Data from FDA - Curated by EPG Health - Last updated 30 April 2018

Indication(s)

1 INDICATIONS AND USAGE TAGRISSO is a kinase inhibitor indicated for •the first-line treatment of patients with metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. (1.1, 2.1) •the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy. (1.2, 2.1) 1.1 First-line Treatment of EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) TAGRISSO is indicated for the first-line treatment of patients with metastatic 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 (2.1) ] . 1.2 Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC TAGRISSO is indicated for the treatment of 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 (2.1)].

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS 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)] Most common adverse reactions (≥20%) were diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue and decreased appetite. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or www.TAGRISSO.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the Warnings and Precautions section reflect exposure to TAGRISSO in 1142 patients with EGFR mutation-positive NSCLC who received TAGRISSO at the recommended dose of 80 mg once daily in two randomized, active-controlled trials [FLAURA (n=279) and AURA3 (n=279)], two single arm trials [AURA Extension (n=201) and AURA2 (n=210)], and one dose-finding study, AURA1 (n=173) [see Warnings and Precautions (5)]. The data described below reflect exposure to TAGRISSO (80 mg daily) in 558 patients with EGFR mutation-positive, metastatic NSCLC in two randomized, active-controlled trials [FLAURA (n=279) and AURA3 (n=279)]. 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 enrollment in these studies. Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind randomized (1:1) active controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO was 16.2 months. The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), and decreased appetite (20%). Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%). 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 (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%). Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA. FLAURA 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 ≥10% of Patients Receiving TAGRISSO in FLAURA Adverse Reaction TAGRISSO (N=279) EGFR TKI comparator (gefitinib or erlotinib) (N=277) Any Grade (%) Grade 3 or higher (%) Any Grade (%) Grade 3 or higher (%) Gastrointestinal Disorders DiarrheaOne grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator 58 2.2 57 2.5 Stomatitis 29 0.7 20 0.4 Nausea 14 0 19 0 Constipation 15 0 13 0 Vomiting 11 0 11 1.4 Skin Disorders RashIncludes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion. 58 1.1 78 6.9 Dry skinIncludes dry skin, skin fissures, xerosis, eczema, xeroderma. 36 0.4 36 1.1 Nail toxicityIncludes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia. 35 0.4 33 0.7 PruritusIncludes pruritus, pruritus generalised, eyelid pruritus. 17 0.4 17 0 Metabolism and Nutrition Disorders Decreased appetite 20 2.5 19 1.8 Respiratory, Thoracic and Mediastinal Disorders Cough 17 0 15 0.4 Dyspnea 13 0.4 7 1.4 Neurologic Disorders Headache 12 0.4 7 0 Cardiac Disorders Prolonged QT IntervalThe frequency of “Prolonged QT interval” represents reported adverse events in the FLAURA study. Frequencies of QTc intervals of >500 ms or >60 ms are presented in Section 5.2. 10 2.2 4 0.7 General Disorders and Administration Site Conditions FatigueIncludes fatigue, asthenia. 21 1.4 15 1.4 Pyrexia 10 0 4 0.4 Infection and Infestation Disorders Upper Respiratory Tract Infection 10 0 7 0 * NCI CTCAE v4.0 Table 3. Laboratory Abnormalities Worsening from Baseline ≥ 20% of Patients in FLAURA Laboratory Abnormality NCI CTCAE v4.0 Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO range: 267 - 273 and EGFR TKI comparator range: 256 - 268) TAGRISSO (N=279) EGFR TKI comparator (gefitinib or erlotinib) (N=277) Change from Baseline All Grades (%) Change from Baseline to Grade 3 or Grade 4 (%) Change from Baseline All Grades (%) Change from Baseline to Grade 3 or Grade 4 (%) Hematology Lymphopenia 63 5.6 36 4.2 Anemia 59 0.7 47 0.4 Thrombocytopenia 51 0.7 12 0.4 Neutropenia 41 3.0 10 0 Chemistry HyperglycemiaHyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO (179) and EGFR comparator (191) 37 0 31 0.5 Hypermagnesemia 30 0.7 11 0.4 Hyponatremia 26 1.1 27 1.5 Increased AST 22 1.1 43 4.1 Increased ALT 21 0.7 52 8 Hypokalemia 16 0.4 22 1.1 Hyperbilirubinemia 14 0 29 1.1 Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell Lung Cancer 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 4 and 5 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 4 and 5. Table 4. Adverse Reactions Occuring in ≥10% of Patients Receiving TAGRISSO in AURA3* Adverse Reaction TAGRISSO (N=279) Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=136) All Grades No grade 4 events were reported. (%) Grade 3/4 (%) All Grade (%) Grade 3/4 (%) Gastrointestinal disorders Diarrhea 41 1.1 11 1.5 Nausea 16 0.7 49 3.7 Stomatitis 15 0 15 1.5 Constipation 14 0 35 0 Vomiting 11 0.4 20 2.2 Skin disorders RashIncludes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis and acneform dermatitis. 34 0.7 5.9 0 Dry skinIncludes dry skin, eczema, skin fissures, xerosis. 23 0 4.4 0 Nail toxicityIncludes 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, paronychia. 22 0 1.5 0 Pruritus 13 0 5.1 0 Metabolism and Nutrition Disorders Decreased appetite 18 1.1 36 2.9 Respiratory, Thoracic and Mediastinal Disorders Cough 17 0 14 0 Musculoskeletal and Connective Tissue Disorders Back pain 10 0.4 9 0.7 General Disorders and Administration Site Conditions FatigueIncludes fatigue, asthenia. 22 1.8 40 * NCI CTCAE v4.0. Table 5. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3 Laboratory Abnormality NCI CTCAE v4.0 Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 279, EGFR TKI comparator 131) TAGRISSO (N=279) Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=131) Change from Baseline All Grades (%) Change from Baseline to Grade 3 or Grade 4 (%) Change from Baseline All Grades (%) Change from Baseline to Grade 3 or Grade 4 (%) Hematology Anemia 43 0 79 3.1 Lymphopenia 63 8.2 61 9.9 Thrombocytopenia 46 0.7 48 7.4 Neutropenia 27 2.2 49 12 Chemistry Hypermagnesemia 27 1.8 9.2 1.5 Hyponatremia 26 2.2 36 1.5 HyperglycemiaHyperglycemiais based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO 270, Chemotherapy 5 (fasting glucose was not a protocol requirement for patients in the chemotherapy arm) 20 0 NA NA Hypokalemia 9.0 1.4 18 1.5 NA=not applicable

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended dosage: 80 mg orally once daily, with or without food. (2.2) 2.1 Patient Selection Select patients for the first-line treatment of metastatic EGFR-positive NSCLC with TAGRISSO based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor specimens [see Clinical Studies (14)]. If these mutations are not detected in a plasma specimen, test tumor tissue if feasible. Select patients for the treatment of metastatic EGFR T790M mutation-positive NSCLC with TAGRISSO following progression on or after EGFR TKI therapy based on the presence of an EGFR T790M mutation in tumor or plasma specimens [see Clinical Studies (14)]. Testing for the presence of the T790M mutation in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If this mutation is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. Information on FDA-approved tests for the detection of EGFR mutations is available at http://www.fda.gov/companiondiagnostics. . 2.2 Recommended Dosage Regimen The recommended dosage of TAGRISSO is 80 mg tablet once a day until disease progression or unacceptable toxicity. TAGRISSO can be taken with or without food. If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled. 2.3 Administration to Patients Who Have Difficulty Swallowing Solids Disperse 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 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). 2.4 Dosage Modifications Adverse Reactions Table 1. Recommended Dosage Modifications for TAGRISSO Target Organ Adverse ReactionAdverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0). Dosage Modification Pulmonary Interstitial lung disease (ILD)/Pneumonitis Permanently discontinue TAGRISSO. Cardiac QTcQTc = QT interval corrected for heart rate interval greater than 500 msec on at least 2 separate ECGsECGs = Electrocardiograms 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. Other 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. Drug Interactions Strong CYP3A4 Inducers If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when coadministering 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)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed. (8.2) 8.1 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. 8.2 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 final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Contraception TAGRISSO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. 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) 8.4 Pediatric Use The safety and effectiveness of TAGRISSO in pediatric patients have not been established. 8.5 Geriatric Use Forty-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. 8.6 Renal Impairment 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) or severe (CLcr 15-29 mL/min) renal impairment. There is no recommended dose of TAGRISSO for patients with end-stage renal disease [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment is recommended in patients with mild hepatic impairment [total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 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 [see Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS Strong CYP3A Inducers: Avoid if possible. If not possible, increase TAGRISSO to 160 mg daily in patients receiving a strong CYP3A4 inducer. (2.4, 7.1) 7.1 Effect of Other Drugs on Osimertinib Strong CYP3A Inducers Coadministering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone [see Clinical Pharmacology (12.3)]. Decreased osimertinib exposure may lead to reduced efficacy. Avoid coadministering TAGRISSO with strong CYP3A inducers. Increase the TAGRISSO dosage when coadministering with a strong CYP3A4 inducer if concurrent use is unavoidable [see Dosage and Administration (2.4)]. No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers. 7.2 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 [see Clinical Pharmacology (12.3)]. Increased BCRP substrate exposure may increase the risk of exposure-related toxicity. Monitor for adverse reactions of the BCRP substrate, unless otherwise instructed in its approved labeling, when coadministered with TAGRISSO. 7.3 Drugs That Prolong the QTc Interval 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 [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

More information

Category Value
Authorisation number NDA208065
Agency product number 3C06JJ0Z2O
Orphan designation No
Product NDC 0310-1350,0310-1349
Date Last Revised 18-04-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1721583
Marketing authorisation holder AstraZeneca Pharmaceuticals LP