression or unacceptable toxicity |
Administration
Administer TAGRISSO 80 mg tablet orally once daily with or without food. Tablets may be dispersed in water for patients who have difficulty swallowing, or for nasogastric tube administration [see Dosage and Administration (2.4)].
Missed Dose
If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled.
Administration to Patients Who Have Difficulty Swallowing Solids
Disperse TAGRISSO tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces) of water and immediately drink.
If administration via nasogastric tube is required, disperse the TAGRISSO tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL). 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. The dispersion and residues should be administered within 30 minutes of the addition of the tablets to water.
Dosage Modifications for Adverse Reactions
The recommended dose reductions for adverse reactions are provided in Table 3.
| Target Organ | Adverse Reaction * | Dosage Modification |
|---|---|---|
| ||
Pulmonary (Patients who have not received recent definitive platinum-based chemoradiation therapy) [see Error! Hyperlink reference not valid.] | Any Grade Interstitial lung disease (ILD)/Pneumonitis | Permanently discontinue TAGRISSO. |
Pulmonary (Patients who have received recent definitive platinum-based chemoradiation therapy) [see Error! Hyperlink reference not valid.] | Grade 1 ILD/Pneumonitis | Withhold or continue TAGRISSO, as clinically indicated. |
Grade ≥2 ILD/Pneumonitis | Permanently discontinue TAGRISSO. | |
Cardiac [see Error! Hyperlink reference not valid.2, Error! Hyperlink reference not valid.] | QTc † interval greater than 500 msec on at least 2 separate ECGs ‡ | Withhold TAGRISSO until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume at 40 mg dose. |
QTc interval prolongation with signs/symptoms of life-threatening arrhythmia | Permanently discontinue TAGRISSO. | |
Symptomatic congestive heart failure | Permanently discontinue TAGRISSO. | |
Cutaneous [see Error! Hyperlink reference not valid.] | Erythema Multiforme Major (EMM), Stevens-Johnson syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) | Withhold TAGRISSO if suspected and permanently discontinue if confirmed. |
Blood and bone marrow [see Error! Hyperlink reference not valid.] | Aplastic anemia | Withhold TAGRISSO if aplastic anemia is suspected and permanently discontinue if confirmed. |
Other [see Adverse Reactions (6.1)] | Adverse reaction of Grade 3 or greater severity | Withhold TAGRISSO for up to 3 weeks. |
If improvement to Grade 0-2 within 3 weeks | Resume at 80 mg or 40 mg daily. | |
If no improvement within 3 weeks | Permanently discontinue TAGRISSO. | |
Dosage Modifications for Combination Therapy
When TAGRISSO is administered in combination with pemetrexed and platinum-based chemotherapy, modify the dose of any one of the treatments for the management of adverse reactions, as appropriate. For TAGRISSO dose modification instructions, see Table 3. Withhold, reduce the dose or permanently discontinue pemetrexed, cisplatin or carboplatin according to their respective Prescribing Information.
Drug Interactions
Strong CYP3A4 Inducers
Avoid concomitant use of strong CYP3A4 inducers with TAGRISSO. If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when co-administering with a strong CYP3A inducer. Resume TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
80 mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and plain on the reverse.
40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain on the reverse.
Pregnancy
Risk Summary
Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended clinical dose (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
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), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6.
Lactation
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 [see Use in Specific Populations (8.1)]. 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 last dose.
Females and Males of Reproductive Potential
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 last 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 last 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)].
Pediatric Use
The safety and effectiveness of TAGRISSO in pediatric patients have not been established.
Geriatric Use
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.
Renal Impairment
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) [see Clinical Pharmacology (12.3)].
Hepatic Impairment
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) [see Clinical Pharmacology (12.3)].
None.
Interstitial Lung Disease/Pneumonitis
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)].
QTc Interval Prolongation
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)].
Cardiomyopathy
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)].
Keratitis
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.
Erythema Multiforme Major, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis
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.
Cutaneous Vasculitis
Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO [see Postmarketing (6.2)]. 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.
Aplastic Anemia
Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.06% of 1813) 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 (2.5)].
Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated.
Embryo-Fetal Toxicity
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 last dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the last dose [see Use in Specific Populations (8.1and 8.3)].