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Precautions of Osimertinib

1.Interstitial Lung Disease/Pneumonitis

Interstitial lung disease (ILD)/pneumonitis occurred in 3.7% of the 1479 Osimertinib-treated patients; 0.3% of cases were fatal.

Withhold Osimertinib and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue Osimertinib if ILD is confirmed.

2 QTc Interval Prolongation

Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with Osimertinib. Of the 1479 patients treated with Osimertinib in clinical trials, 0.8% were found to have a QTc > 500 msec, and 3.1% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported.

Clinical trials of Osimertinib 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 Osimertinib in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia.

3.Cardiomyopathy

Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 3% of the 1479 Osimertinib-treated patients; 0.1% 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 3.2% of 1233 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of patients treated with Osimertinib experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. 

Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue Osimertinib.

4. Keratitis

Keratitis was reported in 0.7% of 1479 patients treated with Osimertinib 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..Erythema Multiforme and Stevens-Johnson Syndrome

Postmarketing cases consistent with Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) have been reported in patients receiving Osimertinib. Withhold Osimertinib if SJS or EMM is suspected and permanently discontinue if confirmed.

6.Cutaneous Vasculitis

Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving Osimertinib. Withhold Osimertinib if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of Osimertinib based on severity.

7.Aplastic Anemia

Aplastic anemia has been reported in patients treated with Osimertinib in clinical trials (0.07% of 1479) and postmarketing . 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 Osimertinib and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue Osimertinib.

Perform complete blood count with differential before starting Osimertinib, periodically throughout treatment, and more frequently if indicated.

8.Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, Osimertinib 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 Osimertinib. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Osimertinib and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose.

from FDA，2022.10