TAGRISSO® (osimertinib) tablets, for oral use
Brief Summary of Prescribing Information.
For complete prescribing information consult official package insert.
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, whose disease has progressed on or after EGFR tyrosine kinase inhibitor
DOSAGE AND ADMINIS TRATION
Confirm the presence of a T790M EGFR mutation in tumor or plasma specimens prior to initiation of
treatment with TAGRISSO [see Indications and Usage ( 1) and Clinical Studies ( 14) in full Prescribing
Information]. Testing for the presence of the 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 T790M mutations is available at http://www.fda.gov/
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
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).
Table 1. Recommended Dose Modifications for TAGRISSO
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.
QTc interval prolongation with
signs/symptoms of life-threatening
Permanently discontinue TAGRISSO.
Symptomatic congestive heart failure
or asymptomatic left ventricular
dysfunction that persists ≥ 4 weeks
Permanently discontinue TAGRISSO.
Adverse reaction of Grade 3 or greater
Withhold TAGRISSO for up to 3 weeks.
If improvement to Grade 0-2 within
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 C TCAE v4.0).
b ECGs = Electrocardiograms
† QTc = QT interval corrected for heart rate
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) in full
WARNINGS AND PRECAUTIONS
The following information for ILD/ Pneumonitis, QTc Interval Prolongation, Cardiomyopathy and
Keratitis reflects exposure to TAGRISSO in 833 patients with EGFR T790M mutation-positive
non-small cell lung cancer (NSCLC) who received TAGRISSO at the recommended dose of 80 mg
once daily in AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and an expansion cohort
in the first-in-human trial of osimertinib (AURA1, n=143).
Interstitial Lung Disease/Pneumonitis
Interstitial lung disease (ILD)/pneumonitis occurred in 3.5% (n= 29) of TAGRISSO-treated patients
(n=833); 0.6% (n= 5) of cases were fatal.
Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening
of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever).
Permanently discontinue TAGRISSO if ILD is confirmed [see Dosage and Administration ( 2. 4) and
Adverse Reactions ( 6) in full Prescribing Information].
QTc Interval Prolongation
Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of
the 833 patients treated with TAGRISSO in clinical trials, 0.7% (n= 6) were found to have a QTc
greater than 500 msec, and 2.9% of patients (n= 24) had an increase from baseline QTc greater
than 60 msec [see Clinical Pharmacology ( 12. 2) in full Prescribing Information]. No QTc-related
arrhythmias were reported.
Clinical trials of TAGRISSO did not enroll patients with baseline QTc of greater than 470 msec.
Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc
syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications
known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop
QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and
Administration ( 2. 4) in full Prescribing Information].
Across clinical trials, cardiomyopathy (defined as cardiac failure, congestive heart failure,
pulmonary edema or decreased ejection fraction) occurred in 1.9% (n= 16) of 833 TAGRISSO-treated patients: 0.1% (n= 1) of cases were fatal.
Left Ventricular Ejection Fraction (LVEF) decline greater than or equal to 10% and a drop to less
than 50% occurred in 4.0% (26/655) of patients who had baseline and at least one follow-up
Conduct cardiac monitoring, including an assessment of LVEF at baseline and during treatment in
patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or
symptoms during treatment. For symptomatic congestive heart failure or persistent, asymptomatic
LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO [see
Dosage and Administration ( 2. 4) in full Prescribing Information].
Keratitis was reported in 0.7% (n= 6) of 833 patients treated with TAGRISSO in clinical trials.
Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation,
lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.
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) in full Prescribing Information].
ADVERSE REAC TIONS
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) in full Prescribing
QTc Interval Prolongation [see Warnings and Precautions ( 5. 2) in full Prescribing Information]
Cardiomyopathy [see Warnings and Precautions ( 5. 3) in full Prescribing Information]
Keratitis [see Warnings and Precautions ( 5. 4) in full Prescribing Information]
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 patients with EGFR T790M
mutation-positive metastatic NSCLC in an open-label, randomized, active-controlled trial (AURA3,
n=279) and in two single arm trials, AURA Extension (n=201) and AURA2 (n=210). Patients with
a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that
required: steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on
electrocardiogram were excluded from trial enrollment.
The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized
(2: 1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M
mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment.
A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy,
disease progression, or investigator determination that the patient was no longer benefiting from
treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every
three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy
could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or
investigator determination that the patient was no longer benefiting from treatment. Left Ventricular
Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of
treatment was 8. 1 months for patients treated with TAGRISSO and 4. 2 months for chemotherapy-treated patients. The trial population characteristics were: median age 62 years, age less than 65
(58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%).
The most common adverse reactions (≥20%) in patients treated with TAGRISSO were diarrhea
(41%), rash (34%), dry skin (23%), nail toxicity (22%), and fatigue (22%). Serious adverse reactions
were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No
single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One
patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis).
Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse
reactions leading to dose reductions or interruptions were prolongation of the QT interval as
assessed by ECG ( 1.8%), neutropenia ( 1.1%), and diarrhea ( 1.1%). Adverse reactions resulting in
permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The
most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%).
Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities which
occurred in TAGRISSO-treated patients in AURA3. AURA3 was not designed to demonstrate a