TAGRISSO as monotherapy is indicated for:

•  the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations.
•  the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC.

Treatment with TAGRISSO should be initiated by a physician experienced in the use of anticancer
therapies.
When considering the use of TAGRISSO, EGFR mutation status (in tumour specimens for adjuvant
treatment and tumour or plasma specimens for locally advanced or metastatic setting) should be
determined using a validated test method (see section 4.4).
Posology
The recommended dose is 80 mg osimertinib once a day.
Patients in the adjuvant setting should receive treatment until disease recurrence or unacceptable
toxicity. Treatment duration for more than 3 years was not studied.
Patients with locally advanced or metastatic lung cancer should receive treatment until disease
progression or unacceptable toxicity.
If a dose of TAGRISSO is missed, the dose should be made up unless the next dose is due within 12
hours.
TAGRISSO can be taken with or without food at the same time each day.
Dose adjustments
Dosing interruption and/or dose reduction may be required based on individual safety and tolerability.
If dose reduction is necessary, then the dose should be reduced to 40 mg taken once daily.
Dose reduction guidelines for adverse reactions toxicities are provided in Table 1.
Table 1. Recommended dose modifications for TAGRISSO
Target
organ
Adverse reactiona
Dose modification
Pulmonary ILD/Pneumonitis Discontinue TAGRISSO (see Section 4.4)
Cardiac QTc interval greater than 500 msec
on at least 2 separate ECGs
Withhold TAGRISSO until QTc interval is
less than 481 msec or recovery to baseline if
baseline QTc is greater than or equal to 481
msec, then restart at a reduced dose (40 mg)
QTc interval prolongation with
signs/symptoms of serious
arrhythmia
Permanently discontinue TAGRISSO
Other Grade 3 or higher adverse reaction Withhold TAGRISSO for up to 3 weeks
If Grade 3 or higher adverse
reaction improves to Grade 0-2 after
withholding of TAGRISSO for up
to 3 weeks
TAGRISSO may be restarted at the same dose
(80 mg) or a lower dose (40 mg)
Grade 3 or higher adverse reaction
that does not improve to Grade 0-2
after withholding for up to 3 weeks
Permanently discontinue TAGRISSO
a Note: The intensity of clinical adverse events graded by the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) version 4.0.
ECGs: Electrocardiograms; QTc: QT interval corrected for heart rate
Special populations
4
No dosage adjustment is required due to patient age, body weight, gender, ethnicity and smoking
status (see section 5.2).
Hepatic impairment
Based on clinical studies, no dose adjustments are necessary in patients with mild hepatic impairment
(Child Pugh A) or moderate hepatic impairment (Child Pugh B). Similarly, based on population
pharmacokinetic analysis, no dose adjustment is recommended in patients with mild hepatic
impairment (total bilirubin ≤upper limit of normal (ULN) and aspartate aminotransferase (AST)
>ULN or total bilirubin >1.0 to 1.5x ULN and any AST) or moderate hepatic impairment (total
bilirubin between 1.5 to 3 times ULN and any AST). The safety and efficacy of this medicinal product
has not been established in patients with severe hepatic impairment. Until additional data become
available, use in patients with severe hepatic impairment is not recommended (see section 5.2).
Renal impairment
Based on clinical studies and population PK analysis, no dose adjustments are necessary in patients
with mild, moderate, or severe renal impairment. The safety and efficacy of this medicinal product
has not been established in patients with end-stage renal disease [creatinine clearance (CLcr) less than
15 mL/min, calculated by the Cockcroft and Gault equation], or on dialysis. Caution should be
exercised when treating patients with severe and end-stage renal impairment (see section 5.2).
Paediatric population
The safety and efficacy of TAGRISSO in children or adolescents aged less than 18 years have not
been established. No data are available.
Method of administration
This medicinal product is for oral use. The tablet should be swallowed whole with water and it should
not be crushed, split or chewed.
If the patient is unable to swallow the tablet, the tablet may first be dispersed in 50 mL of
non-carbonated water. It should be dropped in the water, without crushing, stirred until dispersed and
immediately swallowed. An additional half a glass of water should be added to ensure that no residue
remains and then immediately swallowed. No other liquids should be added.
If administration via nasogastric tube is required, the same process as above should be followed but
using volumes of 15 mL for the initial dispersion and 15 mL for the residue rinses. The resulting
30 mL of liquid should be administered as per the naso-gastric tube manufacturer’s instructions with
appropriate water flushes. The dispersion and residues should be administered within 30 minutes of
the addition of the tablets to water.

Assessment of EGFR mutation status

When considering the use of TAGRISSO as adjuvant treatment after complete tumour resection in patients with NSCLC, it is important that the EGFR mutation positive status (exon 19 deletions (Ex19del) or exon 21 L858R substitution mutations (L858R)) indicates treatment eligibility. A validated test should be performed in a clinical laboratory using tumour tissue DNA from biopsy or surgical specimen.

When considering the use of TAGRISSO as a treatment for locally advanced or metastatic NSCLC, it is important that the EGFR mutation positive status is determined. A validated test should be performed using either tumour DNA derived from a tissue sample or circulating tumour DNA (ctDNA) obtained from a plasma sample.

Positive determination of EGFR mutation status (activating EGFR mutations for first-line treatment or T790M mutations following progression on or after EGFR TKI therapy) using either a tissue-based or plasma-based test indicates eligibility for treatment with TAGRISSO. However, if a plasma-based ctDNA test is used and the result is negative, it is advisable to follow-up with a tissue test wherever possible due to the potential for false negative results using a plasma-based test.

Only robust, reliable and sensitive tests with demonstrated utility for the determination of EGFR mutation status should be used.

Interstitial Lung Disease (ILD)

Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) were reported in 4.0% and were fatal in 0.4% (n=7) of the 1813 patients who received TAGRISSO monotherapy in ADAURA, FLAURA, FLAURA2 and AURA studies.[i]^,[ii],[iii] The incidence of ILD was 11.2% in patients of Japanese ethnicity, 2.3% in patients of non‑Japanese Asian ethnicity and 2.7% in non-Asian patients. The median time from first dose to onset of ILD or ILD-like adverse reactions was 2.8 months.[iv]^,[v]

ILD or ILD-like adverse reactions were reported in 3.3% and were fatal in 0.4% (n=1) of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in FLAURA2. The incidence of ILD was 14.9% in patients of Japanese ethnicity and 1.7% in non-Asian patients; no patients of non-Japanese Asian ethnicity had an event of ILD in the FLAURA2 combination arm. The median time from first dose to onset of ILD or ILD-like adverse reactions was 5.3 months.40

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. dyspnoea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed.

Stevens-Johnson syndrome (SJS)

Case reports of SJS have been reported rarely in association with TAGRISSO treatment. Before initiating treatment, patients should be advised of signs and symptoms of SJS. If signs and symptoms suggestive of SJS appear, TAGRISSO should be interrupted or discontinued immediately.

QTc interval prolongation

QTc interval prolongation occurs in patients treated with TAGRISSO. QTc interval prolongation may lead to an increased risk for ventricular tachyarrhythmias (e.g. torsade de pointes) or sudden death. No arrhythmic events were reported in ADAURA, FLAURA or AURA studies (see section 4.8). Patients with clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. QTc interval greater than 470 msec) were excluded from these studies (see section 4.8).

When possible, the use of osimertinib in patients with congenital long QT syndrome should be avoided. Periodic monitoring with electrocardiograms (ECGs) and electrolytes should be considered in patients with congestive heart failure, electrolyte abnormalities, or those who are taking medicinal products that are known to prolong the QTc interval. Treatment should be withheld in patients who develop a QTc interval greater than 500 msec on at least 2 separate ECGs until the QTc interval is less than 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec, then resume TAGRISSO at a reduced dose as described in Table 1. Osimertinib should be permanently discontinued in patients who develop QTc interval prolongation in combination with any of the following: Torsade de pointes, polymorphic ventricular tachycardia, signs/symptoms of serious arrhythmia.

Changes in cardiac contractility

Across clinical trials, Left Ventricular Ejection Fraction (LVEF) decreases greater than or equal to 10 percentage points and a drop to less than 50% occurred in 4.2% (65/1557) of patients treated with TAGRISSO monotherapy who had baseline and at least one follow-up LVEF assessment.[vi] In a placebo controlled trial (ADAURA), 1.5% (5/325) of patients treated with TAGRISSO and 1.5% (5/331) of patients treated with placebo experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%.[vii] In the FLAURA2 study, 8.0% (21/262) of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%.44

Based on the available clinical trial data, a causal relationship between effects on changes in cardiac contractility and TAGRISSO has not been established. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including an assessment of LVEF at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring including LVEF assessment should be considered.

Keratitis

Keratitis was reported in 0.6% (n=10) of the 1813 patients treated with TAGRISSO monotherapy in the ADAURA, FLAURA, FLAURA2 and AURA studies.37 Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist (see section 4.2).

Aplastic Anaemia

Rare cases of aplastic anaemia, including fatal events, have been reported in association with osimertinib treatment. Before initiating treatment, patients should be advised of signs and symptoms of aplastic anaemia including but not limited to persistent fever, bruising, bleeding, pallor, infection and fatigue. If signs and symptoms suggestive of aplastic anaemia develop, close patient monitoring and drug interruption or discontinuation of osimertinib should be considered. Osimertinib should be discontinued in patients with confirmed aplastic anaemia (see section 4.2).

Age and body weight

Elderly patients (>65 years) or patients with low body weight (<50 kg) may be at increased risk of developing adverse events of Grade 3 or higher. Close monitoring is recommended in these patients (see section 4.8).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Pharmacokinetic interactions

Strong CYP3A4 inducers can decrease the exposure of osimertinib. Osimertinib may increase the exposure of breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp) substrates.

Active substances that may increase osimertinib plasma concentrations

In vitro studies have demonstrated that the Phase I metabolism of osimertinib is predominantly via CYP3A4 and CYP3A5. In a clinical pharmacokinetic study in patients, co‑administration with 200 mg itraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on the exposure of osimertinib (area under the curve (AUC) increased by 24% and C_max decreased by 20%). Therefore, CYP3A4 inhibitors are not likely to affect the exposure of osimertinib. Further catalyzing enzymes have not been identified.

Active substances that may decrease osimertinib plasma concentrations

In a clinical pharmacokinetic study in patients, the steady-state AUC of osimertinib was reduced by 78% when co-administered with rifampicin (600 mg daily for 21 days). Similarly, the exposure to metabolite AZ5104 decreased by 82% for the AUC and 78% for C_max. It is recommended that concomitant use of strong CYP3A inducers (e.g. Phenytoin, rifampicin and carbamazepine) with TAGRISSO should be avoided. Moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil) may also decrease osimertinib exposure and should be used with caution, or avoided when possible. There are no clinical data available to recommend a dose adjustment of TAGRISSO. Concomitant use of St. John’s Wort is contraindicated (see section 4.3).

Effect of gastric acid reducing active substances on osimertinib

In a clinical pharmacokinetic study, co-administration of omeprazole did not result in clinically relevant changes in osimertinib exposures. Gastric pH modifying agents can be concomitantly used with TAGRISSO without any restrictions.

Active substances whose plasma concentrations may be altered by TAGRISSO

Based on in vitro studies, osimertinib is a competitive inhibitor of BCRP transporters.

In a clinical PK study, co-administration of TAGRISSO with rosuvastatin (sensitive BCRP substrate) increased the AUC and C_max of rosuvastatin by 35% and 72%, respectively. Patients taking concomitant medicinal products with disposition dependent upon BCRP and with narrow therapeutic index should be closely monitored for signs of changed tolerability of the concomitant medication as a result of increased exposure whilst receiving TAGRISSO (see section 5.2).

In a clinical PK study, co-administration of TAGRISSO with simvastatin (sensitive CYP3A4 substrate) decreased the AUC and C_max of simvastatin by 9% and 23% respectively. These changes are small and not likely to be of clinical significance. Clinical PK interactions with CYP3A4 substrates are unlikely. A risk for decreased exposure of hormonal contraceptives cannot be excluded.

In a clinical Pregnane X Receptor (PXR) interaction study, co-administration of TAGRISSO with fexofenadine (P-gp substrate) increased the AUC and C_max of fexofenadine by 56% (90% CI 35, 79) and 76% (90% CI 49, 108) after a single dose and 27% (90% CI 11, 46) and 25% (90% CI 6, 48) at steady-state, respectively. Patients taking concomitant medications with disposition dependent upon P-gp and with narrow therapeutic index (e.g. digoxin, dabigatran, aliskiren) should be closely monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst receiving TAGRISSO (see section 5.2).

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving TAGRISSO. Patients should be advised to use effective contraception for the following periods after completion of treatment with this medicinal product: at least 2 months for females and 4 months for males. A risk for decreased exposure of hormonal contraceptives cannot be excluded.

Pregnancy

There are no or limited amount of data from the use of osimertinib in pregnant women. Studies in animals have shown reproductive toxicity (embryolethality, reduced foetal growth, and neonatal death, see section 5.3). Based on its mechanism of action and preclinical data, osimertinib may cause foetal harm when administered to a pregnant woman. TAGRISSO should not be used during pregnancy unless the clinical condition of the woman requires treatment with osimertinib.

Breast-feeding

It is unknown whether osimertinib/metabolites are excreted in human milk. There is insufficient information on the excretion of osimertinib/metabolites in animal milk. However, osimertinib and its metabolites were detected in the suckling pups and there was poor pup growth and a reduction in pup survival (see section 5.3). A risk to the suckling child cannot be excluded. Breast‑feeding should be discontinued during treatment with TAGRISSO.

Fertility

There are no data on the effect of TAGRISSO on human fertility. Results from animal studies have shown that osimertinib has effects on male and female reproductive organs and could impair fertility (see section 5.3).

TAGRISSO has no or negligible influence on the ability to drive and use machines.

Overall summary of the safety profile

Studies in EGFR mutation-positive NSCLC patients

The safety of TAGRISSO as a monotherapy is based on pooled data from 1813 patients with EGFR mutation-positive NSCLC.[i] These patients received TAGRISSO at a dose of 80 mg daily in four randomised Phase 3 studies (ADAURA, adjuvant; FLAURA and FLAURA2 (monotherapy arm), first-line; AURA3, second-line only), two single-arm Phase 2 studies (AURAex; AURA2, second-line or greater) and one Phase 1 study (AURA1, first-line or greater) (see section 5.1).[ii]

Most adverse reactions were Grade 1 or 2 in severity. The most commonly reported adverse drug reactions (ADRs) were diarrhoea (47%), rash (46%), paronychia (34%), dry skin (32%), and stomatitis (24%). Grade 3 and Grade 4 adverse reactions with TAGRISSO were 9.2% and 0.2%, respectively.37 In patients treated with TAGRISSO 80 mg once daily, dose reductions due to adverse reactions occurred in 3.6% of the patients. Discontinuation due to adverse reactions was 4.7%.[iii]

The safety of TAGRISSO given in combination with pemetrexed and platinum-based chemotherapy is based on data in 276 patients with EGFR mutation-positive NSCLC and was consistent with TAGRISSO monotherapy and known safety profiles of pemetrexed and platinum-based chemotherapy.67

Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from clinical studies. Patients with clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. QTc interval greater than 470 msec) were excluded from these studies. Patients were evaluated for LVEF at screening and every 12 weeks thereafter.

Tabulated list of adverse reactions

Adverse reactions have been assigned to the frequency categories in Table 2 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the 1813 EGFR mutation positive NSCLC patients who received TAGRISSO Monotherapy at a dose of 80 mg daily in the ADAURA, FLAURA, FLAURA2, AURA3, AURAex, AURA 2 and AURA1 studies.

Adverse reactions are listed according to system organ class (SOC) in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the CIOMS III convention and is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).

Table 2. Adverse reactions reported in ADAURA, FLAURA, FLAURA2 (monotherapy arm) and AURA studies^a

^a     Data is pooled from ADAURA, FLAURA, FLAURA2 (monotherapy arm) and AURA (AURA3, AURAex, AURA2 and AURA1) studies; only events for patients receiving at least one dose of TAGRISSO as their randomised treatment are summarised.65

^b     National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

^c     Includes: corneal erosion, corneal epithelium defect, keratitis, punctate keratitis.

^d     Includes: interstitial lung disease, pneumonitis, organising pneumonia.

^e     Seven CTCAE Grade 5 events (fatal) were reported.40

^f     Includes: mouth ulceration, stomatitis.37

^g     Includes: acne, dermatitis, dermatitis acneiform, drug eruption, erythema, folliculitis, pustule, rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin erosion.

^h     Includes: nail bed disorder, nail bed infection, nail bed inflammation, nail discolouration, nail disorder, nail dystrophy, nail infection, nail pigmentation, nail ridging, nail toxicity, onychalgia[iv], onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.

ⁱ     Includes: dry skin, eczema, skin fissures, xeroderma, xerosis.

^j     Includes: eyelid pruritus, pruritus.

^k     Six of the 1813 patients in the ADAURA, FLAURA, FLAURA2 (monotherapy arm) and AURA studies reported erythema multiforme. Post-marketing reports of erythema multiforme have also been received, including 7 reports from a post-marketing surveillance study (N=3578).

^l     Estimated frequency. The upper limit of the 95% CI for the point estimate is 3/1813 (0.17%). No reports in clinical trials.

^m    One event reported in a post-marketing study, and the frequency has been derived from the ADAURA, FLAURA, FLAURA2 (monotherapy arm) and AURA studies and the post-marketing study (N=5391).

ⁿ      Represents the incidence of patients who had a QTcF prolongation >500 msec.

^o     Represents the incidence of laboratory findings, not of reported adverse events.

Table 3. Adverse reactions reported in ADAURA^a study[v]

In ADAURA, the median duration of study treatment was 22.5 months for patients in the TAGRISSO arm and 18.7 months for patients in the placebo arm.

^a     Only events for patients receiving at least one dose of their randomised treatment are summarised.

^b     National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

^c     All events were Grade 3. There were no deaths.

^d     Includes: keratitis, punctate keratitis, corneal erosion, corneal epithelium defect.

^e     Includes: interstitial lung disease, pneumonitis.

^f       Includes: stomatitis, mouth ulceration.

^g     Includes: acne, dermatitis, dermatitis acneiform, drug eruption, erythema, folliculitis, pustule, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin erosion.

^h     Includes: nail bed disorder, nail bed infection, nail bed inflammation, nail discolouration, nail disorder, nail dystrophy, nail infection, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.

ⁱ     Includes: dry skin, eczema, skin fissures, xeroderma, xerosis.

^j     Includes: eyelid pruritus, pruritus, pruritus generalised.

^k      Represents the incidence of patients who had a QTcF prolongation >500 msec.

^l     Represents the incidence of laboratory findings, not of reported adverse events.

Table 4. Adverse reactions reported in FLAURA^a study78^,[vi]^,[vii]

In FLAURA, the median duration of study treatment was 16.2 months for patients in the TAGRISSO arm and 11.5 months for patients in the EGFR TKI comparator arm.[x]

^a     Only events for patients receiving at least one dose of their randomised treatment are summarised.

^b     National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0

^c     Includes: corneal erosion, corneal epithelium defect, keratitis, punctuate keratitis.

^d     Includes: interstitial lung disease, pneumonitis.

^e     1 CTCAE Grade 5 event (fatal) was reported in the EGFR TKI comparator arm.80

^f     Includes: mouth ulceration, stomatitis.

^g     Includes: acne, dermatitis, dermatitis acneiform, drug eruption, erythema, folliculitis, pustule, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin erosion.

^h     Includes: dry skin, eczema, skin fissures, xeroderma, xerosis.

ⁱ     Includes: nail bed disorder, nail bed infection, nail bed inflammation, nail discolouration, nail disorder, nail dystrophy, nail infection, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.

^j     Includes: eyelid pruritus, pruritus, pruritus generalised.

^k      Represents the incidence of patients who had a QTcF prolongation >500 msec.

^l     Represents the incidence of laboratory findings, not of reported adverse events.

Table 5. Adverse reactions reported in FLAURA2^a study37

In FLAURA2, the median duration of study treatment was 22.3 months for patients in the TAGRISSO with pemetrexed and platinum-based chemotherapy arm and 19.3 months for patients in the TAGRISSO monotherapy arm.^[xi]

^a     Only events for patients receiving at least one dose of their randomised treatment are summarised.

^b     National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0

^c     Includes: corneal erosion, corneal epithelium defect, keratitis, punctuate keratitis.

^d    Includes: interstitial lung disease, pneumonitis, organising pnuemonia.

^e     One CTCAE Grade 5 event (fatal) was reported.

^f     Includes: mouth ulceration, stomatitis.

^g     Includes: acne, dermatitis, dermatitis acneiform, drug eruption, erythema, folliculitis, pustule, rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin erosion.

^h     Includes: nail bed disorder, nail bed infection, nail bed inflammation, nail discolouration, nail disorder, nail dystrophy, nail infection, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.

ⁱ     Includes: dry skin, eczema, skin fissures, xeroderma, xerosis.

^j     Includes: eyelid pruritus, pruritus.

^k      Represents the incidence of patients who had a QTcF prolongation >500 msec.

^l     Represents the incidence of laboratory findings, not of reported adverse events.

Table 6. Adverse reactions reported in AURA3^a study78^,[xii]

In AURA3, the median duration of study treatment was 8.1 months for patients in the TAGRISSO arm and 4.2 months for patients in the chemotherapy arm.[xxv]

^a     Only events for patients receiving at least one dose of their randomised treatment are summarised.

^b     National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

^c     Includes: corneal erosion, corneal epithelium defect, keratitis, punctuate keratitis.

^d     Includes: interstitial lung disease, pneumonitis.

^e     1 CTCAE Grade 5 event (fatal) was reported.

^f     Includes: mouth ulceration, stomatitis.

^g     Includes: acne, dermatitis, dermatitis acneiform, erythema, folliculitis, pustule, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pustular.

^h     Includes: dry skin, eczema, skin fissures, xerosis.

ⁱ     Includes: nail bed disorder, nail bed inflammation, nail bed tenderness, nail discolouration, nail disorder, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, paronychia.

^j     Includes: eyelid pruritus, pruritus, pruritus generalised.

^k      Represents the incidence of patients who had a QTcF prolongation >500 msec.

^l     Represents the incidence of laboratory findings, not of reported adverse events.

Safety findings in the single-arm Phase 2 AURAex and AURA2 studies were generally consistent with those observed in the AURA3 TAGRISSO arm. No additional or unexpected toxicity has been observed and adverse events have been aligned in type, severity and frequency.[xxvi]

Description of selected adverse reactions

Haematological events

Early reductions in the median laboratory counts of leukocytes, lymphocytes, neutrophils and platelets have been observed in patients treated with TAGRISSO, which stabilised over time and then remained above the lower limit of normal. Adverse events of leukopenia, lymphopenia, neutropenia and thrombocytopenia have been reported, most of which were mild or moderate in severity and did not lead to dose interruptions.76

Interstitial lung disease (ILD)

In the ADAURA, FLAURA and AURA studies, the incidence of ILD was 11% in patients of Japanese ethnicity, 1.6% in patients of non-Japanese Asian ethnicity and 2.5% in non-Asian patients. The median time to onset of ILD or ILD-like adverse reactions was 84 days (see section 4.4).

QTc prolongation

Of the 1813 patients in ADAURA, FLAURA, FLAURA2 and AURA studies treated with TAGRISSO monotherapy (80 mg), 1.1% of patients (n=20) were found to have a QTc greater than 500 msec,37 and 4.3% of patients (n=78) had an increase from baseline QTc greater than 60 msec.[xxvii] A pharmacokinetic analysis with TAGRISSO predicted a concentration-dependent increase in QTc interval prolongation.[xxviii] No QTc-related arrhythmia events were reported in the FLAURA, FLAURA2, AURA, or ADAURA studies (see section 4.4).[xxix]^,[xxx]

Gastrointestinal effects

In the ADAURA, FLAURA and AURA studies, diarrhoea was reported in 47% of patients of which 38% were Grade 1 events, 7.9% Grade 2 and 1.4% were Grade 3; no Grade 4 or 5 events were reported. Dose reduction was required in 0.3% of patients and dose interruption in 2%. Four events (0.3%) led to discontinuation. In ADAURA, FLAURA and AURA3 the median time to onset was 22 days, 19 days and 22 days, respectively, and the median duration of the Grade 2 events was 11 days, 19 days and 6 days, respectively.

Haematological events

Early reductions in the median laboratory counts of leukocytes, lymphocytes, neutrophils and platelets have been observed in patients treated with TAGRISSO, which stabilised over time and then remained above the lower limit of normal. Adverse events of leukopenia, lymphopenia, neutropenia and thrombocytopenia have been reported, most of which were mild or moderate in severity and did not lead to dose interruptions. Rare cases of aplastic anaemia, including fatal events, have been reported in association with osimertinib treatment. Osimertinib should be discontinued in patients with confirmed aplastic anaemia (see section 4.2 and 4.4).

Elderly

In ADAURA, FLAURA, FLAURA2 and AURA (TAGRISSO monotherapy; N=1813), 42% of patients were 65 years of age and older, and 11% were 75 years of age and older.[xxxi] Compared with younger patients (<65), more patients ≥65 years old had reported adverse reactions that led to study drug dose modifications (interruptions or reductions) (14% versus 10%).[xxxii] The types of adverse reactions reported were similar regardless of age.[xxxiii] Older patients reported more Grade 3 or higher adverse reactions compared to younger patients (11% versus 9%).[xxxiv] No overall differences in efficacy were observed between older and younger patients.[xxxv]

To report any side effect(s):

• Saudi Arabia:

·   Other GCC States:

-    Please contact the relevant competent authority.

In TAGRISSO clinical trials a limited number of patients were treated with daily doses of up to

240 mg without dose limiting toxicities. In these studies, patients who were treated with TAGRISSO daily doses of 160 mg and 240 mg experienced an increase in the frequency and severity of a number of typical EGFR-induced AEs (primarily diarrhoea and skin rash) compared to the 80 mg dose. There is limited experience with accidental overdoses in humans. All cases were isolated incidents of

patients taking an additional daily dose of TAGRISSO in error, without any resulting clinical consequences.

There is no specific treatment in the event of TAGRISSO overdose. In case of suspected overdose, TAGRISSO should be withheld and symptomatic treatment initiated.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors; ATC code: L01EB04
. Mechanism of action
Osimertinib is a Tyrosine Kinase Inhibitor (TKI). It is an irreversible inhibitor of Epidermal Growth
Factor Receptors (EGFRs) harboring sensitising-mutations (EGFRm) and TKI-resistance mutation
T790M.
Pharmacodynamic effects
In vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against
EGFR across a range of all clinically relevant EGFR sensitising-mutant and T790M mutant non-small
cell lung cancer (NSCLC) cell lines (apparent IC50s from 6 nM to 54 nM against phospho-EGFR).
This leads to inhibition of cell growth, while showing significantly less activity against EGFR in
wild-type cell lines (apparent IC50s from 480 nM to 1.8 μM against phospho-EGFR). In vivo oral
administration of osimertinib lead to tumour shrinkage in both EGFRm and T790M NSCLC xenograft
and transgenic mouse lung tumour models.
Cardiac electrophysiology
The QTc interval prolongation potential of TAGRISSO was assessed in 210 patients who received
osimertinib 80 mg daily in AURA2. Serial ECGs were collected following a single dose and at
steady-state to evaluate the effect of osimertinib on QTc intervals. A
pharmacokinetic/pharmacodynamic analysis predicted a drug-related QTc interval prolongation at
80 mg of 14 msec with an upper bound of 16 msec (90% CI).
Adjuvant treatment of EGFR mutation positive NSCLC, with or without prior adjuvant chemotherapy
– ADAURA
The efficacy and safety of TAGRISSO for the adjuvant treatment of patients with EGFR mutationpositive
(Ex19del or L858R) NSCLC who have had complete tumour resection with or without prior
adjuvant chemotherapy was demonstrated in a randomised, double-blind, placebo-controlled study
(ADAURA).
Eligible Patients with resectable tumours stage IB – IIIA (according to American Joint
Commission on Cancer [AJCC] 7th edition) were required to have EGFR mutations (Ex19del or
L858R), identified by the cobas EGFR Mutation Test performed prospectively using biopsy or
surgical specimen in a central laboratory.
Patients were randomised 1:1 to receive TAGRISSO (n=339, 80 mg orally once daily) or placebo
(n=343) following recovery from surgery and standard adjuvant chemotherapy where given. Patients
not receiving adjuvant chemotherapy were randomised within 10 weeks and patients receiving
adjuvant chemotherapy within 26 weeks following surgery. Randomisation was stratified by EGFR
mutation type (Ex19del or L858R), ethnicity (Asian or non-Asian) and staging based on percutaneous
transthoracic needle biopsy (pTNM) (IB or II or IIIA) according to AJCC 7th edition. Treatment was
15
given until disease recurrence, unacceptable toxicity, or for 3 years.
The major efficacy outcome measure was disease-free survival (DFS) by investigator assessment in
the stage II-IIIA population. DFS by investigator assessment in the stage IB-IIIA population (overall
population) was an additional efficacy outcome measure. Otheradditional efficacy outcome
measures included DFS rate, overall survival (OS), OS rate, and time to deterioration in healthrelated
quality of life (HRQoL) SF-36.
The baseline demographic and disease characteristics of the overall study population were: median
age 63 years (range 30-86 years), ≥75 years old (11%), female (70%), Asian (64%), never smokers
(72%), World Health Organization (WHO) performance status of 0 (64%) or 1 (36%), stage IB
(31%), stage II (34%), and IIIA (35%). With regards to EGFR mutation status 55% were exon 19
deletions and 45% were exon 21 L858R substitution mutations; 9 patients (1%) also had a concurrent
de novo T790M mutation. The majority (60%) of patients received adjuvant chemotherapy prior to
randomization (26% IB; 71% IIA; 73% IIB; 80% IIIA).
There were 37 patients who had disease recurrence on TAGRISSO. The most commonly reported
sites of recurrence were: lung (19 patients); lymph nodes (10 patients) and CNS (5 patients). There
were 157 patients who had disease recurrence on placebo. The most commonly reported sites were:
lung (61 patients); lymph nodes (48 patients) and CNS (34 patients).
ADAURA demonstrated a statistically significant reduction in the risk of disease recurrence or death for
patients treated with TAGRISSO compared to patients treated with placebo in the stage II-IIIA population.
Similar results were observed in the stage IB-IIIA population. Overall survival (OS) data were not mature at
the time of DFS analysis. Efficacy results from ADAURA by investigator assessment are summarised in
Table 3.
Table 3. Efficacy results from ADAURA by investigator assessment
Stage II-IIIA population Stage IB-IIIA population
Efficacy Parameter TAGRISSO
(N=233)
Placebo
(N=237)
TAGRISSO
(N=339)
Placebo
(N=343)
Disease-Free Survival
Number of events (%) 26 (11) 130 (55) 37 (11) 159 (46)
Recurrent disease (%) 26 (11) 129 (54) 37 (11) 157 (46)
Deaths (%) 0 1 (0.4) 0 2 (0.6)
Median, months (95%
CI)
NC (38.8, NC) 19.6 (16.6, 24.5) NC (NC, NC) 27.5 (22.0, 35.0)
HR (99.06% CI); P-value 0.17 (0.11, 0.26); <0.0001a 0.20 (0.14, 0.30); <0.0001b
DFS rate at 12 months
(%) (95% CI)
97 (94, 99) 61 (54, 67) 97 (95, 99) 69 (63, 73)
DFS rate at 24 months
(%) (95% CI)
90 (84, 93) 44 (37, 51) 52 (46, 58)
16
DFS rate at 36 months
(%) (95% CI)c, d
78 (65, 87) 28 (19, 38) 79 (69, 86) 40 (32, 48)
HR=Hazard Ratio; CI=Confidence Interval; NC=Not Calculable
DFS results based on RECIST investigator assessment
A HR< 1 favours TAGRISSO
Median follow-up time for DFS was 22.1 months for patients receiving TAGRISSO, 14.9 months for patients receiving placebo (stage
II-IIIA population) and 16.6 months for patients receiving placebo (stage IB-IIIA population).
a Adjusted for an interim analysis (33% maturity) a p-value < 0.0094 was required to achieve statistical significance.
b Adjusted for an interim analysis (29% maturity) a p-value <0.0088 was required to achieve statistical significance.
c The number of patients at risk at 36 months was 18 patients in the osimertinib arm and 9 patients in the placebo arm (stage II-IIIA
population).
d The number of patients at risk at 36 months was 27 patients in the osimertinib arm and 20 patients in the placebo arm (stage IB-IIIA
population).
Figure 1. Kaplan-Meier curve of Disease-Free Survival (Stage II-IIIA Patients) by Investigator
Assessment
17
Figure 2. Kaplan-Meier curve of Disease-Free Survival in stage IB-IIIA (overall
population) by Investigator Assessment
The DFS benefit of TAGRISSO compared to placebo was consistent across all predefined subgroups
analysed, including ethnicity, age, gender, and EGFR mutation type (Ex19Del or L858R).
An exploratory analysis of CNS DFS (time to CNS recurrence or death) for patients on TAGRISSO
compared to patients on placebo a HR of 0.18 (95% CI: 0.10, 0.33; p <0.0001) for the overall
population (stage IB-IIIA),
18
Patient Reported Outcomes
Health-related quality of life (HRQL) in ADAURA was assessed using the Short Form (36) Health
Survey version 2 (SF-36v2) questionnaire. SF-36v2 was administered at 12 weeks, 24 weeks and then
every 24 weeks relative to randomisation until treatment completion or discontinuation. Overall,
HRQoL was maintained in both arms, with more than 75% of patients in the stage II-IIIA population
not experiencing a clinically meaningful deterioration in the physical component of the SF-36 or
death (75.1% vs 83.5% for TAGRISSO vs placebo), or in the mental component of the SF-36 ordeath
(77.7% vs 78.1% for TAGRISSO vs placebo). A trend of shorter time to deterioration (TTD) for the
physical component of SF-36 or death was observed in the TAGRISSO arm (HR=1.43, 95% CI: 0.96,
2.13), with a median TTD that was not reached in either arm. There was no difference between the
arms in the TTD for the mental component of SF-36 or death (HR=0.90, 95% CI: 0.61, 1.33), with a
median TTD of 39.0 months (95% CI: NC, NC) in the TAGRISSO arm and not reached in the
placebo arm.
Previously untreated EGFR mutation positive locally advanced or metastatic NSCLC – FLAURA
The efficacy and safety of TAGRISSO for the treatment of patients with EGFR mutation positive
locally advanced, not amenable to curative surgery or radiotherapy, or metastatic NSCLC, who had
not received previous systemic treatment for advanced disease, was demonstrated in a randomised,
double-blind, active-controlled study (FLAURA). Patient tumour tissue samples were required to
have one of the two common EGFR mutations known to be associated with EGFR TKI sensitivity
(Ex19del or L858R), as identified by local or central testing.
Patients were randomised 1:1 to receive either TAGRISSO (n=279, 80 mg orally once daily) or EGFR
TKI comparator (n=277; gefitinib 250 mg orally once daily or erlotinib 150 mg orally once daily).
Randomisation was stratified by EGFR mutation type (Ex19del or L858R) and ethnicity (Asian or
non-Asian). Patients received study therapy until intolerance to therapy, or the investigator
determined that the patient was no longer experiencing clinical benefit. For patients receiving EGFR
TKI comparator, post-progression crossover to open-label TAGRISSO was permitted provided
tumour samples tested positive for the T790M mutation. The primary efficacy end-point was
progression-free survival (PFS) as assessed by investigator.
The baseline demographic and disease characteristics of the overall study population were: median
age 64 years (range 26-93 years), ≥75 years old (14%), female (63%), White (36%), Asian (62%),
never smokers (64%), World Health Organization (WHO) performance status of 0 or 1 (100%),
metastatic bone disease (36%), extra-thoracic visceral metastases (35%), CNS metastases (21%,
identified by CNS lesion site at baseline, medical history, and/or prior surgery, and/or prior
radiotherapy to CNS metastases).
TAGRISSO demonstrated a clinically meaningful and statistically significant improvement in PFS
compared to EGFR TKI comparator (median 18.9 months and 10.2 months, respectively, HR=0.46,
95% CI: 0.37, 0.57; P<0.0001). Efficacy results from FLAURA by investigator assessment are
summarised in Table 5, and the Kaplan-Meier curve for PFS is shown in Figure 3. The final analysis
of overall survival (OS, 58% maturity) demonstrated a statistically significant improvement with an
HR of 0.799 (95.05% CI: 0.641, 0.997) and a clinically meaningful longer median survival time in
patients randomized to TAGRISSO compared to EGFR TKI comparator (Table 5 and Figure 4). A
greater proportion of patients treated with TAGRISSO were alive at 12, 18, 24 and 36 months (89%,
81%, 74% and 54% respectively) compared to patients treated with EGFR TKI comparator (83%,
71%, 59% and 44% respectively). Analysis of post-progression end–points demonstrated that the PFS
benefit was preserved through subsequent lines of therapy.
19
Table 5. Efficacy results from FLAURA by Investigator Assessment
Efficacy Parameter
TAGRISSO
(N=279)
EGFR TKI comparator
(gefitinib or erlotinib)
(N=277)
Progression-Free Survival
Number of Events (62% maturity)
136 (49)
206 (74)
Median, Months (95% CI)
18.9 (15.2, 21.4)
10.2 (9.6, 11.1)
HR (95% CI) ; P-value
0.46 (0.37, 0.57); P<0.0001
Overall Survival
Number of deaths, (58% maturity)
155 (56)
166 (60)
Median OS in months (95% CI)
38.6 (34.5, 41.8)
31.8 (26.6, 36.0)
HR (95.05% CI); P-value 0.799 (0.641, 0.997); P=0.0462†
Objective Response Rate*1
Number of responses (n), Response Rate
(95% CI)
223
80% (75, 85)
210
76% (70, 81)
Odds ratio (95% CI); P-value
1.3 (0.9, 1.9); P=0.2421
Duration of Response (DoR)*
Median, Months (95% CI)
17.2 (13.8, 22.0)
8.5 (7.3, 9.8)
Second PFS after start of first subsequent therapy (PFS2)
Number of patients with second progression
(%)
73 (26)
106 (38)
Median PFS2, months (95% CI)
NC (23.7, NC)
20.0 (18.0, NC)
HR (95% CI); P-value
0.58 (0.44, 0.78); P=0.0004
20
Time from randomisation to first subsequent treatment or death (TFST)
Number of patients who had first
subsequent treatment or died (%)
115 (41)
175 (63)
Median TFST, months (95% CI)
23.5 (22.0, NC)
13.8 (12.3, 15.7)
HR (95% CI); P-value
0.51 (0.40, 0.64); P<0.0001
Time from randomisation to second subsequent treatment or death (TSST)
Number of patients who had second
subsequent treatment or died (%)
75 (27)
110 (40)
Median TSST, months (95% CI)
NC (NC, NC)
25.9 (20.0, NC)
HR (95% CI); P-value
0.60 (0.45, 0.80); P=0.0005
HR=Hazard Ratio; CI=Confidence Interval, NC=Not Calculable
PFS, ORR, DoR and PFS2 results based on RECIST investigator assessment
Based on unconfirmed response
Median follow-up time was 15.0 months for patients receiving TAGRISSO and 9.7 months for patients receiving EGFR TKI
comparator
Median survival follow-up time was 35.8 months for patients receiving TAGRISSO and 27.0 months for patients receiving
EGFR TKI comparator.
PFS, ORR, DoR, PFS2, TFST and TSST results are from data cut-off 12 June 2017. OS results are from data cut-off 25 June
2019.
A HR <1 favours TAGRISSO, an Odds ratio of >1 favours TAGRISSO
† Adjusted for an interim analysis (25% maturity) a p-value <0.0495 was required to achieve statistical significance
1 ORR results by Blinded Independent Central Review (BICR) were consistent with those reported via investigator
assessment; ORR by BICR assessment was 78% (95% CI:73, 83) on TAGRISSO and 70% (95% CI:65, 76) on EGFR TKI
comparator.
21
Figure 3. Kaplan-Meier Curves of Progression-Free Survival as assessed by investigator in
FLAURA
22
Figure 4. Kaplan-Meier Curves of Overall Survival in FLAURA
+ Censored patients.
The values at the base of the figure indicate number of subjects at risk.
The PFS benefit of TAGRISSO compared to EGFR TKI comparator was consistent across all
predefined subgroups analysed, including ethnicity, age, gender, smoking history, CNS metastases
status at study entry and EGFR mutation type (Exon 19 deletion or L858R).
CNS metastases efficacy data in FLAURA study
Patients with CNS metastases not requiring steroids and with stable neurologic status for at least two
weeks after completion of the definitive therapy and steroids were eligible to be randomised in the
FLAURA study. Of 556 patients, 200 patients had available baseline brain scans. A BICR assessment
of these scans resulted in a subgroup of 128/556 (23%) patients with CNS metastases and these data
are summarised in Table 6. CNS efficacy by RECIST v1.1 in FLAURA demonstrated a statistically
significant improvement in CNS PFS (HR=0.48, 95% CI 0.26, 0.86; P=0.014).
Table 6. CNS efficacy by BICR in patients with CNS metastases on a baseline brain scan in
FLAURA
Efficacy Parameter TAGRISSO
N=61
EGFR TKI comparator
(gefitinib or erlotinib)
N=67
CNS Progression-free survival1
Number of Events (%) 18 (30) 30 (45)
Median, Months (95% CI) NC (16.5, NC) 13.9 (8.3, NC)
HR (95% CI); P-value 0.48 (0.26, 0.86); P=0.014
TAGRISSO (N=279)
Median 38.6 months
SoC (N=277)
Median 31.8 months
Hazard Ratio = 0.799
95.05% CI (0.641, 0.997)
P-value 0.0462
TAGRISSO
SoC
Number at risk Time from randomisation (months)
Probability of Overall Survival
23
Patient Reported Outcomes (PRO)
Patient-reported symptoms and health-related quality of life (HRQL) were electronically collected
using the EORTC QLQ-C30 and its lung cancer module (EORTC QLQ-LC13). The LC13 was
initially administered once a week for the first 6 weeks, then every 3 weeks before and after
progression. The C30 was assessed every 6 weeks before and after progression. At baseline, no
differences in patient reported symptoms, function or HRQL were observed between TAGRISSO and
EGFR TKI comparator (gefitinib or erlotinib) arms. Compliance over the first 9 months was generally
high (≥70%) and similar in both arms.
CNS progression free and alive at 6
months (%) (95% CI)
87 (74, 94) 71 (57, 81)
CNS progression free and alive at 12
months (%) (95% CI)
77 (62, 86) 56 (42, 68)
HR=Hazard Ratio; CI=Confidence Interval, NC=Not Calculable
A HR <1 favours TAGRISSO, an Odds ratio of >1 favours TAGRISSO
1 CNS PFS determined by RECIST v1.1by CNS BICR (CNS measurable and non-measurable lesions at baseline by
BICR) n=61 for TAGRISSO and n=67 for EGFR TKI comparator; responses areunconfirmed
A pre-specified PFS subgroup based on CNS metastases status (identified by CNS lesion site at
baseline, medical history, and/or prior surgery, and/or prior radiotherapy to CNS metastases) at study
entry was performed in FLAURA and is shown in Figure 5. Irrespective of CNS lesion status at study
entry, patients in the TAGRISSO arm demonstrated an efficacy benefit over those in the EGFR TKI
comparator arm and there were fewer patients with new CNS lesions in the TAGRISSO arm
compared to the EGFR TKI comparator arm (TAGRISSO, 11/279 [3.9%] compared to EGFR TKI
comparator, 34/277 [12.3%]). In the subset of patients without CNS lesions at baseline, there were a
lower number of new CNS lesions in the TAGRISSO arm compared to the EGFR TKI comparator
arm (7/226 [3.1%] vs. 15/214 [7.0%], respectively).
Figure 5. Overall PFS by Investigator Assessment by CNS metastases status at study entry,
Kaplan-Meier plot (full analysis set) in FLAURA
24
Key lung cancer symptoms analysis
Data collected from baseline up to month 9 showed similar improvements in TAGRISSO and EGFR
TKI comparator groups for the five pre-specified primary PRO symptoms (cough, dyspnoea, chest
pain, fatigue, and appetite loss) with improvement in cough reaching the established clinically
relevant cutoff. Up to month 9 there were no clinically meaningful differences in patient-reported
symptoms between TAGRISSO and EGFR TKI comparator groups (as assessed by a difference of
≥10 points).
HRQL and physical functioning improvement analysis
Both groups reported similar improvements in most functioning domains and global health
status/HRQL, indicating that patients’ overall health status improved. Up to month 9, there were no
clinically meaningful differences between the TAGRISSO and EGFR TKI comparator groups in
functioning or HRQL.
Pre-treated T790M positive NSCLC patients-AURA3
The efficacy and safety of TAGRISSO for the treatment of patients with locally advanced or
metastatic T790M NSCLC whose disease has progressed on or after EGFR TKI therapy, was
demonstrated in a randomised, open-label, active-controlled Phase 3 study (AURA3). All patients
were required to have EGFR T790M mutation-positive NSCLC identified by the cobas EGFR
mutation test performed in a central laboratory prior to randomisation. The T790M mutation status
was also assessed using ctDNA extracted from a plasma sample taken during screening. The primary
efficacy outcome was progression-free survival (PFS) as assessed by investigator. Additional efficacy
outcome measures included ORR, DoR and overall survival (OS) as assessed by investigator.
Patients were randomised in a 2:1 (TAGRISSO: platinum-based doublet chemotherapy) ratio to
receive TAGRISSO (n=279) or platinum-based doublet chemotherapy (n=140). Randomisation was
stratified by ethnicity (Asian and non-Asian). Patients in the TAGRISSO arm received TAGRISSO
80 mg orally once daily until intolerance to therapy, or the investigator determined that the patient
was no longer experiencing clinical benefit. Chemotherapy consisted of pemetrexed 500 mg/m2 with
carboplatin AUC5 or pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 on Day 1 of every 21-day cycle
for up to 6 cycles. Patients whose disease has not progressed after four cycles of platinum-based
chemotherapy may receive pemetrexed maintenance therapy (pemetrexed 500 mg/m2 on Day 1 of
every 21-day cycle). Subjects on the chemotherapy arm who had objective radiological progression
(by the investigator and confirmed by independent central imaging review) were given the
opportunity to begin treatment with TAGRISSO.
The baseline demographic and disease characteristics of the overall study population were: median
age 62, ≥75 years old (15%), female (64%), white (32%), Asian (65%), never smoker (68%), WHO
performance status 0 or 1 (100%). Fifty-four percent (54%) of patients had extra-thoracic visceral
metastases, including 34% with CNS metastases (identified by CNS lesion site at baseline, medical
history, and/or prior surgery, and/or prior radiotherapy to CNS metastases) and 23% with liver
metastases. Forty-two percent (42%) of patients had metastatic bone disease.
AURA3 demonstrated a statistically significant improvement in PFS in the patients treated with
TAGRISSO compared to chemotherapy. Efficacy results from AURA3 by investigator assessment are
summarised in Table 7, and the Kaplan-Meier curve for PFS is shown in Figure 6. No statistically
significant difference was observed between the treatment arms at the final OS analysis.
25
Table 7. Efficacy results from AURA3 by Investigator Assessment
Efficacy Parameter TAGRISSO
(N=279)
Chemotherapy
(Pemetrexed/Cisplatin or
Pemetrexed/Carboplatin)
(N=140)
Progression-Free Survival
Number of Events (% maturity) 140 (50) 110 (79)
Median, Months (95% CI) 10.1 (8.3,
12.3)
4.4 (4.2, 5.6)
HR (95% CI); P-value 0.30 (0.23,0.41); P<0.001
Overall Survival (OS)1
Number of Deaths (% maturity) 188 (67.4) 93 (66.4)
Median OS, Months (95% CI) 26.8 (23.5,
31.5)
22.5 (20.2, 28.8)
HR (95.56% CI); P-value 0.87 (0.67, 1.13); P=0.277
Objective Response Rate2
Number of responses, Response Rate (95% CI)
197
71% (65, 76)
44
31% (24, 40)
Odds ratio (95% CI); P-value 5.4 (3.5, 8.5); P<0.001
Duration of Response (DoR)2
Median, Months (95% CI) 9.7 (8.3, 11.6) 4.1 (3.0, 5.6)
HR=Hazard Ratio; CI=confidence interval; NC=non-calculable; OS=Overall Survival
All efficacy results based on RECIST investigator assessment
1The final analysis of OS was performed at 67% maturity. The CI for the HR has been adjusted for previous interim
analyses. The OS analysis was not adjusted for the potentially confounding effects of crossover (99 [71%] patients on the
chemotherapy arm received subsequent osimertinib treatment).
2 ORR and DoR results by investigator assessment were consistent with those reported via Blinded Independent Central
Review (BICR); ORR by BICR assessment was 64.9% [95% CI: 59.0, 70.5] on osimertinib and 34.3 % [95% CI: 26.5, 42.8]
on chemotherapy; DoR by BICR assessment was 11.2 months (95% CI: 8.3, NC) on osimertinib and 3.1 months
(95% CI: 2.9, 4.3) on chemotherapy.
26
Figure 6. Kaplan-Meier curves of Progression-Free Survival as assessed by investigator in
AURA3
A sensitivity analysis of PFS was conducted by a Blinded Independent Central Review (BICR) and
showed a median PFS of 11.0 months with TAGRISSO compared with 4.2 months with
chemotherapy. This analysis demonstrated a consistent treatment effect (HR 0.28; 95% CI: 0.20, 0.38)
with that observed by investigator assessment.
Clinically meaningful improvements in PFS with HRs less than 0.50 in favour of patients receiving
TAGRISSO compared to those receiving chemotherapy were consistently observed in all predefined
subgroups analysed, including ethnicity, age, gender, smoking history and EGFR mutation (Exon 19
deletion and L858R).
CNS metastases efficacy data in AURA3 study
Patients with asymptomatic, stable brain metastases not requiring steroids for at least 4 weeks prior to
the start of study treatment were eligible to be randomised in the study. A BICR assessment of CNS
efficacy by RECIST v1.1 in the subgroup of 116/419 (28%) patients identified to have CNS
metastases on a baseline brain scan are summarised in Table 8.
27
Table 8. CNS efficacy by BICR in patients with CNS metastases on a baseline brain scan in
AURA3
Efficacy Parameter TAGRISSO Chemotherapy
(Pemetrexed/Cisplatin or
Pemetrexed/Carboplatin)
CNS Objective Response Rate1
CNS response rate % (n/N)
(95% CI)
70% (21/30)
(51, 85)
31% (5/16)
(11%, 59%)
Odds ratio (95% CI); P-value 5.1 (1.4, 21); P=0.015
CNS Duration of Response2
Median, Months (95% CI) 8.9 (4.3, NC) 5.7 (NC, NC)
CNS Disease control rate
CNS disease control rate
87% (65/75)
(77, 93)
68% (28/41)
(52, 82)
Odds ratio (95% CI); P-value 3 (1.2, 7.9); P=0.021
CNS Progression-free survival3 N=75 N=41
Number of Events (% maturity) 19 (25) 16 (39)
Median, Months (95% CI) 11.7 (10, NC) 5.6 (4.2, 9.7)
HR (95% CI); P-value 0.32 (0.15, 0.69); P=0.004
1 CNS Objective Response Rate and Duration of Response determined by RECIST v1.1 by CNS BICR in the
evaluable for response population (CNS measurable lesions at baseline by BICR) n=30 for TAGRISSO and
n=16 for Chemotherapy
2 Based on patients with response only; DoR defined as the time from the date of first documented response
(complete response or partial response) until progression or death event; DCR defined as the proportion of
patients with response (complete response or partial response), or stable disease ≥6 weeks
3 CNS Progression Free Survival determined by RECIST v1.1 by CNS BICR in the full analysis set
population (CNS measurable and non-measurable lesions at baseline by BICR) n=75 for TAGRISSO and
n=41 for Chemotherapy
A HR <1 favours TAGRISSO
A pre-specified PFS subgroup analysis based on CNS metastases status at study entry was performed
in AURA3 and is shown in Figure 7.
28
Figure 7. Overall PFS by Investigator Assessment by CNS metastases status at study entry,
Kaplan-Meier plot (full analysis set) in AURA3
AURA3 demonstrated a statistically significant improvement in PFS for patients receiving
TAGRISSO compared to those receiving chemotherapy irrespective of CNS metastases status at study
entry.
Patient Reported Outcomes
Patient-reported symptoms and health-related quality of life (HRQL) were electronically collected
using the EORTC QLQ-C30 and its lung cancer module (EORTC QLQ-LC13). The LC13 was
initially administered once a week for the first 6 weeks, then every 3 weeks before and after
progression. The C30 was assessed every 6 weeks before and after progression.
Key lung cancer symptoms analysis
TAGRISSO improved patient-reported lung cancer symptoms compared to chemotherapy by
demonstrating a statistically significant difference in mean change from baseline versus chemotherapy
during the overall time period from randomisation until 6 months for 5 pre-specified primary PRO
symptoms (appetite loss, cough, chest pain, dyspnoea, and fatigue) as shown in Table 9.
Table 9. Mixed Model Repeated Measures – Key lung cancer symptoms - mean change from
baseline in TAGRISSO patients compared with chemotherapy
Appetite Loss Cough Chest Pain Dyspnoea Fatigue
Arms TAGRISS
O
(279)
Chemo
-
therapy
(140)
TAGRISS
O
(279)
Chemo
-
therapy
(140)
TAGRISS
O
(279)
Chemo
-
therapy
(140)
TAGRISS
O
(279)
Chemo
-
therapy
(140)
TAGRISS
O
(279)
Chemo
-
therapy
(140)
N 239 97 228 113 228 113 228 113 239 97
Adj Mean -5.51 2.73 -12.22 -6.69 -5.15 0.22 -5.61 1.48 -5.68 4.71
Estimated -8.24 -5.53 -5.36 -7.09 -10.39
Differenc (-12.88, 3.60) (-8.89, -2.17) (-8.20, -2.53) (-9.86, -4.33) (-14.55, -6.23)
e
(95%CI)
p-value p <0.001 p=0.001 p<0.001 p<0.001 p<0.001
29
Adjusted mean and estimated differences obtained from a Mixed Model Repeated Measures (MMRM) analysis. The model included patient,
treatment, visit, treatment-by-visit interaction, baseline symptom score, and baseline symptom score-by-visit interaction and used an
unstructured covariance matrix.
HRQL and physical functioning improvement analysis
Patients on TAGRISSO had significantly greater chances of achieving a clinically meaningful
improvement of greater than or equal to 10 points on the global health status and physical functioning
of the EORTC-C30 questionnaire compared with chemotherapy during the study period Odds Ratio
(OR) global health status: 2.11, (95% CI 1.24, 3.67, p=0.007); OR physical functioning 2.79 (95%
CI 1.50, 5.46, p=0.002).
Pre-treated T790M positive NSCLC patients - AURAex and AURA2
Two single-arm, open-label clinical studies, AURAex (Phase 2 Extension cohort, (n=201)) and
AURA2 (n=210) were conducted in patients with EGFR T790M mutation-positive lung cancer who
have progressed on one or more prior systemic therapies, including an EGFR TKI. All patients were
required to have EGFR T790M mutation-positive NSCLC identified by the cobas EGFR mutation test
performed in a central laboratory prior to treatment. The T790M mutation status was also assessed
retrospectively using ctDNA extracted from a plasma sample taken during screening. All patients
received TAGRISSO at a dose of 80 mg once daily. The primary efficacy outcome measure of these
two trials was ORR according to RECIST v1.1 as evaluated by a Blinded Independent Central Review
(BICR). Secondary efficacy outcome measures included Duration of Response (DoR) and
Progression-Free Survival (PFS).
Baseline characteristics of the overall study population (AURAex and AURA2) were as follows:
median age 63 years, 13% of patients were ≥75 years old, female (68%), White (36%), Asian (60%).
All patients received at least one prior line of therapy. Thirty-one percent (31%) (N=129) had
received 1 prior line of therapy (EGFR-TKI treatment only), 69% (N=282) had received 2 or more
prior lines. Seventy-two percent (72%) of patients were never smokers, 100% of patients had a World
Health Organization (WHO) performance status of 0 or 1. Fifty-nine percent (59%) of patients had
extra-thoracic visceral metastasis including 39% with CNS metastases (identified by CNS lesion site
at baseline, medical history, and/or prior surgery and/or prior radiotherapy to CNS metastases) and
29% with liver metastases. Forty-seven percent (47%) of patients had metastatic bone disease. The
median duration of follow up for PFS was 12.6 months.
In the 411 pre-treated EGFR T790M mutation-positive patients, the total ORR by Blinded
Independent Central Review (BICR) was 66% (95% CI: 61, 71). In patients with a confirmed
response by BICR, the median DoR was 12.5 months (95% CI: 11.1, NE). The ORR by BICR in
AURAex was 62% (95% CI: 55, 68) and 70% (95% CI: 63, 77) in AURA2. The median PFS was
11.0 months 95% CI (9.6, 12.4).
Objective response rates by BICR above 50% were observed in all predefined subgroups analysed,
including line of therapy, ethnicity, age and region.
In the evaluable for response population, 85% (223/262) had documentation of response at the time of
the first scan (6 weeks); 94% (247/262) had documentation of response at the time of the second scan
(12 weeks).
CNS metastases efficacy data in Phase 2 studies (AURAex and AURA2)
A BICR assessment of CNS efficacy by RECIST v 1.1 was performed in a subgroup of 50 (out of
411) patients identified to have measurable CNS metastases on a baseline brain scan. A CNS ORR of
54% (27/50 patients; 95% CI: 39.3, 68.2) was observed with 12% of these responses being complete
responses.
Clinical studies have not been conducted in patients with de novo EGFR T790M mutation-positive
NSCLC.
30
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
TAGRISSO in all subsets of the paediatric population in NSCLC (see section 4.2 for information on
paediatric use).

Osimertinib pharmacokinetic parameters have been characterised in healthy subjects and NSCLC
patients. Based on population pharmacokinetic analysis, osimertinib apparent plasma clearance is
14.3 L/h, apparent volume of distribution is 918 L and terminal half-life of approximately 44 hours.
The AUC and Cmax increased dose proportionally over 20 to 240 mg dose range. Administration of
osimertinib once daily results in approximately 3 fold accumulation with steady-state exposures
achieved by 15 days of dosing. At steady-state, circulating plasma concentrations are typically
maintained within a 1.6 fold range over the 24-hour dosing interval.
Absorption
Following oral administration of TAGRISSO, peak plasma concentrations of osimertinib were
achieved with a median (min-max) tmax of 6 (3-24) hours, with several peaks observed over the first 24
hours in some patients. The absolute bioavailability of TAGRISSO is 70% (90% CI 67, 73). Based on
a clinical pharmacokinetic study in patients at 80 mg, food does not alter osimertinib bioavailability to
a clinically meaningful extent. (AUC increase by 6% (90% CI -5, 19) and Cmax decrease by 7% (90%
CI -19, 6)). In healthy volunteers administered an 80 mg tablet where gastric pH was elevated by
dosing of omeprazole for 5 days, osimertinib exposure was not affected (AUC and Cmax increase by
7% and 2%, respectively) with the 90% CI for exposure ratio contained within the 80-125% limit.
Distribution
Population estimated mean volume of distribution at steady-state (Vss/F) of osimertinib is 918 L
indicating extensive distribution into tissue. In vitro plasma protein binding of osimertinib is 94.7%
(5.3% free). Osimertinib has also been demonstrated to bind covalently to rat and human plasma
proteins, human serum albumin and rat and human hepatocytes.
Biotransformation
In vitro studies indicate that osimertinib is metabolised predominantly by CYP3A4, and CYP3A5.
However, with current available data, alternative metabolic pathways cannot be fully ruled out. Based
on in vitro studies, 2 pharmacologically active metabolites (AZ7550 and AZ5104) have subsequently
been identified in the plasma of preclinical species and in humans after oral dosing with osimertinib;
AZ7550 showed a similar pharmacological profile to TAGRISSO while AZ5104 showed greater
potency across both mutant and wild-type EGFR. Both metabolites appeared slowly in plasma after
administration of TAGRISSO to patients, with a median (min-max) tmax of 24 (4-72) and 24 (6-72)
hours, respectively. In human plasma, parent osimertinib accounted for 0.8%, with the 2 metabolites
contributing 0.08% and 0.07% of the total radioactivity with the majority of the radioactivity being
covalently bound to plasma proteins. The geometric mean exposure of both AZ5104 and AZ7550,
based on AUC, was approximately 10% each of the exposure of osimertinib at steady-state.
The main metabolic pathway of osimertinib was oxidation and dealkylation. At least 12 components
were observed in the pooled urine and faecal samples in humans with 5 components accounting for
>1% of the dose of which unchanged osimertinib, AZ5104 and AZ7550, accounted for approximately
1.9, 6.6 and 2.7% of the dose while a cysteinyl adduct (M21) and an unknown metabolite (M25)
accounted for 1.5% and 1.9% of the dose, respectively.
Based on in vitro studies, osimertinib is a competitive inhibitor of CYP 3A4/5 but not CYP1A2, 2A6,
2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 at clinically relevant concentrations. Based on in vitro studies,
osimertinib is not an inhibitor of UGT1A1 and UGT2B7 at clinically relevant concentrations
hepatically. Intestinal inhibition of UGT1A1 is possible but the clinical impact is unknown.
31
Elimination
Following a single oral dose of 20 mg, 67.8% of the dose was recovered in faeces (1.2% as parent)
while 14.2% of the administered dose (0.8% as parent) was found in urine by 84 days of sample
collection. Unchanged osimertinib accounted for approximately 2% of the elimination with 0.8% in
urine and 1.2% in faeces.
Interactions with transport proteins
In vitro studies have shown that osimertinib is not a substrate of OATP1B1 and OATP1B3. In vitro,
osimertinib does not inhibit OAT1, OAT3, OATP1B1, OATP1B3, MATE1, OCT2 and MATE2K at
clinically relevant concentrations.
Based on in vitro studies, osimertinib is a substrate of P-gp and BCRP, Based on in vitro data,
osimertinib is an inhibitor of BCRP and P-gp (see section 4.5).
Special populations
In a population based pharmacokinetic analyses (n=1367), no clinically significant relationships were
identified between predicted steady-state exposure (AUCss) and patient’s age (range: 25 to 91 years),
gender (65% female), ethnicity (including White, Asian, Japanese, Chinese and non-Asian-non-White
patients), line of therapy and smoking status (n=34 current smokers, n=419 former smokers).
Population PK analysis indicated that body weight was a significant covariate with a less than 20%
change in osimertinib AUCss expected across a body weight range of 88 kg to 43 kg respectively
(95% to 5% quantiles) when compared to the AUCss for the median body weight of 61 kg. Taking the
extremes of body weight into consideration, from <43 kg to >88 kg, AZ5104 metabolite ratios ranged
from 11.8% to 9.6% while for AZ7550 it ranged from 12.8% to 8.1%, respectively. Based on
population PK analysis, serum albumin was identified as a significant covariate with a <30% change
in osimertinib AUCss expected across the albumin range of 29 to 46 g/L respectively (95% to 5%
quantiles) when compared to the AUCss for the median baseline albumin of 39 g/L. These exposure
changes due to body weight or baseline albumin differences are not considered clinically relevant.
Hepatic impairment
Osimertinib is eliminated mainly via the liver. In a clinical trial, patients with different types of
advanced solid tumours and with mild hepatic impairment (Child Pugh A, mean score =5.3, n=7) or
moderate hepatic impairment (Child Pugh B, mean score =8.2, n=5) had no increase in exposure
compared to patients with normal hepatic function (n=10) after a single 80 mg dose of TAGRISSO.
The geometric mean ratio (90% CI) of osimertinib AUC and Cmax was 63.3% (47.3, 84.5) and 51.4%
(36.6, 72.3) in patients with mild hepatic impairment and 68.4% (49.6, 94.2) and 60.7% (41.6, 88.6)
in patients with moderate hepatic impairment; for the metabolite AZ5104 the AUC and Cmax were
66.5% (43.4, 101.9) and 66.3% (45.3, 96.9) in patients with mild hepatic impairment and 50.9%
(31.7, 81.6) and 44.0% (28.9, 67.1) in patients with moderate hepatic impairment, compared to the
exposure in patients with normal hepatic function. Based on population PK analysis, there was no
relationship between markers of hepatic function (ALT, AST, bilirubin) and osimertinib exposure.
The hepatic impairment marker serum albumin showed an effect on the PK of osimertinib. Clinical
studies that were conducted excluded patients with AST or ALT >2.5x upper limit of normal (ULN),
or if due to underlying malignancy, >5.0x ULN or with total bilirubin >1.5x ULN. Based on a
pharmacokinetic analysis of 134 patients with mild hepatic impairment, 8 patients with moderate
hepatic impairment and 1216 patients with normal hepatic function osimertinib exposures were
similar. There are no data available on patients with severe hepatic impairment (see section 4.2).
Renal impairment
In a clinical trial, patients with severe renal impairment (CLcr 15 to less than 30 mL/min; n=7)
compared to patients with normal renal function (CLcr greater than or equal to 90 mL/min; n=8) after
a single 80 mg oral dose of TAGRISSO showed a 1.85-fold increase in AUC (90% CI; 0.94, 3.64)
32
and a 1.19-fold increase in Cmax (90% CI: 0.69, 2.07). Furthermore, based on a population
pharmacokinetic analysis of 593 patients with mild renal impairment (CLcr 60 to less than
90 mL/min), 254 patients with moderate renal impairment (CLcr 30 to less than 60 mL/min), 5
patients with severe renal impairment (CLcr 15 to less than 30 mL/min) and 502 patients with normal
renal function (greater than or equal to 90 mL/min), osimertinib exposures were similar. Patients with
CLcr less than or equal to 10 mL/min were not included in the clinical trials.
 

The main findings observed in repeat dose toxicity studies in rats and dogs comprised atrophic, inflammatory and/or degenerative changes affecting the epithelia of the cornea (accompanied by corneal translucencies and opacities in dogs at ophthalmology examination), GI tract (including tongue), skin, and male and female reproductive tracts with secondary changes in spleen. These findings occurred at plasma concentrations that were below those seen in patients at the 80 mg therapeutic dose. The findings present following 1 month of dosing were largely reversible within 1 month of cessation of dosing with the exception of partial recovery for some of the corneal changes.

Lens fibre degeneration was found in the 104-week carcinogenicity rat study at exposures 0.2-times the human AUC, at the recommended clinical dose of 80 mg once a day. Lens opacities were first noted from week 52 of this study and showed a gradual increase in incidence and severity with increased duration of dosing. The clinical relevance of this finding cannot be ruled out.

Osimertinib penetrated the intact blood-brain barrier of the cynomolgus monkey (intravenous dosing), rat and mouse (oral administration).

Non-clinical data indicate that Osimertinib and its metabolite (AZ5104) inhibit the h-ERG channel, and QTc prolonging effect cannot be excluded.

Osimertinib did not cause genetic damage in in vitro and in vivo assays. Osimertinib showed no carcinogenic potential when administered orally to Tg rasH2 transgenic mice for 26 weeks.  

An increased incidence of proliferative vascular lesions (angiomatous hyperplasia and haemangioma) in the mesenteric lymph node was observed in the rat 104-week carcinogenicity study at exposures 0.2 times the AUC at the recommended clinical dose of 80 mg once daily, and is unlikely to be relevant for humans.

Reproductive toxicity

Degenerative changes were present in the testes in rats and dogs exposed to Osimertinib for ≥1 month and there was a reduction in male fertility in rats following exposure to Osimertinib for 3 months. These findings were seen at clinically relevant plasma concentrations. Pathology findings in the testes seen following 1 month dosing were reversible in rats; however, a definitive statement on reversibility of these lesions in dogs cannot be made.

Based on studies in animals, female fertility may be impaired by treatment with Osimertinib. In repeat dose toxicity studies, an increased incidence of anoestrus, corpora lutea degeneration in the ovaries and epithelial thinning in the uterus and vagina were seen in rats exposed to Osimertinib for ≥1 month at clinically relevant plasma concentrations. Findings in the ovaries seen following 1 month dosing were reversible. In a female fertility study in rats, administration of Osimertinib at 20 mg/kg/day (approximately equal to the recommended daily clinical dose of 80 mg) had no effects on oestrus cycling or the number of females becoming pregnant, but caused early embryonic deaths. These findings showed evidence of reversibility following a 1 month off-dose.

In a modified embryofoetal development study in the rat, Osimertinib caused embryo lethality when administered to pregnant rats prior to embryonic implantation. These effects were seen at a maternally tolerated dose of 20 mg/kg where exposure was equivalent to the human exposure at the recommended dose of 80 mg daily (based on total AUC). Exposure at doses of 20 mg/kg and above during organogenesis caused reduced foetal weights but no adverse effects on external or visceral foetal morphology. When Osimertinib was administered to pregnant female rats throughout gestation and then through early lactation, there was demonstrable exposure to Osimertinib and its metabolites in suckling pups plus a reduction in pup survival and poor pup growth (at doses of 20 mg/kg and above).

Tablet core

Mannitol

Microcrystalline cellulose

Low-substituted hydroxpropyl cellulose

Sodium stearyl fumarate

Tablet coating

Polyvinyl alcohol Titanium dioxide

(E 171) Macrogol 3350

Talc

Yellow iron oxide (E 172)

Red iron oxide (E 172)

Black iron oxide (E 172)

Not applicable.

This medicinal product does not require any special storage conditions.

Al/Al perforated unit dose blisters. Cartons of 30 x 1 tablets (3 blister strips).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.