OSIMERTINIB Drug Interactions: What You Need to Know

INTERACTIONS Strong CYP3A Inducers : Avoid concomitant use. If not possible, increase TAGRISSO to 160 mg daily in patients receiving a strong CYP3A4 inducer. ( 2.5 , 7.1 )

7.1 Effect of Other Drugs on Osimertinib Strong CYP3A Inducers Co-administering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Decreased osimertinib exposure may lead to reduced efficacy. Avoid co-administering TAGRISSO with strong CYP3A inducers. Increase the TAGRISSO dosage when co-administering with a strong CYP3A4 inducer if concurrent use is unavoidable <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> . No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers.

7.2 Effect of Osimertinib on Other Drugs Co-administering TAGRISSO with a breast cancer resistant protein (BCRP) or P-glycoprotein (P-gp) substrate increased the exposure of the substrate compared to administering it alone <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Increased BCRP or P-gp substrate exposure may increase the risk of exposure-related toxicity. Monitor for adverse reactions of the BCRP or P-gp substrate, unless otherwise instructed in its approved labeling, when co-administered with TAGRISSO.

7.3 Drugs That Prolong the QTc Interval The effect of co-administering medicinal products known to prolong the QTc interval with TAGRISSO is unknown. When feasible, avoid concomitant administration of drugs known to prolong the QTc interval with known risk of Torsades de pointes. If not feasible to avoid concomitant administration of such drugs, conduct periodic ECG monitoring <span class="opacity-50 text-xs">[see Error! Hyperlink reference not valid. and Clinical Pharmacology (12.2) ]</span>.

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AND PRECAUTIONS

• 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 , Error! Hyperlink reference not valid. )
• 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 , Error! Hyperlink reference not valid. )
• 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 , Error! Hyperlink reference not valid. )
• Keratitis: Promptly refer patients with signs and symptoms of keratitis to an ophthalmologist for evaluation. ( Error! Hyperlink reference not valid. )
• 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 , Error! Hyperlink reference not valid. )
• 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. ( Error! Hyperlink reference not valid. )
• Aplastic Anemia: Withhold TAGRISSO if aplastic anemia is suspected and permanently discontinue TAGRISSO if confirmed. ( 2.5 , Error! Hyperlink reference not valid. )
• 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. ( Error! Hyperlink reference not valid. , 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) and Adverse Reactions (6.1) ]</span>. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) and Adverse Reactions (6.1) ]</span>.

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 &gt;500 msec, and 4.3% of patients had an increase from baseline QTc &gt;60 msec <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span>. 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 &gt;500 msec, and 10.5% of patients had an increase from baseline QTc &gt;60 msec. No QTc-related arrhythmias were reported. Clinical trials of TAGRISSO did not enroll patients with baseline QTc of &gt;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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>.

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>.

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 Epidermal Necrolysis Postmarketing cases consistent with erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving TAGRISSO <span class="opacity-50 text-xs">[see Postmarketing (6.2) ]</span> . Withhold TAGRISSO if EMM, SJS, or TEN is suspected and permanently discontinue if confirmed.

5.6 Cutaneous Vasculitis Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO <span class="opacity-50 text-xs">[see Postmarketing (6.2) ]</span> . 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 of TAGRISSO based on severity.

5.7 Aplastic Anemia Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.06% of 1813) and postmarketing <span class="opacity-50 text-xs">[see Postmarketing (6.2) ]</span> . Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> . Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated.

5.8 Embryo-Fetal Toxicity Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 and 8.3) ]</span>.