HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TAGRISSO safely and effectively. See full prescribing information for TAGRISSO. T
AGRISSO™ (osimertinib) tablets, for oral use Initial U.S. Approval: 2015
--------------------------- INDICATIONS AND USAGE --------------------------
TAGRISSO is a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutationpositive non-small cell lung cancer (NSCLC), as detected by an FDAapproved test, who have progressed on or after EGFR TKI therapy. (1) This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1)
---------------------- DOSAGE AND ADMINISTRATION ----------------------
Confirm the presence of T790M mutation in tumor specimens prior to initiation of treatment with TAGRISSO. (2.1)· · 80 mg orally once daily, with or without food. (2.2)
--------------------- DOSAGE FORMS AND STRENGTHS
-------------------- Tablets: 80 mg and 40 mg (3)
------------------------------ CONTRAINDICATIONS ----------------------------- None. (4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 3.3% of patients. Permanently discontinue TAGRISSO in patients diagnosed with ILD/Pneumonitis. (5.1) ·
QTc Interval Prolongation: Monitor electrocardiograms and electrolytes in patients who have a history or predisposition for QTc prolongation, or those who are taking medications that are known to prolong the QTc interval. Withhold then restart at a reduced dose or permanently discontinue TAGRISSO. (2.4, 5.2) ·
Cardiomyopathy: Occurred in 1.4% of patients. Assess left ventricular ejection fraction (LVEF) before treatment and then every 3 months thereafter. (2.4, 5.3) ·
Embryo-Fetal Toxicity: TAGRISSO can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with TAGRISSO and for 6 weeks after final dose. Advise males to use effective contraception for 4 months, after the last dose of TAGRISSO. (5.3, 8.1, 8.3)·
------------------------------ ADVERSE REACTIONS -----------------------------
Most common adverse reactions (≥25%) were diarrhea, rash, dry skin, and nail toxicity. (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.
------------------------------ 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)
------------------------USE IN SPECIFIC POPULATIONS-----------------------
Lactation: Do not breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 8/2016 FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection 2.2 Recommended Dosage Regimen 2.3 Administration to Patients Who Have Difficulty Swallowing Solids 2.4 Dosage Modification
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Interstitial Lung Disease/Pneumonitis 5.2 QTc Interval Prolongation 5.3 Cardiomyopathy 5.4 Embryo-Fetal Toxicity
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on Osimertinib 7.2 Effect of Osimertinib on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 3971806
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
TAGRISSO is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection Confirm the presence of a T790M EGFR mutation in tumor specimens prior to initiation of treatment with TAGRISSO [see Indications and Usage (1) and Clinical Studies (14)]. Information on FDAapproved tests for the detection of T790M mutations is available at http://www.fda.gov/companiondiagnostics.
2.2 Recommended Dosage Regimen The recommended dose 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 naso-gastric tube is required, disperse the tablet as above in 15 mL of noncarbonated 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 Modification Adverse Reactions 2 Reference ID: 3971806
Table 1 Recommended Dose Modifications for TAGRISSO Target Organ Adverse Reactiona Dose Modification Pulmonary Interstitial lung disease (ILD)/Pneumonitis Permanently discontinue TAGRISSO. QTc† interval greater than 500 msec on at least 2 separate ECGsb 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. Cardiac QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Permanently discontinue TAGRISSO. Asymptomatic, absolute decrease in LVEFc of 10% from baseline and below 50% Withhold TAGRISSO for up to 4 weeks. • If improved to baseline LVEF, resume. • If not improved to baseline, permanently discontinue. Symptomatic congestive heart failure Permanently discontinue TAGRISSO. Grade 3 or higher adverse reaction Withhold TAGRISSO for up to 3 weeks. Other 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. a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0). b ECGs = Electrocardiograms c LVEF = Left Ventricular Ejection Fraction † QTc = QT interval corrected for heart rate 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)]. 3 Reference ID: 3971806 3 DOSAGE FORMS AND STRENGTHS 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. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Interstitial Lung Disease/Pneumonitis Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 3.3% (n=27) of TAGRISSO treated patients (n=813); 0.5% (n=4) were fatal. Withhold TAGRISSO and promptly investigate for ILD in any patient who presents 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 The heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 411 patients in Study 1 and Study 2, one patient (0.2%) was found to have a QTc greater than 500 msec, and 11 patients (2.7%) had an increase from baseline QTc greater than 60 msec [see Clinical Pharmacology (12.2)]. In Study 1 and 2, patients with baseline QTc of 470 msec or greater were excluded. 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 Across clinical trials, cardiomyopathy (defined as cardiac failure, pulmonary edema, ejection fraction decreased or stress cardiomyopathy) occurred in 1.4% (n=11) of TAGRISSO treated patients (n=813); 0.2% (n=2) were fatal. In Study 1 and Study 2, Left Ventricular Ejection Fraction (LVEF) decline >10% and a drop to <50% occurred in 2.4% (9/375) of patients who had baseline and at least one follow-up LVEF assessment. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAGRISSO and then at 3 month intervals while on treatment. Withhold treatment with TAGRISSO if ejection fraction decreases by 10% from pretreatment values and is less than 50%. For symptomatic 4 Reference ID: 3971806 congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO [see Dosage and Administration (2.4)].
b 5.4 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 human 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 in patients at the 80 mg dose level. 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 [see Use in Specific Populations (8.1), (8.3) and Clinical Pharmacology (12.3)].
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)]
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 described below reflect exposure to TAGRISSO (80 mg daily) in 411 patients with EGFR T790M mutation-positive non-small cell lung cancer who received prior EGFR TKI therapy, in two single-arm studies, Study 1 and Study 2. Patients with a past medical history of ILD or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 ms were excluded from Study 1 and Study 2. Baseline patient and disease characteristics were: median age 63 years, 13% of patients were ≥75 years old, female (68%), White (36%), Asian (60%), metastatic (96%), sites of brain metastases (39%), World Health Organization (WHO) performance status of 0 (37%) or 1 (63%), 1 prior line of therapy [EGFR-TKI treatment only, second line, chemotherapy-naïve (31%)], 2 or more prior lines of therapy (69%). Of the 411 patients, 333 patients were exposed to TAGRISSO for at least 6 months; 97 patients were exposed for at least 9 months; however, no patient was exposed to TAGRISSO for 12 months. In Studies 1 and 2, the most common (>20%) adverse reactions (all grades) observed in TAGRISSOtreated patients were diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). Dose reductions occurred in 4.4% of patients treated with TAGRISSO. The most frequent adverse reactions 5 Reference ID: 3971806 that led to dose reductions or interruptions were: electrocardiogram QTc prolonged (2.2%) and neutropenia (1.9%). Serious adverse reactions reported in 2% or more patients were pneumonia and pulmonary embolus. There were 4 patients (1%) treated with TAGRISSO who developed fatal adverse reactions of ILD/pneumonitis. Other fatal adverse reactions occurring in more than 1 patient included pneumonia (4 patients) and CVA/cerebral hemorrhage (2 patients). Discontinuation of therapy due to adverse reactions occurred in 5.6% of patients treated with TAGRISSO. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis and cerebrovascular accidents/infarctions. Tables 2 and 3 summarize the common adverse reactions and laboratory abnormalities observed in TAGRISSO-treated patients.
Table 2 Adverse Reactions (>10% for all NCI CTCAE* Grades or >2% for Grades 3-4) in Study 1 and Study 2 Adverse Reaction TAGRISSO N=411 All Grades Grade 3-4f % % Gastrointestinal disorders Diarrhea 42 1.0 Nausea 17 0.5 Decreased appetite 16 0.7 Constipation 15 0.2 Stomatitis 12 0 Skin disorders Rasha 41 0.5 Dry skinb 31 0 Nail toxicityc 25 0 Pruritus 14 0 Eye Disordersd 18 0.2 Respiratory Cough 14 0.2 General Fatigue 14 0.5 Musculoskeletal Back pain 13 0.7 Central Nervous System Headache 10 0.2 Infections Pneumonia 4 2.2 6 Reference ID: 3971806 Adverse Reaction TAGRISSO N=411 All Grades Grade 3-4f % % Vascular events Venous thromboembolisme 7 2.4 * NCI CTCAE v4.0. a Includes cases reported within the clustered terms for rash adverse events: Rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis and acneform dermatitis. b Includes dry skin, eczema, skin fissures, xerosis. c Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, onychoclasis, onycholysis, onychomadesis, paronychia. d Includes dry eye, vision blurred, keratitis, cataract, eye irritation, blepharitis, eye pain, lacrimation increased, vitreous floaters. Other ocular toxicities occurred in <1% of patients. e Includes deep vein thrombosis, jugular venous thrombosis, and pulmonary embolism. f No grade 4 events have been reported. Additional clinically significant adverse reactions occurring in 2% or more of patients treated with TAGRISSO included cerebrovascular accident (2.7%). Table 3 Laboratory Abnormalities (>20% for all NCI CTCAE Grades) in Study 1 and Study 2 Laboratory Abnormality TAGRISSO N=411 Change from Baseline All Grades (%) Change from Baseline to Grade 3 or Grade 4 (%)a Clinical Chemistry Hyponatremia 26 3.4 Hypermagnesemia 20 0.7 Hematologic Lymphopenia 63 3.3 Thrombocytopenia 54 1.2a Anemia 44 0.2 Neutropenia 33 3.4 a The only grade 4 laboratory abnormality was 1 patient with grade 4 thrombocytopenia.
7 DRUG INTERACTIONS
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 (e.g., phenytoin, rifampin, carbamazepine, St. John’s Wort) [note: effect of St. John’s Wort varies widely and is preparationdependent]. Increase the TAGRISSO dosage when coadministering with a strong CYP3A4 inducer if 7 Reference ID: 3971806 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 (e.g., rosuvastatin, sulfasalazine, topotecan), unless otherwise instructed in its approved labeling, when coadministered with TAGRISSO.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Risk
Summary Based on data from animal studies and its mechanism of action, 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 human 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 in patients at the recommended dose of 80 mg), 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 in human milk, the effects of osimertinib on the breastfed infant or on milk production. Administration to rats during gestation and early lactation was 8 Reference ID: 3971806 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 a lactating woman not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose.
8.3 Females and Males of Reproductive Potential
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)].
8.4 Pediatric Use
The safety and effectiveness of TAGRISSO in pediatric patients have not been established.
8.5 Geriatric Use One hundred eighty-seven (45%) of the 411 patients in clinical trials of TAGRISSO were 65 years of age and older, and 54 patients (13%) were 75 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 (32% versus 25%) and more frequent dose modifications for adverse reactions (23% versus 17%) 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)] 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 [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
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 [see Clinical Pharmacology (12.3)]. 9 Reference ID: 3971806
11 DESCRIPTION
Osimertinib is a kinase inhibitor for oral use.
The molecular formula for osimertinib mesylate is C28H33N7O2•CH4O3S, and the molecular weight is 596 g/mol. The chemical name is N-(2-{2 dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2 yl]amino}phenyl)prop-2-enamide mesylate salt. Osimertinib has the following structural formula (as osimertinib mesylate): TAGRISSO tablets contain 40 or 80 mg of osimertinib, equivalent to 47.7 and 95.4 mg of osimertinib mesylate, respectively. Inactive ingredients in the tablet core are mannitol, microcrystalline cellulose, low-substituted hydroxpropyl cellulose and sodium stearyl fumarate. The tablet coating consists of polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, ferric oxide yellow, ferric oxide red and ferric oxide black.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action Osimertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately 9 fold lower concentrations than wild-type. In cultured cells and animal tumor implantation models, osimertinib exhibited anti-tumor activity against NSCLC lines harboring EGFR-mutations (T790M/L858R, L858R, T790M/exon 19 deletion, and exon 19 deletion) and, to a lesser extent, wild-type EGFR amplifications. Two pharmacologically-active metabolites (AZ7550 and AZ5104 circulating at approximately 10% of the parent) with similar inhibitory profiles to osimertinib have been identified in the plasma after oral administration of osimertinib. AZ7550 showed a similar potency to osimertinib, while AZ5104 showed greater potency against exon 19 deletion and T790M mutants (approximately 8 fold) and wild-type (approximately 15-fold) EGFR. In vitro, osimertinib also inhibited the activity of HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations.
12.2 Pharmacodynamics
Cardiac Electrophysiology The QTc interval prolongation potential of osimertinib was assessed in 210 patients who received TAGRISSO 80 mg daily in Study 2. A central tendency analysis of the QTcF data at steady-state demonstrated that the maximum mean change from baseline was 16.2 msec (upper bound of two-sided 90% confidence interval (CI) 17.6 msec). A pharmacokinetic/pharmacodynamic analysis in Study 2 10 Reference ID: 3971806 suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of TAGRISSO 80 mg.
12.3 Pharmacokinetics The area under the plasma concentration-time curve (AUC) and maximal plasma concentration (Cmax) of osimertinib increased dose proportionally over 20 to 240 mg dose range (i.e., 0.25 to 3 times the recommended dosage) after oral administration and exhibited linear pharmacokinetics (PK). Administration of TAGRISSO orally once daily resulted in approximately 3-fold accumulation with steady state exposures achieved after 15 days of dosing. At steady state, the Cmax to Cmin (minimal concentration) ratio was 1.6-fold. Absorption The median time to Cmax of osimertinib was 6 hours (range 3-24 hours). Following administration of a 20 mg TAGRISSO tablet with a high-fat, high-calorie meal (containing approximately 58 grams of fat and 1000 calories), the Cmax and AUC of osimertinib were comparable to that under fasting conditions. Distribution The mean volume of distribution at steady-state (Vss/F) of osimertinib was 986 L. Plasma protein binding of osimertinib is likely high based on its physiochemical properties. Elimination Osimertinib plasma concentrations decreased with time and a population estimated mean half-life of osimertinib was 48 hours, and oral clearance (CL/F) was 14.2 (L/h). Metabolism The main metabolic pathways of osimertinib were oxidation (predominantly CYP3A) and dealkylation in vitro. Two pharmacologically active metabolites (AZ7550 and AZ5104) have been identified in the plasma after TAGRISSO oral administration. The geometric mean exposure (AUC) of each metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of osimertinib at steady-state. Excretion Osimertinib is primarily eliminated in the feces (68%) and to a lesser extent in the urine (14%). Unchanged osimertinib accounted for approximately 2% of the elimination. Specific Populations No clinically significant differences in the pharmacokinetics of osimertinib were observed based on age, sex, ethnicity, body weight, smoking status, mild (CLcr 60-89 mL/min, as estimated by C-G) or moderate (CLcr 30-59 mL/min, as estimated by C-G) renal impairment, or mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN or total bilirubin between 1 to 1.5 times ULN and any AST). The pharmacokinetics of osimertinib in patients with severe renal impairment (CLcr less than 30 mL/min) or with moderate to severe hepatic impairment (moderate: total bilirubin between 1.5 to 3 11 Reference ID: 3971806 times ULN and any AST, and severe: total bilirubin between 3 to 10 times ULN and any AST) are unknown.
Drug Interactions Effect of Other Drugs on TAGRISSO in Clinical Pharmacokinetic Studies
Strong CYP3A Inducers: The steady-state AUC of osimertinib was reduced by 78% in patients when coadministered with rifampin (600 mg daily for 21 days) in a clinical pharmacokinetic study [see Drug Interactions (7.1)].
Strong CYP3A Inhibitors: Coadministering TAGRISSO with 200 mg itraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on the exposure of osimertinib (AUC increased by 24% and Cmax decreased by 20%).
Gastric Acid Reducing Agents: The exposure of osimertinib was not affected by concurrent administration of a single 80 mg TAGRISSO tablet following 40 mg omeprazole administration for 5 days.
Effect of Osimertinib on Other Drugs in Clinical Pharmacokinetic Studies BCRP substrates: Co-administering TAGRISSO with rosuvastatin (a BCRP substrate) increased rosuvastatin AUC by 35% and Cmax by 72% in a clinical pharmacokinetic study [see Drug Interactions (7.2)]. CYP3A4 substrates: Coadministering TAGRISSO with simvastatin (a CYP3A4 substrate) had no clinically significant effect on the exposure of simvastatin in a clinical pharmacokinetic study. In Vitro Studies CYP450 Metabolic Pathways: Osimertinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1. Osimertinib induced CYP1A2 enzymes. Transporter Systems: Osimertinib is a substrate of P-glycoprotein and BCRP and is not a substrate of OATP1B1 and OATP1B3. Osimertinib is an inhibitor of BCRP and does not inhibit P-glycoprotein, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, MATE2K and OCT2.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with osimertinib. Osimertinib did not cause genetic damage in in vitro and in vivo assays. Based on studies in animals, male fertility may be impaired by treatment with TAGRISSO. Degenerative changes were present in the testes in rats and dogs exposed to osimertinib for 1 month or more with evidence of reversibility in the rat. Following administration of osimertinib to rats for approximately 10 weeks at a dose of 40 mg/kg, at exposures 0.5-times the AUC observed in patients at the recommended 12 Reference ID: 3971806 dose of 80 mg, there was a reduction in male fertility, demonstrated by increased pre-implantation loss in untreated females mated to treated males. Based on studies in animals, female fertility may be impaired by treatment with TAGRISSO. In repeat dose toxicity studies, histological evidence of anestrus, corpora lutea degeneration in the ovaries and epithelial thinning in the uterus and vagina were seen in rats exposed to osimertinib for 1 month or more at exposures 0.3-times the AUC observed in patients at the recommended dose of 80 mg. Findings in the ovaries seen following 1 month of dosing exhibited evidence of reversibility. In a female fertility study in rats, administration of osimertinib from 2 weeks prior to mating through Day 8 of gestation at a dose of 20 mg/kg/day (approximately 1.5-times the human Cmax at the recommended dose of 80 mg/day) had no effects on oestrus cycling or the number of females becoming pregnant, but caused early embryonic deaths. These findings showed evidence of reversibility when females were mated 1 month after treatment discontinuation. 14 CLINICAL STUDIES The efficacy of TAGRISSO was demonstrated in two multicenter, single-arm, open-label clinical trials, Study 1 and Study 2, in patients with metastatic EGFR T790M mutation-positive NSCLC who had progressed on prior systemic therapy, including an EGFR TKI. All patients were required to have EGFR T790M mutation-positive NSCLC as detected by the cobas® EGFR mutation test and received TAGRISSO 80 mg once daily. The major efficacy outcome measure of both trials was ORR according to RECIST v1.1 as evaluated by a Blinded Independent Central Review (BICR). Duration of response (DOR) was an additional outcome measure. Study 1 population characteristics were: median age 62 years (range 37 to 89), female (66%), White (38%), Asian (58%), never smoker (67%), World Health Organization (WHO) performance status 0 (34%) or 1 (66%), adenocarcinoma histology (97%), 1 prior line of therapy [EGFR-TKI treatment only, second line, chemotherapy-naïve] (30%), 2 or more prior lines of therapy (70%). Sites of extra-thoracic metastasis included liver (32%), bone (51%), and brain (37%). Somatic EGFR mutations in addition to T790M were exon 19 deletion (71%), L858R (25%), G719X (2%), and S768I (2%). Study 2 population characteristics were: median age 64 years (range 35 to 88), female (70%), White (34%), Asian (63%), never smoker (76%), World Health Organization (WHO) performance status 0 (40%) or 1 (60%), adenocarcinoma histology (95%), 1 prior line of therapy [EGFR-TKI treatment only, second line, chemotherapy-naïve] (32%), 2 or more prior lines of therapy (68%). Sites of extra-thoracic metastasis included liver (26%), bone (43%), and brain (41%). Somatic EGFR mutations in addition to T790M were exon 19 deletion (65%), L858R (32%), G719X (2%), and S768I (1%). Efficacy results by BICR from Study 1 and Study 2 are summarized in Table 4. The majority (96%) of patients with confirmed objective responses had ongoing responses ranging from 1.1 to 5.6 months after a median duration of follow-up of 4.2 months for Study 1 and 4.0 months for Study 2. 13 Reference ID: 3971806 Table 4 Efficacy Results by BICR in Study 1 and Study 2 Efficacy Parameter Study 1 (N=201) Study 2 (N=210) Overall2 (N=411) Objective Response Rate1 (95% CI) 57% (50, 64) 61% (54, 68) 59% (54, 64) Complete Response 0 1% 0.5% Partial Response 57% 60% 59% 1 Objective response rate determined by RECIST v1.1 as assessed by BICR 2 Pooled analysis of Study 1 and 2. In a separate dose finding part of Study 1, 63 patients with centrally confirmed T790M-positive NSCLC progressed on prior systemic therapy, including an EGFR TKI were administered TAGRISSO 80 mg. In these patients, the BICR-confirmed objective response rate was 51% (32/63) and the median duration of response was 12.4 months from the time of first documented response.
16 HOW SUPPLIED/STORAGE AND HANDLING
80 mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1350-30).
40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1349-30).
Store TAGRISSO bottles at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Interstitial Lung Disease/Pneumonitis Inform patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.1)].
QTc Interval Prolongation Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications [see Warnings and Precautions (5.2)].
Cardiomyopathy
TAGRISSO can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.3)]. 14 Reference ID: 3971806·
Embryo-Fetal Toxicity · TAGRISSO can cause fetal harm if taken during pregnancy. Advise pregnant women of the potential risk to a fetus. ·Advise females to inform their healthcare provider if they become pregnant or if pregnancy is suspected, while taking TAGRISSO [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)]. Females and Males of Reproductive Potential · 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 (8.3)]. · Advise males to use effective contraception during treatment and for 4 months after the final dose of TAGRISSO [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose [see Use in Specific Populations (8.2)]. Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 TAGRISSO is a trademark of the AstraZeneca group of companies ©AstraZeneca 2015 15 Reference ID: 3971806 Patient Information TAGRISSO™ (tuh-GRISS-oh) (osimertinib) tablet What is the most important information I should know about TAGRISSO? TAGRISSO may cause serious side effects, including: · lung problems. TAGRISSO may cause lung problems that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your doctor right away if you have any new or worsening lung symptoms, including trouble breathing, shortness of breath, cough, or fever. · heart problems, including heart failure. TAGRISSO may cause heart problems that may lead to death. Your doctor should check your heart function before you start taking TAGRISSO and during treatment. Tell your doctor 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, feeling lightheaded. See “What are the possible side effects of TAGRISSO?” for more information about side effects. What is TAGRISSO? TAGRISSO is a prescription medicine used to treat non-small cell lung cancer (NSCLC). TAGRISSO may be used when your non-small cell lung cancer has spread to other parts of the body and: · has a certain type of abnormal epidermal growth factor receptor (EGFR) gene, called T790M, and · you have had previous treatment with an EGFR tyrosine kinase inhibitor medicine and it has stopped working. Your doctor will perform a test to make sure that TAGRISSO is right for you. It is not known if TAGRISSO is safe and effective in children. Before taking TAGRISSO, tell your doctor about all of your medical conditions, including if you: · have lung or breathing problems · have heart problems, including a condition called long QTc syndrome · have problems with your electrolytes, such as sodium, potassium, calcium or magnesium · are pregnant or plan to become pregnant. TAGRISSO can harm your unborn baby. Tell your doctor right away if you become pregnant during treatment with TAGRISSO or think you may be pregnant. o Females who are able to become pregnant should use an effective birth control during treatment with TAGRISSO and for 6 weeks after the final dose of TAGRISSO. o Males who have female partners that are able to become pregnant should use effective birth control during treatment with TAGRISSO and for 4 months after the final dose of TAGRISSO. · are breastfeeding or plan to breastfeed. It is not known if TAGRISSO passes into your breast milk. Do not breastfeed during treatment with TAGRISSO and for 2 weeks after your final dose of TAGRISSO. Talk to your doctor about the best way to feed your baby during this time. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements. Especially tell your doctor if you take a heart or blood pressure medicine. How should I take TAGRISSO? · Take TAGRISSO exactly as your doctor tells you to take it. · Your doctor may change your dose, temporarily stop, or permanently stop treatment with TAGRISSO if you have side effects. 16 Reference ID: 3971806 · Take TAGRISSO 1 time each day. · You can take TAGRISSO with or without food. · If you miss a dose of TAGRISSO, do not make up for the missed dose. Take your next dose at your regular time. · If you cannot swallow TAGRISSO tablets whole: o place your dose of TAGRISSO in a container that contains 60 mL (2 ounces) of water. Do not use carbonated water or any other liquids. o stir the TAGRISSO tablet and water until the TAGRISSO tablet is in small pieces (the tablet will not completely dissolve). Do not crush, heat, or use ultrasound to prepare the mixture. o drink the TAGRISSO and water mixture right away. o add 120 mL to 240 mL (4 to 8 ounces) of water into the container and drink to make sure that you take your full dose of TAGRISSO. 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?” The most common side effects of TAGRISSO are: · diarrhea · rash · dry skin · changes in your nails, including: redness, tenderness, pain, inflammation, brittleness, separation from nailbed, and shedding of nails Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of TAGRISSO. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088. How should I store TAGRISSO? · Store TAGRISSO at room temperature between 68°F to 77°F (20°C to 25°C). ·Safely throw away medicine that is out of date or that you no longer need. · Keep TAGRISSO and all medicines out of the reach of children. General information about the safe and effective use of TAGRISSO. · Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TAGRISSO for a condition for which it was not prescribed. Do not give TAGRISSO to other people, even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about TAGRISSO that is written for a health care professional. What are the ingredients in TAGRISSO? Active ingredient: osimertinib Inactive ingredients: mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and sodium stearyl fumarate. Tablet coating contains: polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, ferric oxide yellow, ferric oxide red and ferric oxide black. For more information, go to www.TAGRISSO.com or call 1-800-236-9933. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 © AstraZeneca 2015 This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: August 2016 17 Reference ID: 3971806
