4.1. Therapeutic indications

TAGRISSO as monotherapy is indicated for:

• the adjuvant treatment after complete tumour resection in adult patients with stage IB-IIIA non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations (see section 5.1).

• the treatment of adult patients with locally advanced, unresectable (stage III) NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations and whose disease has not progressed during or following platinum‑based chemoradiation therapy.

• the first-line treatment of adult patients with locally advanced or metastatic NSCLC with activating EGFR mutations.

• the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC.

TAGRISSO is indicated in combination with:

• pemetrexed and platinum-based chemotherapy for the first-line treatment of adult patients with advanced NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

4.2. Posology and method of administration

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 or for locally advanced, unresectable tumours and tumour or plasma specimens for locally advanced or metastatic setting) should be determined using a validated test method (see section 4.4).

Posology

Monotherapy

The recommended dose is 80 mg osimertinib once a day.

Combination therapy

The recommended dose of TAGRISSO is 80 mg osimertinib once a day when taken with pemetrexed and platinum‑based chemotherapy.

Refer to the Summary of Product Characteristics for pemetrexed and cisplatin or carboplatin for the respective dosing information.

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 TAGRISSO 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

Pulmonaryb,c

ILD/Pneumonitis

Discontinue TAGRISSO

ILD/Pneumonitis following definitive platinum-based chemoradiation therapy: Asymptomatic (Grade 1)

Continue TAGRISSO or interrupt and restart, as appropriate.

ILD/Pneumonitis following definitive platinum-based chemoradiation therapy: Grade ≥2

Permanently discontinue TAGRISSO

Cardiacb

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

Cutaneousb

Stevens-Johnson Syndrome and Toxic epidermal necrolysis

Permanently discontinue TAGRISSO

Blood and lymphatic systemb

Aplastic anaemia

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 5.0.

b Refer to section 4.4.

c Refer to section 4.4 for modification instructions in patients with radiation pneumonitis following definitive platinum-based chemoradiation therapy.

ECGs: Electrocardiograms; QTc: QT interval corrected for heart rate.

Combination therapy

When TAGRISSO is used in combination, any of the treatment components should be dose modified, as appropriate. For TAGRISSO dose modification instructions, see Table 1. The pemetrexed, cisplatin or carboplatin dose should be modified in accordance with the instructions in their respective Summary of Product Characteristics. Cisplatin and/or carboplatin should be used for up to 4 cycles.

Special populations

No dose 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 1.5 times 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 nasogastric 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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

St. John's Wort should not be used together with TAGRISSO (see section 4.5).

4.4. Special warnings and precautions for use

Assessment of EGFR mutation status

When considering the use of TAGRISSO as adjuvant treatment after complete tumour resection in patients with NSCLC, 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 in patients with locally advanced, unresectable (stage III) NSCLC, EGFR mutation positive status (exon 19 deletions or exon 21 [L858R] substitution mutations) indicates treatment eligibility. A validated test should be performed in a clinical laboratory using tumour tissue DNA from a biopsy 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.

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

Positive determination of EGFR mutation status (activating EGFR mutations for first-line treatment, exon 19 deletion or exon 21 (L858R) substitution mutations when TAGRISSO is given in combination with pemetrexed and platinum-based chemotherapy 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.

Interstitial Lung Disease (ILD)

Severe, life-threatening or fatal ILD or ILD-like adverse reactions (e.g. pneumonitis) have been observed in patients treated with TAGRISSO in clinical studies. Most cases improved or resolved with interruption of treatment. Patients with a past 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 (see section 4.8).

ILD or ILD-like adverse reactions (e.g. pneumonitis) were reported in 4.0% of the 1813 patients who received TAGRISSO monotherapy in the ADAURA, FLAURA, FLAURA2 and AURA studies. Seven fatal cases were reported in the locally advanced or metastatic setting. No fatal cases were reported in the adjuvant setting. 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 (see section 4.8).

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 161 days.

Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude ILD. Treatment with this medicinal product should be interrupted pending investigation of these symptoms. If ILD is diagnosed, TAGRISSO should be discontinued and appropriate treatment initiated as necessary. Reintroduction of TAGRISSO should be considered only after careful consideration of the individual patient's benefits and risk.

ILD following definitive platinum-based chemoradiation therapy

In the LAURA study, following definitive platinum-based chemoradiation therapy, ILD or ILD‑like adverse reactions (e.g. pneumonitis) were reported in 7.7% of the 143 patients who received TAGRISSO and 1.4% of the 73 patients who received placebo. There were 0.7% fatal cases reported for ILD or ILD-like adverse reactions in the TAGRISSO arm and no fatal cases in the placebo arm (see section 4.8).

For patients treated with TAGRISSO following definitive platinum‑based chemoradiation therapy, use the following dose modification instructions:

• If patients develop asymptomatic (Grade 1) ILD or ILD-like adverse reactions, continue TAGRISSO, or alternatively interrupt and restart TAGRISSO, as clinically indicated

• Permanently discontinue the use of TAGRISSO if the patient develops a Grade ≥2 ILD or ILD‑like adverse reaction.

Radiation pneumonitis

Radiation pneumonitis is usually observed for up to a year after patients receive radiation therapy to the lungs. In the LAURA study, following definitive platinum-based chemoradiation therapy, radiation pneumonitis was reported in 48% of the 143 patients who received TAGRISSO and 38% of the 73 patients who received placebo. The median time from first dose to onset of radiation pneumonitis was 1.7 months in the TAGRISSO arm and 1.8 months in the placebo arm. The median time from last dose of radiotherapy to onset of radiation pneumonitis was 2.5 months in the TAGRISSO arm and 2.6 months in the placebo arm. Three (2.1%) patients had Grade 3 events, all in the TAGRISSO arm, and no Grade 4 or Grade 5 events were reported in either arm.

For patients treated with TAGRISSO following definitive platinum‑based chemoradiation therapy, use the following dose modification instructions:

• If patients develop symptomatic (Grade 2) radiation pneumonitis, interrupt TAGRISSO until symptoms resolve; TAGRISSO may be restarted.

• Permanently discontinue the use of TAGRISSO if:

- symptoms do not resolve after 4 weeks of interrupting TAGRISSO;

- symptomatic (Grade 2) radiation pneumonitis recurs after restarting TAGRISSO;

- patients develop severe or life threatening (Grade 3 or 4) radiation pneumonitis.

Severe Cutaneous Adverse Reactions (SCARs)

Case reports of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with frequency categories of rare and not known, respectively, in association with TAGRISSO treatment. Before initiating treatment, patients should be advised of signs and symptoms of SJS and TEN. If signs and symptoms suggestive of SJS or TEN appear, TAGRISSO should be interrupted. TAGRISSO should be discontinued immediately if SJS or TEN are diagnosed.

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 QTc related arrythmias were reported in ADAURA, LAURA, FLAURA, FLAURA2 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 TAGRISSO 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. TAGRISSO 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 studies, 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. 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. In an adjuvant placebo‑controlled study (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%. In the LAURA study, following platinum‑based chemoradiation therapy, 3.0% (4/135) of patients treated with TAGRISSO and no patients treated with placebo experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. 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%.

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. 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 Table 1).

Aplastic anaemia

Rare cases of aplastic anaemia, including fatal events, have been reported in association with TAGRISSO 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 TAGRISSO should be considered. TAGRISSO 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).

Hepatitis B Virus (HBV) reactivation

Hepatitis B virus reactivation can occur in patients treated with TAGRISSO, and in some cases, may result in fulminant hepatitis, hepatic failure, and death. Patients with evidence of positive HBV serology should be monitored for clinical and laboratory signs of HBV reactivation while receiving TAGRISSO. In patients who develop reactivation of HBV while on TAGRISSO, treatment with TAGRISSO should be withheld and they should be managed according to local institutional guidelines.

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

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 Cmax decreased by 20%). Therefore, CYP3A4 inhibitors are not likely to affect the exposure of osimertinib. Further catalysing 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 Cmax. 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 Cmax 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 Cmax 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 Cmax 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).

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 non-small cell lung cancer. 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 and AURA3, second line only), two Phase 2 single-arm studies (AURAex and AURA2, second line or later) and one Phase 1 study (AURA1, first-line or later) (see section 5.1). 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 across the studies were 11% and 0.2%, respectively. In patients treated with TAGRISSO 80 mg once daily, dose reductions due to adverse reactions occurred in 3.9% of the patients. Discontinuation due to adverse reactions was 5.2%.

The safety of TAGRISSO (80 mg once daily) following platinum‑based chemoradiation therapy is based on data from 143 patients with EGFR mutation‑positive NSCLC. It was manageable and was consistent with TAGRISSO monotherapy and the known safety profile of treatment following platinum-based chemoradiation therapy. The most commonly reported adverse drug reactions (ADRs) were diarrhoea (36%), rash (36%), paronychia (23%) and dry skin (17%). Grade 3 and Grade 4 adverse reactions were 9.1% and 0%, respectively. Dose reduction due to adverse reactions occurred in 5.6% of patients. Discontinuation due to adverse reactions was 3.5%.

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. The most commonly reported ADRs when TAGRISSO was given in combination with pemetrexed and platinum‑based chemotherapy were rash (49%), diarrhoea (43%), decreased appetite (31%), stomatitis (31%), paronychia (27%) and dry skin (24%). When TAGRISSO is administered as combination therapy, refer to the Summary of Product Characteristics for the respective combination therapy components prior to initiation of treatment.

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, AURA2 and AURA1 studies, in 143 patients treated with TAGRISSO following platinum‑based chemoradiation therapy in the LAURA study and in 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study.

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, LAURA, FLAURA, FLAURA2 and AURA studies

MedDRA SOC

TAGRISSOa

TAGRISSO following platinum‑based chemoradiationb

TAGRISSO with pemetrexed and platinum-based chemotherapyc

All Gradesd

Grade 3 or higherd

All Gradesd

Grade 3 or higherd

All Gradesd

Grade 3 or higherd

Infections and infestations

Hepatitis B reactivatione

Not known

0%

0%

0%

0%

Blood and lymphatic system disorders

Aplastic anaemia

Rare (0.06%)

0.06%

0%

0%

0%

0%

Leukopenia

Common (5.4%)

0.4%

Common (2.8%)

0%

Very common (12.7%)

2.9%

Lymphopenia

Common (1.7%)

0.2%

Common (1.4%)

0.7%

Common (2.5%)

1.1%

Thrombocytopenia

Common (7.6%)

0.6%

Common (2.8%)

0.7%

Very common (18.5%)

6.9%

Neutropenia

Common (6%)

0.9%

Common (4.9%)

0.7%

Very common (24.6%)

13.4%

Metabolism and nutrition disorders

Decreased appetite

Very common (19%)

1.2%

Very common (15%)

0.7%

Very common (31%)

2.9%

Eye disorders

Keratitisf

Uncommon (0.6%)

0.06%

Uncommon (0.7%)

0%

Uncommon (0.7%)

0%

Cardiac disorders

Cardiac failure

Uncommon (0.5%)

0.2%

0%

0%

Common (1.8%)

1.1%g

Respiratory, thoracic and mediastinal disorders

Epistaxis

Common (6%)

0%

Uncommon (0.7%)

0%

Common (7%)

0.4%

Interstitial lung disease

Common (4.0%)h

1.4%i

Common (8%)j

2.1%k

Common (3.3%)l

0.7%m

Gastrointestinal disorders

Diarrhoea

Very common (47%)

1.4%

Very common (36%)

2.1%

Very common (43%)

2.9%

Stomatitisn

Very common (24%)

0.4%

Very common (15%)

0%

Very common (31%)

0.4%

Skin and subcutaneous tissue disorders

Rasho

Very common (46%)

0.8%

Very common (36%)p

0.7%p

Very common (49%)

2.5%

Paronychiaq

Very common (34%)

0.4%

Very common (23%)

0%

Very common (27%)

0.7%

Dry skinr

Very common (32%)

0.1%

Very common (17%)

0.7%

Very common (24%)

0%

Prurituss

Very common (17%)

0.06%

Very common (13%)t

0%

Common (8%)

0%

Alopecia

Common (5%)

0%

Common (1.4%)

0%

Common (9%)

0%

Palmar-plantar erythrodysaesthesia syndrome

Common (2.1%)

0%

0%

0%

Common (5%)

0%

Urticaria

Common (1.9%)

0.1%

Common (1.4%)

0%

Common (1.4%)

0.4%

Skin hyperpigmentationt

Common (1.0%)

0%

0%

0%

Common (2.5%)

0%

Erythema multiformeu

Uncommon (0.3%)

0%

0%

0%

Common (1.4%)

0.7%

Cutaneous vasculitisv

Uncommon (0.2%)

0%

0%

0%

0%

Stevens-Johnson syndromew

Rare (0.02%)

0%

0%

0%

0%

Toxic Epidermal Necrolysise

Not known

0%

0%

0%

0%

Investigations

Left ventricular ejection fraction decreasedx,y

Common (4.2%)

Common (3.0%)

Common (8%)

QTc interval prolongationz

Common (1.1%)

Uncommon (0.7%)

Common (1.8%)

Blood creatine phosphokinase increased

Common (1.9%)

0.3%

Common (3.5%)

1.4%

Common (3.3%)

1.1%

Investigations (Findings based on test results presented as CTCAE grade shifts)

Leucocytes decreasedx

Very common (65%)

1.8%

Very Common (66%)

2.8%

Very common (88%)

20%

Lymphocytes decreasedx

Very common (64%)

8%

Very Common (70%)

3.5%

Very common (78%)

16%

Platelet count decreasedx

Very common (53%)

1.3%

Very Common (51%)

1.4%

Very common (85%)

16%

Neutrophils decreasedx

Very common (36%)

4.0%

Very Common (42%)

2.1%

Very common (85%)

36%

Blood creatinine increased*

Common (9%)

0.2%

Very Common (19%)

0%

Very common (22%)

0.4%

Musculoskeletal and connective tissue disorders

Myositis

Uncommon (0.2%)

0%

0%

0%

0%

0%

Muscle spasms

Common (8.2%)

0.1%

Common (4.2%)

0%

Common (3.3%)

0%

a Data is pooled from ADAURA, FLAURA, FLAURA2 (monotherapy arm) and AURA (AURA3, AURAex, AURA 2 and AURA1) studies; only events for patients receiving at least one dose of TAGRISSO as their randomised treatment are summarised.

b Data is from the TAGRISSO arm of the LAURA study; only events for the patients receiving at least one dose of TAGRISSO as their randomised treatment are summarised. The median duration of study treatment was 24.0 months for patients in the TAGRISSO arm and 8.3 months for patients in the placebo arm.

c Data is from the combination arm of the FLAURA2 study; only events for the patients receiving at least one dose of study treatment (TAGRISSO, pemetrexed, cisplatin or carboplatin) as their randomised treatment are summarised. The median duration of study treatment was 22.3 months for patients in the TAGRISSO with pemetrexed and platinum-based chemotherapy arm.

d National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

e Reported during post-marketing use.

f Includes cases reported within the clustered terms: Keratitis, punctate keratitis, corneal erosion, corneal epithelium defect.

g Two CTCAE Grade 5 events (fatal) were reported.

h Includes cases reported within the clustered terms: Interstitial lung disease (1.9%), pneumonitis (2.0%), organising pneumonia (0.1%).

i Seven CTCAE Grade 5 events (fatal) were reported.

j Includes: interstitial lung disease (0.7%), pneumonitis (5.6%), pulmonary fibrosis (2.1%), organising pneumonia (0%).

k One CTCAE Grade 5 event (fatal) was reported.

l Includes: interstitial lung disease (1.8%), pneumonitis (1.1%), organising pneumonia (0.4%).

m One CTCAE Grade 5 event (fatal) was reported.

n Includes cases reported within the clustered terms: Stomatitis, mouth ulceration.

o Includes cases reported within the clustered terms for rash AEs: Rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion, pustule.

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

q Includes cases reported within the clustered terms: Nail bed disorder, nail bed inflammation, nail bed infection, nail discolouration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.

r Includes cases reported within the clustered terms: Dry skin, skin fissures, xerosis, eczema, xeroderma.

s Includes cases reported within the clustered terms: pruritus, eyelid pruritus.

t Cases of erythema dyschromicum perstans have been reported in the post-marketing setting.

u 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).

v Estimated frequency. The upper limit of the 95% CI for the point estimate is 3/1813 (0.2 %).

w One event was 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).

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

y Represents decreases greater than or equal to 10 percentage points and a drop to less than 50%.

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

* Patients with a lower baseline blood creatinine clearance (≥30mL/min) were permitted to enrol in the LAURA study compared to other monotherapy TAGRISSO studies (≥50mL/min), so grade shifts were more likely to occur.

Description of selected adverse reactions

Interstitial lung disease (ILD)

In the ADAURA, FLAURA, FLAURA2 (monotherapy arm) and AURA studies, 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 85 days (see section 4.4).

ILD following definitive platinum-based chemoradiation therapy

In the TAGRISSO arm of the LAURA study, the incidence of ILD or ILD-like adverse reactions was 6.6% (6 of 91 patients) in patients of non‑Japanese Asian ethnicity and 17.2% (5 of 29 patients) in non-Asian patients; no patients of Japanese ethnicity had an event of ILD. The median time from first dose to onset of ILD or ILD-like adverse reactions was 1.9 months in the TAGRISSO arm. The median time from last dose of radiotherapy to onset of ILD or ILD-like adverse reactions was 3.0 months in the TAGRISSO arm (see section 4.4).

QTc interval 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, and 4.3% of patients (n=78) had an increase from baseline QTc greater than 60 msec. A pharmacokinetic/pharmacodynamic analysis with TAGRISSO predicted a concentration-dependent increase in QTc interval prolongation. No QTc-related arrhythmias were reported in the ADAURA, LAURA, FLAURA, FLAURA2 or AURA studies (see sections 4.4 and 5.1). In patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, the proportion of patients who experienced a QTc interval prolongation of greater than 500 msec with a greater than 60 msec increase from baseline was low and was similar with monotherapy (1.8% versus 1.5%).

Gastrointestinal effects

In the ADAURA, FLAURA, FLAURA2 and AURA studies (TAGRISSO monotherapy; N=1813), diarrhoea was reported in 47% of patients of which 37% were Grade 1 events, 8.6% Grade 2 and 1.4% were Grade 3; no Grade 4 or 5 events were reported. Dose reduction was required in 0.5% of patients and dose interruption in 1.9%. Four events (0.2%) led to discontinuation. In ADAURA, FLAURA, FLAURA2 (monotherapy arm) and AURA3 the median time to onset was 22 days, 19 days, 22 days and 22 days, respectively, and the median duration of the Grade 2 events was 11 days, 19 days, 17 days and 6 days, respectively. In patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, diarrhoea was reported in 43% of patients versus 41% of patients in monotherapy, most of these diarrhoea events were Grade 1 and Grade 2 events.

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 TAGRISSO treatment. TAGRISSO should be discontinued in patients with confirmed aplastic anaemia (see section 4.2 and 4.4).

Elderly

In ADAURA, FLAURA, FLAURA2 and AURA3 (TAGRISSO monotherapy; N=1813), 42% of patients were 65 years of age and older, and 11% were 75 years of age and older. Compared with younger patients (<65), more patients ≥65 years old had reported adverse reactions that led to study dose modifications (interruptions or reductions) (17% versus 10%). The types of adverse events reported were similar regardless of age. Older patients reported more Grade 3 or higher adverse reactions compared to younger patients (14% versus 10%). No overall differences in efficacy were observed between older and younger patients. Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, 104 patients were ≥65 years and 23 patients were ≥75 years of age. Older patients (≥65 years) reported similar Grade 3 or higher adverse reactions compared to <65 years old patients (36% versus 36%) respectively. Dose modification for adverse reactions were reported in a higher proportion of patients ≥65 years as compared to <65 years (34% vs 20%).

Low body weight

Patients receiving TAGRISSO monotherapy (80 mg) with low body weight (<50 kg) reported higher frequencies of Grade ≥3 adverse reactions (20% versus 10%) and QTc prolongation (13% versus 6%) than patients with higher body weight (≥50 kg). Patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy with low body weight (<50 kg) reported similar frequencies of Grade ≥3 adverse reactions (32% versus 37%) when compared to patients with higher body weight (≥50 kg). In contrast, dry skin (34% versus 22%) and stomatitis (40% versus 30%) were reported at higher frequencies in patients with low body weight (<50 kg) versus higher body weight (≥50 kg).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In TAGRISSO clinical studies 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 TKI-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.