WARNINGS AND PRECAUTIONS

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, 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, which may further prolong the QTc. Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of the QTc prolongation.

Interstitial Lung Disease (ILD)/PneumonitisEXKIVITY 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.

Cardiac ToxicityEXKIVITY 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.

DiarrheaEXKIVITY 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.

Embryo-Fetal ToxicityBased on findings from animal studies and its mechanism of action, EXKIVITY can cause fetal harm when administered to a pregnant woman. 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.

ADVERSE REACTIONSThe most common (>20%) adverse reactions are diarrhea (92%), rash (78%), stomatitis (46%), vomiting (40%), decreased appetite (39%), paronychia (39%), nausea (37%), musculoskeletal pain (34%), dry skin (32%), fatigue (29%), pruritus (24%), cough (24%) and decreased weight (21%). The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (15%), increased amylase (13%), increased lipase (10%), decreased potassium (5.3%), decreased red blood cells (3.5%), increased creatinine (2.7%), decreased magnesium (2.7%), and increased alanine aminotransferase (2.7%).

DRUG INTERACTIONSCYP3A InhibitorsCoadministration of EXKIVITY with strong or moderate CYP3A inhibitors increased mobocertinib plasma concentrations, which may increase the risk of adverse reactions, including QTc interval prolongation. Avoid concomitant use of strong or moderate CYP3A inhibitors with EXKIVITY. If concomitant use of moderate CYP3A inhibitors cannot be avoided, reduce the EXKIVITY dose and monitor the QTc interval more frequently with ECGs.CYP3A InducersCoadministration of EXKIVITY with strong or moderate CYP3A inducers decreased mobocertinib plasma concentrations, which may reduce EXKIVITY anti-tumor activity. Avoid concomitant use of strong or moderate CYP3A inducers with EXKIVITY.CYP3A SubstratesCoadministration of EXKIVITY with CYP3A substrates may decrease plasma concentrations of CYP3A substrates, which may reduce the efficacy of these substrates. Avoid concomitant use of hormonal contraceptives with EXKIVITY. Avoid concomitant use of EXKIVITY with other CYP3A substrates where minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with the approved product Prescribing Information.Prolonged QTc IntervalEXKIVITY can cause QTc interval prolongation. Coadministration of EXKIVITY with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation. Avoid concomitant use of other medications known to prolong the QTc interval with EXKIVITY. If concomitant use is unavoidable, monitor the QTc interval more frequently with ECGs.

USE IN SPECIFIC POPULATIONSPregnancyBased on findings from animal studies and its mechanism of action, EXKIVITY can cause fetal harm when administered to a pregnant woman. There are no available data on EXKIVITY use in pregnant women. Advise pregnant women of the potential risk to a fetus.Females and Males of Reproductive PotentialEXKIVITY can cause fetal harm when administered to pregnant women. Verify pregnancy status in females of reproductive potential prior to initiating EXKIVITY. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with EXKIVITY and for 1 month after the last dose. EXKIVITY may render hormonal contraceptives ineffective. Advise males with female partners of reproductive potential to use effective contraception during treatment with EXKIVITY and for 1 week after the last dose. Based on animal studies EXKIVITY may impair fertility in males and females of reproductive potential.LactationThere are no data on the presence of mobocertinib or its metabolites in human milk or their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with EXKIVITY and for 1 week after the last dose.GeriatricOf the 114 patients who received EXKIVITY in clinical studies, 37% were 65 years and over, and 7% were 75 years and over. No overall difference in effectiveness was observed between patients aged 65 and older and younger patients. Exploratory analysis suggests a higher incidence rate of Grade 3 and 4 adverse reactions (69% vs 47%) and serious adverse reactions (64% vs 35%) in patients 65 years and older as compared to those younger than 65 years.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-844-217-6468 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information, including Boxed Warning.