TAGRISSO 40 mg and 80mg film-coated tablets

New indication added.

TAGRISSO as monotherapy is indicated for:

• the treatment of adult patients with locally advanced, unresectable 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.

New indication added.

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.      Possible side effects

[..]

Uncommon (may affect up to 1 in 100 people)

• Skin greying or darkening (hyperpigmentation).

[..]

'Skin hyperpigmentation' added to Table 2 in section 4.8.

'Skin hyperpigmentation' added to Table 2 in section 4.8.

4.2 Posology and method of administration

[..]

Table 1. Recommended dose modifications for TAGRISSO

[..]

4.4     Special warnings and precautions for use

[..]

Interstitial Lung Disease (ILD)

[..]

ILD or ILD-like adverse reactions were reported in 3.87% 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 10.9 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).

[..]

Stevens Johnson syndrome (SJS) Severe Cutaneous Adverse Reactions (SCARs)

Case reports of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with frequency categories of rarely 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.

[..]

Table 2. Adverse reactions reported in ADAURA, FLAURA and AURA studies^a

[..]

10.      DATE OF REVISION OF THE TEXT

06 October 2022 26 July 2023

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

ONC 22 0023 ONC 23 0021

4. Possible side effects

[..]

Serious side effects

[..]

·              Stevens-Johnson syndrome and toxic epidermal necrolysis, which can appear as reddish target-like macules or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and be preceded by fever and flu-like symptoms. This side effect Stevens-Johnson syndrome is rare: it may affect up to 1 in 1000 people. The frequency of toxic epidermal necrolysis cannot be determined as cases have only been reported since marketing TAGRISSO.

[..]

Other side effects

[..]

Common

[..]

·              Abnormal blood test results related to Increase of a substance in the blood called creatine phosphokinase (an enzyme released into the blood when muscle is damaged).

[..]

6. Contents of the pack and other information

[..]

Manufacturer

AstraZeneca AB

Gärtunavägen

SE‑151 152 85 57 Södertälje

Sweden

Removal of Black Inverted Triangle

Change to section 4.8 

Change to section 10

4.8     Undesirable effects

[...]

Table 2. Adverse reactions reported in ADAURA, FLAURA and AURA studies^a

[...]

5.3     Preclinical safety data

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 (i.v. 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.

10.     DATE OF REVISION OF THE TEXT

21 May 2021

27^th January 2022

Update to the SmPC following the approval of a variation to extend the indication of Tagrisso to include adjuvant treatment after complete tumour resection in EGFRm NSCLC and consequentially delete the limit for a mutagenic impurity.

4.8 Undesirable effects

 Erythema multiforme added as an uncommon side effect to Table 2. Adverse reactions reported in FLAURA and AURA studies

Footnote added to Table 2 about incidence of erythema multiforme

10. DATE OF REVISION OF THE TEXT

Updated to 2 April 2020

(Inserted Text; Deleted Text)

4. Possible side effects

….

Tell your doctor straight away if you notice the following serious side effects:

…..

• Stevens-Johnson syndrome, which can appear as reddish target-like macules or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and be preceded by fever and flu-like symptoms. This side effect is rare: it may affect up to 1 in 1000 people. See also Section 2.
• Target lesions, which are skin reactions that look like rings (suggestive of Erythema multiforme). This side effect is uncommon: it may affect up to 1 in 100 people.

This leaflet was last revised in September 2019 April 2020.

The following significant changes were made:

Section 5.1 Pharmacodynamic properties

Overall survival (OS) data from interim analysis replaced with final data in text and in Table  3.

% patients alive – 24 and 36 months data added, 18-month % in Tagrisso arm corrected.

Kaplan-Meyer OS curve added as Figure 2.

Section 4.2 Posology and method of administration: Updated Renal Impairment section with information based on clinical studies and population PK analysis. 

Section 5.2 Pharmacokinetic properties: Addition of data from renal impairment study.

Under 'other side effects' the word 'pain' was included for skin and nail problems.

'Skin and nail problems - signs may include pain'

Section 4.8 Undesirable effects

'Onychalgia' added under Table 2 section h, as a possible skin and subcutanous tissue disorder adverse reaction.

Section 4.2 Posology and method of administration

Change in dose modification after Interstitial Lung Disease (ILD) with cross-reference to Section 4.4:

Table 1 – Permanently dDiscontinue TAGRISSO (see Section 4.4)
 

Section 4.4 Warnings and precautions
ILD

Last paragraph revised to allow possible reintroduction of TAGRISSO after ILD after careful consideration of the individual patient’s benefit-risk (changed from permanent discontinuation)

 Addition of Stevens-Johnson syndrome:

Stevens-Johnson syndrome

Case reports of Stevens-Johnson syndrome (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.

 Changes in cardiac contractility:

Deletion of one sentence: Based on the available clinical trial data, it is not possible to determine a causal relationship between effects on changes in cardiac contractility and TAGRISSO.
 

Section 4.8 Undesirable effects

SJS added as a rare event in Table 2

Removal of UK adverse event reporting details and update to HPRA reporting details
 

Section 10 Date of revision of the text

Revision date updated to 26th August 2019