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Precautions of Exkivity

1.QTc Prolongation and Torsades de Pointes

Exkivity can cause life-threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal. In the 250 patient subset of the pooled Exkivity safety population who had scheduled and unscheduled electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and 11% of patients had a change-from-baseline QTc interval >60 msec. Grade 4 Torsades de Pointes occurred in 1 patient (0.4%). Clinical trials of Exkivity did not enroll patients with baseline QTc greater than 470 msec.

Assess QTc and electrolytes at baseline and correct abnormalities in sodium, potassium, calcium, and magnesium prior to initiating Exkivity. Monitor QTc and electrolytes periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation, such as patients with congenital long QT syndrome, heart disease, severe renal impairment, or electrolyte abnormalities. Avoid use of concomitant drugs which are known to prolong the QTc interval. Avoid concomitant use of strong or moderate CYP3A inhibitors with Exkivity.

Withhold, reduce the dose, or permanently discontinue Exkivity based on the severity of the QTc prolongation.

2.Interstitial Lung Disease (ILD)/Pneumonitis

Exkivity can cause ILD/pneumonitis, which can be fatal. In the pooled Exkivity safety population , ILD/pneumonitis occurred in 4.3% of patients including 0.8% Grade 3 events and 1.2% fatal events.

Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold Exkivity in patients with suspected ILD/pneumonitis and permanently discontinue Exkivity if ILD/pneumonitis is confirmed .

3.Cardiac Toxicity

Exkivity can cause cardiac toxicity (including decreased ejection fraction, cardiomyopathy, and congestive heart failure) resulting in heart failure which can be fatal. In the pooled Exkivity safety population, heart failure occurred in 2.7% of patients including 1.2% Grade 3 reactions, 0.4% Grade 4 reactions, and one (0.4%) fatal case of heart failure.

Exkivity can cause QTc prolongation resulting in Torsades de Pointes. Atrial fibrillation (1.6%), ventricular tachycardia (0.4%), first degree atrioventricular block (0.4%), second degree atrioventricular block (0.4%), left bundle branch block (0.4%), supraventricular extrasystoles (0.4%) and ventricular extrasystoles (0.4%) also occurred in patients receiving Exkivity.

Monitor cardiac function, including assessment of left ventricular ejection fraction at baseline and during treatment. Withhold, reduce the dose, or permanently discontinue Exkivity based on the severity. 

4.Diarrhea

Exkivity can cause diarrhea, which can be severe. In the pooled Exkivity safety population, diarrhea occurred in 93% of patients, including 20% Grade 3 and 0.4% Grade 4. The median time to first onset of diarrhea was 5 days but diarrhea has occurred within 24 hours after administration of Exkivity. In the 48% of patients whose diarrhea resolved, the median time to resolution was 3 days. Diarrhea may lead to dehydration or electrolyte imbalance, with or without renal impairment. Treat diarrhea promptly.

Advise patients to start an antidiarrheal agent (e.g., loperamide) at first sign of diarrhea or increased bowel movement frequency and to increase fluid and electrolyte intake.Monitor electrolytes and withhold, reduce the dose or permanently discontinue Exkivity based on the severity .

5.Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, Exkivity can cause fetal harm when administered to a pregnant woman. Oral administration of mobocertinib to pregnant rats during the period of organogenesis resulted in embryolethality at maternal exposures approximately 1.7 times the human exposure based on area under the curve (AUC) at the 160 mg once daily clinical dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Exkivity and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Exkivity and for 1 week after the last dose of Exkivity.

from FDA，2023.09