Special Warning : אזהרת שימוש

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, 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)

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 were reported in 3.8% of the 1479 patients who received TAGRISSO in  the ADAURA, FLAURA and AURA studies. Five 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 11.3%  in patients of Japanese ethnicity, 1.6% in patients of Asian ethnicity and 2.5% in non-Asian patients. (See 
Section 4.8).

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.

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 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 studies, left ventricular ejection fraction (LVEF) decreases greater than or equal to 10 percentage points and a drop to less than 50% occurred in 3.2% (40/1233) of patients treated with TAGRISSO 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), 1.6% (5/312) 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%.

Keratitis
Keratitis was reported in 0.7% (n=10) of the 1479 patients treated with TAGRISSO in the ADAURA, 
FLAURA 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  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”.

Effects on Driving

4.7 Effects on ability to drive and use machines

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