tagrisso

Important safety information

Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. For patients receiving TAGRISSO who have not received recent definite platinum-based chemoradiation therapy, permanently discontinue TAGRISSO in patients diagnosed with ILD/Pneumonitis. For patients who received recent definitive platinum-based chemoradiation therapy with Grade 1 ILD/pneumonitis continue TAGRISSO or interrupt and restart, as appropriate. Permanently discontinue TAGRISSO in patients diagnosed with Grade ≥2 ILD/pneumonitis. ( 2.5 , 5.1 ) • QTc Interval Prolongation : Monitor electrocardiograms and electrolytes in patients who have a history or predisposition for QTc prolongation, or those who are taking medications that are known to prolong the QTc interval. Withhold, then restart at a reduced dose or permanently discontinue TAGRISSO based on severity. ( 2.5 , 5.2 ) • Cardiomyopathy : Occurred in 3.8% of patients. Conduct cardiac monitoring, including left ventricular ejection fraction (LVEF) assessment in patients with cardiac risk factors. ( 2.5 , 5.3 ) • Keratitis : Promptly refer patients with signs and symptoms of keratitis to an ophthalmologist for evaluation. ( 5.4 ) • Erythema Multiforme Major, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis : Withhold TAGRISSO if erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN) is suspected and permanently discontinue if confirmed. ( 2.5 , 5.5 ) • Cutaneous Vasculitis : Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation based on severity. ( 5.6 ) • Aplastic Anemia : Withhold TAGRISSO if aplastic anemia is suspected and permanently discontinue TAGRISSO if confirmed. ( 2.5 , 5.7 ) • Embryo-Fetal Toxicity : TAGRISSO can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with TAGRISSO and for 6 weeks after last dose. Advise males to use effective contraception for 4 months after the last dose of TAGRISSO. ( 5.8 , 8.1 , 8.3 ) 5.1 Interstitial Lung Disease/Pneumonitis TAGRISSO can cause severe and fatal ILD/pneumonitis. Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 4% of the 1813 patients treated with TAGRISSO monotherapy who had not received recent definitive chemoradiation therapy; 0.4% of cases were fatal. ILD/Pneumonitis with TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy In the FLAURA2 study, ILD/pneumonitis occurred in 3.3% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 0.4% of cases were fatal. ILD/Pneumonitis Following Definitive Platinum-based Chemoradiation Therapy In the LAURA study, following definitive platinum-based chemoradiation therapy, ILD/pneumonitis, including radiation pneumonitis, occurred in 80 of the 143 patients (56%) who received TAGRISSO monotherapy and 28 of the 73 patients (38%) who received placebo. There was one fatal case (0.7%), 3.5% Grade 3, 34% Grade 2, and 18% Grade 1 adverse reactions of ILD/pneumonitis in TAGRISSO-treated patients. For TAGRISSO-treated patients, ILD/pneumonitis led to permanent discontinuation of TAGRISSO in 7% of patients and dosage interruptions of TAGRISSO in 35% of patients. Among the 46 patients who were rechallenged with TAGRISSO, 11% had recurrence of ILD/pneumonitis. In the 80 TAGRISSO-treated patients, ILD/pneumonitis resolved in 40%, resolved with sequelae in 1.3%, were resolving in 16%, did not resolve in 41%, and resulted in death in 1.3%. For patients receiving TAGRISSO who have not received recent definitive platinum-based chemoradiation therapy, withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening or respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue TAGRISSO if ILD/pneumonitis is confirmed [see Dosage and Administration (2.5) and Adverse Reactions (6.1) ]. For patients who have received recent definitive platinum-based chemoradiation therapy with Grade 1 ILD/pneumonitis continue TAGRISSO or interrupt and restart, as appropriate. Permanently discontinue TAGRISSO in patients diagnosed with Grade ≥2 ILD/pneumonitis [see Dosage and Administration (2.5) and Adverse Reactions (6.1) ]. 5.2 QTc Interval Prolongation TAGRISSO can cause heart rate-corrected QT (QTc) interval prolongation. Of the 1813 patients treated with TAGRISSO monotherapy in clinical trials, 1.1% were found to have a QTc >500 msec, and 4.3% of patients had an increase from baseline QTc >60 msec [see Clinical Pharmacology (12.2) ]. Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study, 1.8% were found to have a QTc >500 msec, and 10.5% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Clinical trials of TAGRISSO did not enroll patients with baseline QTc of >470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.5) ]. 5.3 Cardiomyopathy TAGRISSO can cause cardiomyopathy, including cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction. Across clinical trials, cardiomyopathy occurred in 3.8% of the 1813 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. In the FLAURA2 study, cardiomyopathy occurred in 9% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 1.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10 percentage points from baseline and to less than 50% LVEF occurred in 4.2% of 1557 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of patients treated with TAGRISSO 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% (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% (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%. For patients who will be receiving TAGRISSO monotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. For patients who will be receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in all patients. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO [see Dosage and Administration (2.5) ]. 5.4 Keratitis Keratitis was reported in 0.6% of 1813 patients treated with TAGRISSO monotherapy in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist. 5.5 Erythema Multiforme Major, Stevens-Johnson Syndrome, and Toxic…