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Tagrisso

Generic Name: osimertinib
Dosage Form: tablet, film coated

Indications and Usage for Tagrisso

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.

Tagrisso Dosage and Administration

Patient Selection

Confirm the presence of a T790M EGFR mutation in tumor or, in the absence of tumor, plasma specimens prior to initiation of treatment with Tagrisso [see http://www.fda.gov/companiondiagnostics.

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.

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 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).

Dosage Modification

Adverse Reactions

Table 1 Recommended Dose Modifications for Tagrisso

Target Organ

Adverse Reactiona

Dose Modification

Pulmonary

Interstitial lung disease (ILD)/Pneumonitis

Permanently discontinue Tagrisso.

Cardiac

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.

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.

 

Other

Grade 3 or higher adverse reaction

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.

 

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)].

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.

Contraindications

None.

Warnings and Precautions

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)].

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)].

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 congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue Tagrisso [see Dosage and Administration (2.4)].

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)].

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)]

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 Tagrisso-treated 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 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
* 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.

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

Vascular events

 
Venous thromboembolisme

7

2.4

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
a The only grade 4 laboratory abnormality was 1 patient with grade 4 thrombocytopenia.

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

Drug Interactions

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 preparation-dependent]. 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.

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.

USE IN SPECIFIC POPULATIONS

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.

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 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.

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)].

Pediatric Use

The safety and effectiveness of Tagrisso in pediatric patients have not been established.

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.

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)].

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)].

Tagrisso 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.

Tagrisso - Clinical Pharmacology

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.

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 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.

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 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: Coadministering 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.

Nonclinical Toxicology

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 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.

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%), 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%), 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.

Table 4 Efficacy Results by BICR in Study 1 and Study 2
1 Objective response rate determined by RECIST v1.1 as assessed by BICR
2 Pooled analysis of Study 1 and 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%

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.

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].

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)].

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

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.
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

Tagrisso osimertinib 40 mg

NDC 0310-1349-30

30 Tablets

Each tablet contains 40 mg osimertinib.
USUAL ADULT DOSAGE:
See Prescribing Information.
WARNING: As with all medications, keep out of the reach of children.
Store at room temperature between 68°F to 77°F (20°C to 25°C).

Rx only

AstraZeneca

Tagrisso osimertinib 80 mg

NDC 0310-1350-30

30 Tablets

Each tablet contains 80 mg osimertinib.
USUAL ADULT DOSAGE:
See Prescribing Information.
WARNING: As with all medications, keep out of the reach of children.
Store at room temperature between 68°F to 77°F (20°C to 25°C).

Rx only

AstraZeneca

Tagrisso 
osimertinib tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0310-1349
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
OSIMERTINIB (OSIMERTINIB) OSIMERTINIB 40 
Inactive Ingredients
Ingredient Name Strength
MANNITOL  
CELLULOSE, MICROCRYSTALLINE  
SODIUM STEARYL FUMARATE  
POLYVINYL ALCOHOL  
TITANIUM DIOXIDE  
POLYETHYLENE GLYCOL 3350  
TALC  
FERRIC OXIDE YELLOW  
FERRIC OXIDE RED  
FERROSOFERRIC OXIDE  
HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED  
Product Characteristics
Color BROWN (beige) Score no score
Shape ROUND (biconvex) Size 9mm
Flavor Imprint Code AZ;40
Contains         
Packaging
# Item Code Package Description
1 NDC:0310-1349-30 30 TABLET, FILM COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA208065 11/13/2015
Tagrisso 
osimertinib tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0310-1350
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
OSIMERTINIB (OSIMERTINIB) OSIMERTINIB 80 
Inactive Ingredients
Ingredient Name Strength
MANNITOL  
CELLULOSE, MICROCRYSTALLINE  
SODIUM STEARYL FUMARATE  
POLYVINYL ALCOHOL  
TITANIUM DIOXIDE  
POLYETHYLENE GLYCOL 3350  
TALC  
FERRIC OXIDE YELLOW  
FERRIC OXIDE RED  
FERROSOFERRIC OXIDE  
HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED  
Product Characteristics
Color BROWN (beige) Score no score
Shape OVAL (biconvex) Size 15mm
Flavor Imprint Code AZ;80
Contains         
Packaging
# Item Code Package Description
1 NDC:0310-1350-30 30 TABLET, FILM COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA208065 11/13/2015
Labeler - AstraZeneca Pharmaceuticals LP (054743190)
Registrant - AstraZeneca PLC (230790719)
Revised: 09/2016
 
AstraZeneca Pharmaceuticals LP
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