ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:QTc Prolongation and Torsades de Pointes [see Warnings and Precautions (5.1)] Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2)] Cardiac Toxicity [see Warnings and Precautions (5.3)] Diarrhea [see Warnings and Precautions (5.4)] QTc Prolongation and Torsades de Pointes [see Warnings and Precautions (5.1)] Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2)] Cardiac Toxicity [see Warnings and Precautions (5.3)] Diarrhea [see Warnings and Precautions (5.4)] The most common (>20%) adverse reactions are diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. The most common (>=2%) Grade or laboratory abnormalities were decreased lymphocytes, increased amylase, increased lipase, decreased potassium, decreased hemoglobin, increased creatinine, and decreased magnesium. (6)To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-844-217-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to EXKIVITY as single agent at dose of 160 mg orally once daily in 256 patients, including 114 patients with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC from Study AP32788-15-101, and patients with other solid tumors. Forty-eight percent (48%) were exposed for months or longer and 12% were exposed for greater than one year. The most common (>20%) adverse reactions were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. The most common (>=2%) Grade or laboratory abnormalities were decreased lymphocytes, increased amylase, increased lipase, decreased potassium, decreased hemoglobin, increased creatinine, and decreased magnesium. EGFR Exon 20 Insertion Mutation-Positive Locally Advanced or Metastatic NSCLC Previously Treated with Platinum-Based ChemotherapyThe safety of EXKIVITY was evaluated in subset of patients in Study AP32788-15-101 with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC who received prior platinum-based chemotherapy [see Clinical Studies (14)]. Patients with history of interstitial lung disease, drug-related pneumonitis, radiation pneumonitis that required steroid treatment; significant, uncontrolled, active cardiovascular disease; or prolonged QTc interval were excluded from enrollment in this trial. total of 114 patients received EXKIVITY 160 mg once daily until disease progression or unacceptable toxicity; 60% were exposed for months or longer and 14% were exposed for greater than year.Serious adverse reactions occurred in 46% of patients who received EXKIVITY. Serious adverse reactions in >=2% of patients included diarrhea, dyspnea, vomiting, pyrexia, acute kidney injury, nausea, pleural effusion, and cardiac failure. Fatal adverse reactions occurred in 1.8% of patients who received EXKIVITY, including cardiac failure (0.9%), and pneumonitis (0.9%).Permanent discontinuation occurred in 17% of patients who received EXKIVITY. Adverse reactions requiring permanent discontinuation of EXKIVITY in at least >=2% of patients were diarrhea and nausea.Dosage interruptions of EXKIVITY due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in >5% of patients included diarrhea, nausea and vomiting.Dose reductions of EXKIVITY due to an adverse reaction occurred in 25% of patients. The adverse reaction requiring dose reduction in >5% of patients was diarrhea.Table summarizes the adverse reactions in Study AP32788-15-101.Table 3: Adverse Reactions (>=10%) in Patients with EGFR Exon 20 Insertion Mutation-Positive NSCLC Whose Disease Has Progressed on or after Platinum-Based Chemotherapy in Study AP32788-15-101Adverse ReactionEXKIVITY(N 114)All GradesGraded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 5) (%)Grade or 4(%)Gastrointestinal Disorders Diarrhea9222 StomatitisStomatitis includes angular cheilitis, aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, odynophagia, and stomatitis. 464.4Events of Grade only (no Grade occurred) Vomiting402.6 Decreased appetite390.9 Nausea374.4 Decreased weight210 Abdominal painAbdominal pain includes abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. 181.8 Gastroesophageal reflux disease150 Dyspepsia110Skin and Subcutaneous Tissue Disorders RashRash includes acne, dermatitis, dermatitis acneiform, rash, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, and urticaria. 781.8 ParonychiaParonychia includes nail bed tenderness, nail disorder, nail infection, onycholysis, and paronychia. 390.9 Dry skin320 Pruritus240.9 Alopecia190Musculoskeletal and Connective Tissue Disorders Musculoskeletal painMusculoskeletal pain includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. 342.6 General Disorders and Administration Site Conditions FatigueFatigue includes asthenia, and fatigue. 293.5 Respiratory, Thoracic and Mediastinal Disorders CoughCough includes cough, productive cough, and upper-airway cough syndrome. 240 Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, and upper respiratory tract infection. 160 DyspneaDyspnea includes dyspnea, and dyspnea exertional. 154.4 Rhinorrhea130Eye Disorders Ocular ToxicityOcular toxicity includes dry eye, eye pruritis, abnormal sensation in eye, eye discharge, blepharitis, trichiasis, conjunctival hemorrhage, vitreous floaters, blurred vision and corneal edema. 110Cardiac Disorders QTc interval prolongationQTc interval prolongation includes electrocardiogram QT prolonged, and ventricular arrhythmia. 103.5 HypertensionHypertension includes blood pressure increased, and hypertension. 104.4 Nervous System Disorders Headache100Clinically relevant adverse reactions in <10% of patients receiving EXKIVITY included edema (9%), acute kidney injury (8%), peripheral neuropathy (7%), palmar-plantar erythrodysaesthesia (4.4%), pneumonitis (2.6%) and cardiac failure (2.6%).Table summarizes the laboratory abnormalities in Study AP32788-15-101.Table 4: Select Laboratory Abnormalities (>=20%) Worsening from Baseline in Patients with EGFR Exon 20 Insertion Mutation-Positive NSCLC Whose Disease Has Progressed on or after Platinum-Based Chemotherapy in Study AP32788-15-101Laboratory AbnormalityEXKIVITYThe denominator used to calculate the rate varied from 93 to 113 based on the number of patients with baseline and at least one post-treatment value. The laboratory abnormalities are values that reflect worsening from baseline. (N 114)All GradesGrades per NCI CTCAE v5.0 (%)Grade or 4(%)Hematology Decreased red blood cells593.5 Decreased lymphocytes5215 Decreased platelets260.9 Decreased leukocytes250Chemistry Increased creatinine522.7 Increased amylase4013 Increased lipase3510 Decreased potassium295.3 Increased alkaline phosphatase251.8 Decreased albumin231.8 Decreased magnesium232.7 Increased alanine aminotransferase222.7 Increased aspartate aminotransferase211.8 Decreased sodium200.9.

BOXED WARNING SECTION.

WARNING: 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, and requires monitoring of QTc and electrolytes at baseline and periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation [see Warnings and Precautions (5.1)].Avoid use of concomitant drugs which are known to prolong the QTc interval and use of strong or moderate CYP3A inhibitors with EXKIVITY, which may further prolong the QTc [see Warnings and Precautions (5.1), Drug Interactions (7.1, 7.3)].Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of QTc prolongation [see Dosage and Administration (2.3)].. EXKIVITY can cause life threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal, and requires monitoring of QTc and electrolytes at baseline and periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation [see Warnings and Precautions (5.1)].. Avoid use of concomitant drugs which are known to prolong the QTc interval and use of strong or moderate CYP3A inhibitors with EXKIVITY, which may further prolong the QTc [see Warnings and Precautions (5.1), Drug Interactions (7.1, 7.3)].. Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of QTc prolongation [see Dosage and Administration (2.3)].. WARNING: QTc PROLONGATION AND TORSADES DE POINTESSee full prescribing information for complete boxed warning.EXKIVITY can cause life-threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal, and requires monitoring of QTc and electrolytes at baseline and periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation (5.1).Avoid use of concomitant drugs which are known to prolong the QTc interval and use of strong or moderate CYP3A inhibitors with EXKIVITY, which may further prolong the QTc (5.1, 7.1, 7.3).Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of QTc prolongation (2.3).. EXKIVITY can cause life-threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal, and requires monitoring of QTc and electrolytes at baseline and periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation (5.1).. Avoid use of concomitant drugs which are known to prolong the QTc interval and use of strong or moderate CYP3A inhibitors with EXKIVITY, which may further prolong the QTc (5.1, 7.1, 7.3).. Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of QTc prolongation (2.3).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Mobocertinib is kinase inhibitor of the epidermal growth factor receptor (EGFR) that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild type (WT) EGFR. Two pharmacologically-active metabolites (AP32960 and AP32914) with similar inhibitory profiles to mobocertinib have been identified in the plasma after oral administration of mobocertinib. In vitro, mobocertinib also inhibited the activity of other EGFR family members (HER2 and HER4) and one additional kinase (BLK) at clinically relevant concentrations (IC50 values <2 nM).In cultured cell models, mobocertinib inhibited the proliferation of cells driven by different EGFR exon 20 insertion mutation variants at 1.5- to 10-fold lower concentrations than WT-EGFR signaling inhibition.In animal tumor implantation models, mobocertinib exhibited anti-tumor activity against xenografts with the EGFR exon 20 insertions NPH or ASV.. 12.2 Pharmacodynamics. Mobocertinib exposure-response relationships and the time course of pharmacodynamic response are unknown.. Cardiac ElectrophysiologyThe largest mean increase in QTc was 23.0 msec (UCI: 25.5 msec) following administration of EXKIVITY 160 mg once daily. The increase in QTc interval was concentration-dependent.The largest mean increase in the PR interval was 12.4 msec (UCI: 15.0 msec). PR interval prolongation >220 msec occurred in 5% of patients taking EXKIVITY 160 mg once daily.. 12.3 Pharmacokinetics. After single- and multiple-dose administration, combined molar Cmax and AUC0-24h of mobocertinib and its active metabolites, AP32960 and AP32914, was dose-proportional over the dose range of to 180 mg once daily (0.03 to 1.1 times the approved recommended dosage). No clinically meaningful accumulation was observed after administration of EXKIVITY 160 mg once daily based on the AUC ratio of mobocertinib.. AbsorptionThe median (min, max) time to peak concentration (Tmax) of mobocertinib is hours (1, hours). The mean (%CV) absolute bioavailability is 37% (50%).. Effect of FoodNo clinically meaningful differences in the combined molar AUC and Cmax of mobocertinib, AP32960, and AP32914 were observed following administration of high-fat meal (approximately 900 to 1000 calories, with 150 calories from protein, 250 calories from carbohydrate and 500 to 600 calories from fat) or low fat-meal (approximately 336 calories, with 37 calories from protein, 253 calories from carbohydrate, and 46 calories from fat) compared to administration after an overnight fast.. DistributionMobocertinib was bound to human plasma proteins in concentration independent manner in vitro from 0.5 to 5.0 uM. The mean (standard deviation) bound fraction was 99.3% (0.11%) for mobocertinib, 99.5% (0.16%) for AP32960 and 98.6% (0.36%) for AP32914 in vitro.The blood-to-plasma ratio was 0.76 for mobocertinib, 1.2 for AP32960 and 0.71 for AP32914.The mean (%CV) apparent volume of distribution (Vss/F) of mobocertinib was 3,509 (38%) at steady-state.. EliminationThe mean (%CV) plasma elimination half-life of mobocertinib was 18 hours (21%) at steady-state. The mean apparent oral clearance (CL/F) (%CV) of mobocertinib was 138 L/hr (47%) at steady-state.The mean (%CV) plasma elimination half-life of AP32960 was 24 hours (20%) at steady-state. The mean apparent oral clearance (CL/F) (%CV) of AP32960 was 149 L/hr (36%) at steady-state.The mean (%CV) plasma elimination half-life of AP32914 was 18 hours (21%) at steady-state. The mean apparent oral clearance (CL/F) (%CV) of AP32914 was 159 L/hr (52%) at steady-state.. MetabolismMobocertinib is primarily metabolized by CYP3A. The two active metabolites, AP32960 and AP32914, are equipotent to mobocertinib and account for 36% and 4% of the combined molar AUC, respectively.. ExcretionFollowing administration of single 160 mg oral dose of radiolabeled mobocertinib, approximately 76% of the dose was recovered in feces (approximately 6% as unchanged mobocertinib) and approximately 4% was recovered in urine (approximately 1% as unchanged mobocertinib). The percentage of the administered dose recovered in feces and urine for AP32960 was approximately 12% and 1%, respectively. The metabolite AP32914 was below the detection limit in urine and feces.. Specific PopulationsNo clinically meaningful differences in the pharmacokinetics of mobocertinib were observed based on age (18 to 86 years), race (White, Black, Asian), sex, body weight (37.3 to 132 kg), mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2 by MDRD), or mild (total bilirubin <= ULN and AST ULN or total bilirubin >1 to 1.5 times ULN and any AST)-to-moderate (total bilirubin >=1.5 to times ULN and any AST) hepatic impairment. The effect of severe (eGFR <30 mL/min/1.73 m2) renal impairment and severe (total bilirubin >3 times ULN and any AST) hepatic impairment on mobocertinib pharmacokinetics is unknown.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. Effect of CYP3A Inhibitors on Mobocertinib: Coadministration of EXKIVITY with multiple doses of itraconazole or ketoconazole (strong CYP3A inhibitors) is predicted to increase the steady-state combined molar AUC of mobocertinib and its active metabolites by 374 to 419%.Coadministration of EXKIVITY with multiple doses of moderate CYP3A inhibitor is predicted to increase the steady-state combined molar AUC of mobocertinib and its active metabolites by approximately 100-200%.. Effect of CYP3A Inducers on Mobocertinib: Coadministration of EXKIVITY with multiple doses of rifampin (a strong CYP3A inducer) is predicted to decrease the steady-state combined molar AUC of mobocertinib and its active metabolites by 92%.Coadministration of EXKIVITY with multiple doses of efavirenz (a moderate CYP3A inducer) is predicted to decrease the steady-state combined molar AUC of mobocertinib and its active metabolites by 58%.. Effect of Mobocertinib on CYP3A Substrates: Coadministration of EXKIVITY 160 mg once daily with oral or intravenous midazolam (a CYP3A substrate) decreased the AUC of midazolam by 32% and 16%, respectively.. Effect of Mobocertinib on P-gp Substrates: No clinically meaningful differences in the pharmacokinetics of digoxin or dabigatran etexilate (P-gp substrates) are predicted when coadministered with multiple doses of EXKIVITY.. Effect of Mobocertinib on BCRP Substrates: The clinical significance of changes in the pharmacokinetics of sulfasalazine (a BCRP substrate) when coadministered with multiple doses of EXKIVITY is unknown.. In Vitro Studies. CYP Enzymes: Mobocertinib, AP32960, and AP32914 do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations.. Transporter Systems: Mobocertinib is an inhibitor of P-gp and BCRP. At clinically relevant concentrations, mobocertinib does not inhibit BSEP, MATE1, MATE2-K, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2.Mobocertinib is substrate of P-gp. Mobocertinib is not substrate of BCRP, OATP1B1, and OATP1B3.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of EXKIVITY was evaluated in pooled subset of patients with EGFR exon 20 insertion mutation-positive metastatic or locally advanced NSCLC whose disease had progressed on or after platinum-based chemotherapy enrolled in an international, open-label, multicohort clinical trial (AP32788-15-101, NCT02716116). Patients had histologically or cytologically confirmed locally advanced or metastatic disease (Stage IIIB or IV) and documented EGFR exon 20 insertion mutation based on local testing. Patients received EXKIVITY at dose of 160 mg once daily until disease progression or intolerable toxicity.In the efficacy population, EGFR exon 20 insertion mutation status was determined by prospective local testing using samples from tumor tissue (87%), plasma (5%), or other specimens such as pleural fluid (8%). Of the 114 patients with EGFR exon 20 insertion mutations, 70% of patient tissue samples were tested retrospectively using Life Technologies Corporation Oncomine Dx(TM) Target Test. While 75% of patients were positive for EGFR exon 20 insertion mutation, 14% did not have an EGFR exon 20 insertion mutation identified, and 11% did not generate reportable results.The efficacy population consisted of 114 patients and had the following demographic characteristics: the median age was 60 years (range: 27 to 84 years); 66% were female; 60% were Asian, 37% were White, and 3% were Black; 71% had never smoked; at baseline, 75% had Eastern Cooperative Oncology Group (ECOG) performance status 1. At baseline, 99% of patients had metastatic disease, 98% of patients had adenocarcinoma histology and 35% of patients had brain metastases. The median number of prior therapies was (range: to 7) and 43% percent had received prior immunotherapy.The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by blinded independent central review (BICR). Additional efficacy outcome measures included duration of response (DOR) by BICR.Efficacy results are summarized in Table 5.Table 5: Efficacy Results in Patients with EGFR Exon 20 Insertion Mutation-Positive NSCLC Whose Disease Has Progressed on or after Platinum-Based Chemotherapy in Study AP32788-15-101EXKIVITY(n=114)Overall Response Rate (ORR)Per BICR, CI confidence interval (95% CI)28% (20, 37)All responses were partial responses Duration of Response (DOR) Median (months)Kaplan-Meier estimate using confirmed responses only, (95% CI)17.5 (7.4, 20.3) Patients with DOR >=6 monthsBased on observed duration of response 59%Investigator-assessed ORR was 35% (95% CI: 26, 45) with median DOR of 11.2 months (63% of these patients had observed responses lasting longer than months).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to EXKIVITY as single agent at dose of 160 mg orally once daily in 256 patients, including 114 patients with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC from Study AP32788-15-101, and patients with other solid tumors. Forty-eight percent (48%) were exposed for months or longer and 12% were exposed for greater than one year. The most common (>20%) adverse reactions were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. The most common (>=2%) Grade or laboratory abnormalities were decreased lymphocytes, increased amylase, increased lipase, decreased potassium, decreased hemoglobin, increased creatinine, and decreased magnesium. EGFR Exon 20 Insertion Mutation-Positive Locally Advanced or Metastatic NSCLC Previously Treated with Platinum-Based ChemotherapyThe safety of EXKIVITY was evaluated in subset of patients in Study AP32788-15-101 with EGFR exon 20 insertion mutation-positive locally advanced or metastatic NSCLC who received prior platinum-based chemotherapy [see Clinical Studies (14)]. Patients with history of interstitial lung disease, drug-related pneumonitis, radiation pneumonitis that required steroid treatment; significant, uncontrolled, active cardiovascular disease; or prolonged QTc interval were excluded from enrollment in this trial. total of 114 patients received EXKIVITY 160 mg once daily until disease progression or unacceptable toxicity; 60% were exposed for months or longer and 14% were exposed for greater than year.Serious adverse reactions occurred in 46% of patients who received EXKIVITY. Serious adverse reactions in >=2% of patients included diarrhea, dyspnea, vomiting, pyrexia, acute kidney injury, nausea, pleural effusion, and cardiac failure. Fatal adverse reactions occurred in 1.8% of patients who received EXKIVITY, including cardiac failure (0.9%), and pneumonitis (0.9%).Permanent discontinuation occurred in 17% of patients who received EXKIVITY. Adverse reactions requiring permanent discontinuation of EXKIVITY in at least >=2% of patients were diarrhea and nausea.Dosage interruptions of EXKIVITY due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in >5% of patients included diarrhea, nausea and vomiting.Dose reductions of EXKIVITY due to an adverse reaction occurred in 25% of patients. The adverse reaction requiring dose reduction in >5% of patients was diarrhea.Table summarizes the adverse reactions in Study AP32788-15-101.Table 3: Adverse Reactions (>=10%) in Patients with EGFR Exon 20 Insertion Mutation-Positive NSCLC Whose Disease Has Progressed on or after Platinum-Based Chemotherapy in Study AP32788-15-101Adverse ReactionEXKIVITY(N 114)All GradesGraded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 5) (%)Grade or 4(%)Gastrointestinal Disorders Diarrhea9222 StomatitisStomatitis includes angular cheilitis, aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, odynophagia, and stomatitis. 464.4Events of Grade only (no Grade occurred) Vomiting402.6 Decreased appetite390.9 Nausea374.4 Decreased weight210 Abdominal painAbdominal pain includes abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. 181.8 Gastroesophageal reflux disease150 Dyspepsia110Skin and Subcutaneous Tissue Disorders RashRash includes acne, dermatitis, dermatitis acneiform, rash, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, and urticaria. 781.8 ParonychiaParonychia includes nail bed tenderness, nail disorder, nail infection, onycholysis, and paronychia. 390.9 Dry skin320 Pruritus240.9 Alopecia190Musculoskeletal and Connective Tissue Disorders Musculoskeletal painMusculoskeletal pain includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. 342.6 General Disorders and Administration Site Conditions FatigueFatigue includes asthenia, and fatigue. 293.5 Respiratory, Thoracic and Mediastinal Disorders CoughCough includes cough, productive cough, and upper-airway cough syndrome. 240 Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, and upper respiratory tract infection. 160 DyspneaDyspnea includes dyspnea, and dyspnea exertional. 154.4 Rhinorrhea130Eye Disorders Ocular ToxicityOcular toxicity includes dry eye, eye pruritis, abnormal sensation in eye, eye discharge, blepharitis, trichiasis, conjunctival hemorrhage, vitreous floaters, blurred vision and corneal edema. 110Cardiac Disorders QTc interval prolongationQTc interval prolongation includes electrocardiogram QT prolonged, and ventricular arrhythmia. 103.5 HypertensionHypertension includes blood pressure increased, and hypertension. 104.4 Nervous System Disorders Headache100Clinically relevant adverse reactions in <10% of patients receiving EXKIVITY included edema (9%), acute kidney injury (8%), peripheral neuropathy (7%), palmar-plantar erythrodysaesthesia (4.4%), pneumonitis (2.6%) and cardiac failure (2.6%).Table summarizes the laboratory abnormalities in Study AP32788-15-101.Table 4: Select Laboratory Abnormalities (>=20%) Worsening from Baseline in Patients with EGFR Exon 20 Insertion Mutation-Positive NSCLC Whose Disease Has Progressed on or after Platinum-Based Chemotherapy in Study AP32788-15-101Laboratory AbnormalityEXKIVITYThe denominator used to calculate the rate varied from 93 to 113 based on the number of patients with baseline and at least one post-treatment value. The laboratory abnormalities are values that reflect worsening from baseline. (N 114)All GradesGrades per NCI CTCAE v5.0 (%)Grade or 4(%)Hematology Decreased red blood cells593.5 Decreased lymphocytes5215 Decreased platelets260.9 Decreased leukocytes250Chemistry Increased creatinine522.7 Increased amylase4013 Increased lipase3510 Decreased potassium295.3 Increased alkaline phosphatase251.8 Decreased albumin231.8 Decreased magnesium232.7 Increased alanine aminotransferase222.7 Increased aspartate aminotransferase211.8 Decreased sodium200.9.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dosage: 160 mg orally once daily, with or without food. (2.2). Recommended Dosage: 160 mg orally once daily, with or without food. (2.2). 2.1Patient Selection. Select patients with locally advanced or metastatic NSCLC for treatment with EXKIVITY based on the presence of EGFR exon 20 insertion mutations [see Clinical Studies (14)]. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2Recommended Dosage. The recommended dosage of EXKIVITY is 160 mg orally once daily until disease progression or unacceptable toxicity.Take EXKIVITY with or without food [see Clinical Pharmacology 12.3], at the same time each day. Swallow EXKIVITY capsules whole. Do not open, chew or dissolve the contents of the capsules.If dose is missed by more than hours, skip the dose and take the next dose the following day at its regularly scheduled time.If dose is vomited, do not take an additional dose. Take the next dose as prescribed the following day.. 2.3Dosage Modifications for Adverse Reactions. EXKIVITY dose reduction levels for adverse reactions are summarized in Table 1.Table 1: Recommended EXKIVITY Dose ReductionsDose ReductionsDose LevelFirst dose reduction120 mg once dailySecond dose reduction80 mg once dailyRecommended dosage modifications of EXKIVITY for adverse reactions are provided in Table 2.Table 2: Recommended Dosage Modifications for EXKIVITY Adverse ReactionsAdverse ReactionSeverityGraded per Common Terminology Criteria for Adverse Events Version 5.0 EXKIVITY Dosage ModificationULN upper limit of normalQTc Interval Prolongation and Torsades de Pointes [see Warnings and Precautions (5.1)] Grade 2(QTc interval 481-500 msec)First OccurrenceWithhold EXKIVITY until <= Grade or baseline.Upon recovery, resume EXKIVITY at the same dose.RecurrenceWithhold EXKIVITY until <= Grade or baseline.Upon recovery, resume EXKIVITY at the next lower dose or permanently discontinue EXKIVITY.Grade 3(QTc interval >=501 msec or QTc interval increase of >60 msec from baseline)First OccurrenceWithhold EXKIVITY until <= Grade or baseline.Upon recovery, resume EXKIVITY at the next lower dose or permanently discontinue EXKIVITY.RecurrencePermanently discontinue EXKIVITY.Grade 4(Torsades de Pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia)Permanently discontinue EXKIVITY.Interstitial Lung Disease (ILD)/pneumonitis [see Warnings and Precautions (5.2)] Any gradeWithhold EXKVITY if ILD/pneumonitis is suspected.Permanently discontinue EXKIVITY if ILD/pneumonitis is confirmed.Decreased Ejection Fraction or Heart Failure [see Warnings and Precautions (5.3)] Grade decreased ejection fractionWithhold EXKIVITY until <= Grade or baseline.If recovered to baseline within weeks, resume EXKIVITY at the same dose or the next lower dose.If not recovered to baseline within weeks, permanently discontinue EXKIVITY.>= Grade heart failure or Grade or decreased ejection fractionPermanently discontinue EXKIVITY.Diarrhea [see Warnings and Precautions (5.4)] Intolerable or recurrent Grade or Grade 3Withhold EXKIVITY until <= Grade 1.Resume EXKIVITY at the same dose or the next lower dose.Grade 4First OccurrenceWithhold EXKIVITY until <= Grade 1.Resume EXKIVITY at the next lower dose.RecurrencePermanently discontinue EXKIVITYOther Adverse Reactions [see Adverse Reactions (6.1)] Intolerable or recurrent Grade or Grade 3Withhold EXKIVITY until <= Grade 1.Resume EXKIVITY at the same dose or the next lower dose.Grade 4First OccurrenceWithhold EXKIVITY until <= Grade 1.Resume EXKIVITY at the next lower dose if recovery occurs within weeks.Permanently discontinue EXKIVITY if recovery does not occur within weeks.RecurrencePermanently discontinue EXKIVITY.. Withhold EXKIVITY until <= Grade or baseline.. Upon recovery, resume EXKIVITY at the same dose.. Withhold EXKIVITY until <= Grade or baseline.. Upon recovery, resume EXKIVITY at the next lower dose or permanently discontinue EXKIVITY.. Withhold EXKIVITY until <= Grade or baseline.. Upon recovery, resume EXKIVITY at the next lower dose or permanently discontinue EXKIVITY.. Permanently discontinue EXKIVITY.. Permanently discontinue EXKIVITY.. Withhold EXKVITY if ILD/pneumonitis is suspected.. Permanently discontinue EXKIVITY if ILD/pneumonitis is confirmed.. Withhold EXKIVITY until <= Grade or baseline.. If recovered to baseline within weeks, resume EXKIVITY at the same dose or the next lower dose.. If not recovered to baseline within weeks, permanently discontinue EXKIVITY.. Permanently discontinue EXKIVITY.. Withhold EXKIVITY until <= Grade 1.. Resume EXKIVITY at the same dose or the next lower dose.. Withhold EXKIVITY until <= Grade 1.. Resume EXKIVITY at the next lower dose.. Permanently discontinue EXKIVITY. Withhold EXKIVITY until <= Grade 1.. Resume EXKIVITY at the same dose or the next lower dose.. Withhold EXKIVITY until <= Grade 1.. Resume EXKIVITY at the next lower dose if recovery occurs within weeks.. Permanently discontinue EXKIVITY if recovery does not occur within weeks.. Permanently discontinue EXKIVITY.. 2.4Dosage Modifications for Moderate CYP3A Inhibitors. Avoid concomitant use of moderate CYP3A inhibitors with EXKIVITY. If concomitant use of moderate CYP3A inhibitor cannot be avoided, reduce the EXKIVITY dose by approximately 50% (i.e., from 160 to 80 mg, 120 to 40 mg, or 80 to 40 mg) and monitor the QTc interval more frequently. After the moderate CYP3A inhibitor has been discontinued for to elimination half-lives, resume EXKIVITY at the dose taken prior to initiating the moderate CYP3A inhibitor [see Drug Interactions (7.1)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. CYP3A Inhibitors: Avoid concomitant use of EXKIVITY with strong or moderate CYP3A inhibitors. If concomitant use of moderate CYP3A inhibitor is unavoidable, reduce the dose of EXKIVITY. (2.4, 7.1)CYP3A Inducers: Avoid concomitant use of EXKIVITY with strong or moderate CYP3A inducers. (7.1). CYP3A Inhibitors: Avoid concomitant use of EXKIVITY with strong or moderate CYP3A inhibitors. If concomitant use of moderate CYP3A inhibitor is unavoidable, reduce the dose of EXKIVITY. (2.4, 7.1). CYP3A Inducers: Avoid concomitant use of EXKIVITY with strong or moderate CYP3A inducers. (7.1). 7.1Effect of Other Drugs on EXKIVITY. Strong or Moderate CYP3A InhibitorsClinical ImpactCoadministration of EXKIVITY with strong or moderate CYP3A inhibitors increased mobocertinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions, including QTc interval prolongation.Prevention or ManagementAvoid 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 [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].Strong or Moderate CYP3A InducersClinical ImpactCoadministration of EXKIVITY with strong or moderate CYP3A inducers decreased mobocertinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce EXKIVITY anti-tumor activity.Prevention or ManagementAvoid concomitant use of strong or moderate CYP3A inducers with EXKIVITY.. Coadministration of EXKIVITY with strong or moderate CYP3A inhibitors increased mobocertinib plasma concentrations [see Clinical Pharmacology (12.3)], 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 [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].. Coadministration of EXKIVITY with strong or moderate CYP3A inducers decreased mobocertinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce EXKIVITY anti-tumor activity.. Avoid concomitant use of strong or moderate CYP3A inducers with EXKIVITY.. 7.2Effect of EXKIVITY on Other Drugs. CYP3A SubstratesClinical ImpactCoadministration of EXKIVITY with CYP3A substrates may decrease plasma concentrations of CYP3A substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates.Prevention or ManagementAvoid concomitant use of hormonal contraceptives with EXKIVITY [see Warnings and Precautions (5.5), Use in Specific Populations (8.3)].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.. Coadministration of EXKIVITY with CYP3A substrates may decrease plasma concentrations of CYP3A substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates.. Avoid concomitant use of hormonal contraceptives with EXKIVITY [see Warnings and Precautions (5.5), Use in Specific Populations (8.3)].. 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.. 7.3Drugs that Prolong the QTc Interval. Drugs that Prolong the QTc IntervalClinical ImpactEXKIVITY can cause QTc interval prolongation [see Warnings and Precautions (5.1), Clinical Pharmacology (12.2)]. Coadministration of EXKIVITY with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.1), Clinical Pharmacology (12.2)].Prevention or ManagementAvoid 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 [see Warnings and Precautions (5.1)].. EXKIVITY can cause QTc interval prolongation [see Warnings and Precautions (5.1), Clinical Pharmacology (12.2)]. Coadministration of EXKIVITY with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.1), Clinical Pharmacology (12.2)].. 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 [see Warnings and Precautions (5.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. QTc Interval Prolongation and Torsades de PointesInform patients of the risk of QTc prolongation. Symptoms that may be indicative of significant QTc prolongation include dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and to inform their healthcare provider about the use of any heart medications [see Warnings and Precautions (5.1)].. Interstitial Lung Disease (ILD)/PneumonitisInform patients of the risks of severe or fatal ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms such as cough, shortness of breath or chest pain [see Warnings and Precautions (5.2)].. Cardiac ToxicityInform patients of the risk of heart failure. Advise patients to contact their healthcare provider immediately if they experience any signs or symptoms of heart failure such as palpitations, shortness of breath, chest pain, and syncope [see Warnings and Precautions (5.3)].. DiarrheaInform patients that EXKIVITY may cause diarrhea, which may be severe in some cases and should be treated promptly. Advise patients to have antidiarrheal medicine readily available and promptly start antidiarrheal treatment (e.g., loperamide), increase oral fluids and electrolyte intake, and contact their healthcare provider if diarrhea occurs [see Warnings and Precautions (5.4)].. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective non-hormonal contraception during treatment with EXKIVITY and for month after the last dose [see Use in Specific Populations (8.3)].Advise males with female partners of reproductive potential to use effective contraception during treatment with EXKIVITY and for week after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment with EXKIVITY and for week after the last dose [see Use in Specific Populations (8.2)].. InfertilityAdvise females and males of reproductive potential that EXKIVITY may impair fertility [see Use in Specific Populations (8.3)].. Drug InteractionsAdvise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)]. Inform patients to avoid grapefruit or grapefruit juice while taking EXKIVITY.. Missed DoseAdvise patients that if dose of EXKIVITY is missed by hours or if vomiting occurs, resume treatment as prescribed the next day [see Dosage and Administration (2.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After single- and multiple-dose administration, combined molar Cmax and AUC0-24h of mobocertinib and its active metabolites, AP32960 and AP32914, was dose-proportional over the dose range of to 180 mg once daily (0.03 to 1.1 times the approved recommended dosage). No clinically meaningful accumulation was observed after administration of EXKIVITY 160 mg once daily based on the AUC ratio of mobocertinib.. AbsorptionThe median (min, max) time to peak concentration (Tmax) of mobocertinib is hours (1, hours). The mean (%CV) absolute bioavailability is 37% (50%).. Effect of FoodNo clinically meaningful differences in the combined molar AUC and Cmax of mobocertinib, AP32960, and AP32914 were observed following administration of high-fat meal (approximately 900 to 1000 calories, with 150 calories from protein, 250 calories from carbohydrate and 500 to 600 calories from fat) or low fat-meal (approximately 336 calories, with 37 calories from protein, 253 calories from carbohydrate, and 46 calories from fat) compared to administration after an overnight fast.. DistributionMobocertinib was bound to human plasma proteins in concentration independent manner in vitro from 0.5 to 5.0 uM. The mean (standard deviation) bound fraction was 99.3% (0.11%) for mobocertinib, 99.5% (0.16%) for AP32960 and 98.6% (0.36%) for AP32914 in vitro.The blood-to-plasma ratio was 0.76 for mobocertinib, 1.2 for AP32960 and 0.71 for AP32914.The mean (%CV) apparent volume of distribution (Vss/F) of mobocertinib was 3,509 (38%) at steady-state.. EliminationThe mean (%CV) plasma elimination half-life of mobocertinib was 18 hours (21%) at steady-state. The mean apparent oral clearance (CL/F) (%CV) of mobocertinib was 138 L/hr (47%) at steady-state.The mean (%CV) plasma elimination half-life of AP32960 was 24 hours (20%) at steady-state. The mean apparent oral clearance (CL/F) (%CV) of AP32960 was 149 L/hr (36%) at steady-state.The mean (%CV) plasma elimination half-life of AP32914 was 18 hours (21%) at steady-state. The mean apparent oral clearance (CL/F) (%CV) of AP32914 was 159 L/hr (52%) at steady-state.. MetabolismMobocertinib is primarily metabolized by CYP3A. The two active metabolites, AP32960 and AP32914, are equipotent to mobocertinib and account for 36% and 4% of the combined molar AUC, respectively.. ExcretionFollowing administration of single 160 mg oral dose of radiolabeled mobocertinib, approximately 76% of the dose was recovered in feces (approximately 6% as unchanged mobocertinib) and approximately 4% was recovered in urine (approximately 1% as unchanged mobocertinib). The percentage of the administered dose recovered in feces and urine for AP32960 was approximately 12% and 1%, respectively. The metabolite AP32914 was below the detection limit in urine and feces.. Specific PopulationsNo clinically meaningful differences in the pharmacokinetics of mobocertinib were observed based on age (18 to 86 years), race (White, Black, Asian), sex, body weight (37.3 to 132 kg), mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2 by MDRD), or mild (total bilirubin <= ULN and AST ULN or total bilirubin >1 to 1.5 times ULN and any AST)-to-moderate (total bilirubin >=1.5 to times ULN and any AST) hepatic impairment. The effect of severe (eGFR <30 mL/min/1.73 m2) renal impairment and severe (total bilirubin >3 times ULN and any AST) hepatic impairment on mobocertinib pharmacokinetics is unknown.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. Effect of CYP3A Inhibitors on Mobocertinib: Coadministration of EXKIVITY with multiple doses of itraconazole or ketoconazole (strong CYP3A inhibitors) is predicted to increase the steady-state combined molar AUC of mobocertinib and its active metabolites by 374 to 419%.Coadministration of EXKIVITY with multiple doses of moderate CYP3A inhibitor is predicted to increase the steady-state combined molar AUC of mobocertinib and its active metabolites by approximately 100-200%.. Effect of CYP3A Inducers on Mobocertinib: Coadministration of EXKIVITY with multiple doses of rifampin (a strong CYP3A inducer) is predicted to decrease the steady-state combined molar AUC of mobocertinib and its active metabolites by 92%.Coadministration of EXKIVITY with multiple doses of efavirenz (a moderate CYP3A inducer) is predicted to decrease the steady-state combined molar AUC of mobocertinib and its active metabolites by 58%.. Effect of Mobocertinib on CYP3A Substrates: Coadministration of EXKIVITY 160 mg once daily with oral or intravenous midazolam (a CYP3A substrate) decreased the AUC of midazolam by 32% and 16%, respectively.. Effect of Mobocertinib on P-gp Substrates: No clinically meaningful differences in the pharmacokinetics of digoxin or dabigatran etexilate (P-gp substrates) are predicted when coadministered with multiple doses of EXKIVITY.. Effect of Mobocertinib on BCRP Substrates: The clinical significance of changes in the pharmacokinetics of sulfasalazine (a BCRP substrate) when coadministered with multiple doses of EXKIVITY is unknown.. In Vitro Studies. CYP Enzymes: Mobocertinib, AP32960, and AP32914 do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations.. Transporter Systems: Mobocertinib is an inhibitor of P-gp and BCRP. At clinically relevant concentrations, mobocertinib does not inhibit BSEP, MATE1, MATE2-K, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2.Mobocertinib is substrate of P-gp. Mobocertinib is not substrate of BCRP, OATP1B1, and OATP1B3.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: September 2021PATIENT INFORMATIONEXKIVITY(TM) (ex ki vi tee)(mobocertinib)capsulesWhat is the most important information should know about EXKIVITYEXKIVITY may cause serious side effects, including:Changes in the electrical activity of your heart called QTc prolongation and Torsades de Pointes. QTc prolongation can cause irregular heartbeats that can be life-threatening and may lead to death. Your healthcare provider will check the electrical activity of your heart with test called an electrocardiogram (ECG) and do blood tests to check your electrolytes before starting and during treatment with EXKIVITY. Tell your healthcare provider right away if you feel dizzy, lightheaded, faint or have an irregular heartbeat.See What are the possible side effects of EXKIVITY for more information about side effects.What is EXKIVITYEXKIVITY is prescription medicine used to treat adults with non-small cell lung cancer (NSCLC):that has spread to other parts of the body (metastatic) and cannot be removed by surgery, and has certain abnormal epidermal growth factor receptor (EGFR) gene, and whose disease has worsened while on or after chemotherapy that contains platinumYour healthcare provider will perform test to make sure that EXKIVITY is right for you.It is not known if EXKIVITY is safe and effective in children.Before taking EXKIVITY, tell your healthcare provider about all of your medical conditions, including if you:have heart problems, including condition called long QTc syndromehave problems with your electrolytes, such as sodium, potassium, calcium or magnesiumhave lung or breathing problems other than lung cancerare pregnant or plan to become pregnant. EXKIVITY can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with EXKIVITY.You should use an effective form of non-hormonal birth control during treatment and for month after your last dose of EXKIVITY.Birth control pills (oral contraceptives) and other hormonal forms of birth control may not work as well during treatment with EXKIVITY.Talk to your healthcare provider about birth control methods that might be right for you during this time.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with EXKIVITY. Males who have female partners who are able to become pregnant: You should use effective birth control during treatment and for week after your last dose of EXKIVITY. are breastfeeding or plan to breastfeed. It is not known if EXKIVITY passes into your breast milk. Do not breastfeed during treatment and for week after your last dose of EXKIVITY.Tell your healthcare provider about all the medicines you take, including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements. Tell your healthcare provider if you take medicines for heart problems.EXKIVITY and other medicines may affect each other causing serious side effects.How should take EXKIVITYTake EXKIVITY exactly as your healthcare provider tells you to take it.Take your prescribed dose of EXKIVITY time each day.Take EXKIVITY with or without food.Swallow EXKIVITY capsules whole. Do not open, chew, or dissolve the contents of the capsules.Do not change your dose or stop taking EXKIVITY unless your healthcare provider tells you to.Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with EXKIVITY if you develop certain side effects.If you miss dose of EXKIVITY, and it has been more than hours, skip the dose and take your next dose at your regularly scheduled time the next day.If you vomit dose of EXKIVITY, do not take an extra dose. Take your next dose at your regularly scheduled time the next day.What should avoid while taking EXKIVITYAvoid eating grapefruit or drinking grapefruit juice during treatment with EXKIVITY. Grapefruit may increase the amount of EXKIVITY in your blood.What are the possible side effects of EXKIVITYEXKIVITY may cause serious side effects, including:See What is the most important information should know about EXKIVITY.Lung problems. EXKIVITY may cause severe lung problems that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you develop any new or worsening symptoms, including trouble breathing or shortness of breath, cough, chest pain, or fever.Heart problems, including heart failure. EXKIVITY may cause heart problems that may lead to death. Your healthcare provider should check your heart function before you start and during treatment with EXKIVITY. Tell your healthcare provider right away if you have any signs or symptoms of heart problem, including feeling like your heart is pounding or racing, shortness of breath, chest pain, swelling of your ankles and feet, or feeling faint.Diarrhea. Diarrhea is common during treatment with EXKIVITY, and may sometimes be severe. Diarrhea can cause you to lose too much body fluid (dehydration) and kidney problems. Your healthcare provider may tell you to start drinking more fluids and electrolytes to replace body salts or start taking your antidiarrheal medicines. Tell your healthcare provider right away if you have any loose stools or have stools more often than is normal for you.The most common side effects of EXKIVITY include:diarrhearashnauseamouth soresvomiting decrease appetiteinfection of skin around nailstirednessdry skinmuscle or bone painEXKIVITY may affect fertility in females and males, which may affect your ability to have child. Talk to your healthcare provider if this is concern for you.These are not all of the possible side effects of EXKIVITY.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store EXKIVITYStore EXKIVITY at room temperature between 68F to 77F (20C to 25C).Keep EXKIVITY and all medicines out of the reach of children.General information about the safe and effective use of EXKIVITY.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use EXKIVITY for condition for which it was not prescribed. Do not give EXKIVITY to other people, even if they have the same symptoms you have. It may harm them.You can ask your healthcare provider or pharmacist for information about EXKIVITY that is written for health professionals.What are the ingredients in EXKIVITYActive ingredient: mobocertinib Inactive ingredients: None Capsule shells: gelatin and titanium dioxide. The printing ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water.Distributed by: Takeda Pharmaceuticals America, Inc., Lexington, MA 02421.EXKIVITY(TM) is trademark of Takeda Pharmaceuticals International AG. TAKEDA(R) and the TAKEDA Logo(R) are registered trademarks of Takeda Pharmaceutical Company Limited.(C)2021 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved.For more information, go to www.EXKIVITY.com or call 1-844-217-6468. EXK366 R1. Changes in the electrical activity of your heart called QTc prolongation and Torsades de Pointes. QTc prolongation can cause irregular heartbeats that can be life-threatening and may lead to death. Your healthcare provider will check the electrical activity of your heart with test called an electrocardiogram (ECG) and do blood tests to check your electrolytes before starting and during treatment with EXKIVITY. Tell your healthcare provider right away if you feel dizzy, lightheaded, faint or have an irregular heartbeat.. that has spread to other parts of the body (metastatic) and cannot be removed by surgery, and has certain abnormal epidermal growth factor receptor (EGFR) gene, and whose disease has worsened while on or after chemotherapy that contains platinum. have heart problems, including condition called long QTc syndrome. have problems with your electrolytes, such as sodium, potassium, calcium or magnesium. have lung or breathing problems other than lung cancer. are pregnant or plan to become pregnant. EXKIVITY can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with EXKIVITY.You should use an effective form of non-hormonal birth control during treatment and for month after your last dose of EXKIVITY.Birth control pills (oral contraceptives) and other hormonal forms of birth control may not work as well during treatment with EXKIVITY.Talk to your healthcare provider about birth control methods that might be right for you during this time.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with EXKIVITY. Males who have female partners who are able to become pregnant: You should use effective birth control during treatment and for week after your last dose of EXKIVITY. Your healthcare provider should do pregnancy test before you start treatment with EXKIVITY.. You should use an effective form of non-hormonal birth control during treatment and for month after your last dose of EXKIVITY.. Birth control pills (oral contraceptives) and other hormonal forms of birth control may not work as well during treatment with EXKIVITY.. Talk to your healthcare provider about birth control methods that might be right for you during this time.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with EXKIVITY.. You should use effective birth control during treatment and for week after your last dose of EXKIVITY.. are breastfeeding or plan to breastfeed. It is not known if EXKIVITY passes into your breast milk. Do not breastfeed during treatment and for week after your last dose of EXKIVITY.. Take EXKIVITY exactly as your healthcare provider tells you to take it.. Take your prescribed dose of EXKIVITY time each day.. Take EXKIVITY with or without food.. Swallow EXKIVITY capsules whole. Do not open, chew, or dissolve the contents of the capsules.. Do not change your dose or stop taking EXKIVITY unless your healthcare provider tells you to.. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with EXKIVITY if you develop certain side effects.. If you miss dose of EXKIVITY, and it has been more than hours, skip the dose and take your next dose at your regularly scheduled time the next day.. If you vomit dose of EXKIVITY, do not take an extra dose. Take your next dose at your regularly scheduled time the next day.. Avoid eating grapefruit or drinking grapefruit juice during treatment with EXKIVITY. Grapefruit may increase the amount of EXKIVITY in your blood.. Lung problems. EXKIVITY may cause severe lung problems that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you develop any new or worsening symptoms, including trouble breathing or shortness of breath, cough, chest pain, or fever.. Heart problems, including heart failure. EXKIVITY may cause heart problems that may lead to death. Your healthcare provider should check your heart function before you start and during treatment with EXKIVITY. Tell your healthcare provider right away if you have any signs or symptoms of heart problem, including feeling like your heart is pounding or racing, shortness of breath, chest pain, swelling of your ankles and feet, or feeling faint.. Diarrhea. Diarrhea is common during treatment with EXKIVITY, and may sometimes be severe. Diarrhea can cause you to lose too much body fluid (dehydration) and kidney problems. Your healthcare provider may tell you to start drinking more fluids and electrolytes to replace body salts or start taking your antidiarrheal medicines. Tell your healthcare provider right away if you have any loose stools or have stools more often than is normal for you.. diarrhea. rash. nausea. mouth sores. vomiting decrease appetite. infection of skin around nails. tiredness. dry skin. muscle or bone pain. Store EXKIVITY at room temperature between 68F to 77F (20C to 25C).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], EXKIVITY can cause fetal harm when administered to pregnant woman. There are no available data on EXKIVITY use in pregnant women. Oral administration of mobocertinib to pregnant rats during the period of organogenesis resulted in embryolethality (embryo-fetal death) and maternal toxicity at plasma exposures approximately 1.7 times the human exposure based on AUC at the 160 mg once daily clinical dose (see Data ). Advise pregnant women of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn an embryo-fetal development study, once daily oral administration of mobocertinib to pregnant rats during the period of organogenesis resulted in maternal toxicity (reduced body weight gain and food consumption) at 10 mg/kg (approximately 1.7 times the human exposure based on AUC at the 160 mg once daily clinical dose). Adverse effects on embryo-fetal development at this dose level included embryolethality due to post-implantation loss (embryo-fetal death) and effects on fetal growth (decreased fetal weights). There was no clear evidence of fetal malformations at the high dose level (10 mg/kg).. 8.2 Lactation. Risk SummaryThere 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 week after the last dose.. 8.3 Females and Males of Reproductive Potential. EXKIVITY can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating EXKIVITY.. Contraception. FemalesAdvise females of reproductive potential to use effective non-hormonal contraception during treatment with EXKIVITY and for month after the last dose. EXKIVITY may render hormonal contraceptives ineffective [see Drug Interactions (7.2)].. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with EXKIVITY and for week after the last dose.. InfertilityBased on animal studies, EXKIVITY may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of EXKIVITY in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 114 patients [see Clinical Studies (14)] 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 higher incidence of Grade and 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.. 8.6 Renal Impairment. No dosage adjustment of EXKIVITY is recommended for patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 89 mL/min/1.73 m2 by Modification of Diet in Renal Disease [MDRD] equation). The recommended dosage of EXKIVITY has not been established for patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. No dosage adjustment of EXKIVITY is recommended for patients with mild (total bilirubin <= upper limit of normal [ULN] and aspartate aminotransferase [AST] ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate hepatic impairment (total bilirubin >=1.5 to times ULN and any AST). The recommended dosage of EXKIVITY has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Interstitial Lung Disease (ILD)/Pneumonitis: 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. (2.3, 5.2)Cardiac Toxicity: Monitor cardiac function, including left ventricular ejection fraction, at baseline and during treatment. Withhold, resume at reduced dose or permanently discontinue based on severity. (2.3, 5.3)Diarrhea: Diarrhea may lead to dehydration or electrolyte imbalance, with or without renal impairment. Monitor electrolytes and advise patients to start an antidiarrheal agent at first episode of diarrhea and to increase fluid and electrolyte intake. Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity. (2.3, 5.4)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective non-hormonal contraception. (5.5, 8.1, 8.3). Interstitial Lung Disease (ILD)/Pneumonitis: 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. (2.3, 5.2). Cardiac Toxicity: Monitor cardiac function, including left ventricular ejection fraction, at baseline and during treatment. Withhold, resume at reduced dose or permanently discontinue based on severity. (2.3, 5.3). Diarrhea: Diarrhea may lead to dehydration or electrolyte imbalance, with or without renal impairment. Monitor electrolytes and advise patients to start an antidiarrheal agent at first episode of diarrhea and to increase fluid and electrolyte intake. Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity. (2.3, 5.4). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective non-hormonal contraception. (5.5, 8.1, 8.3). 5.1QTc 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) [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)], 1.2% of patients had QTc interval >500 msec and 11% of patients had change-from-baseline QTc interval >60 msec. Grade Torsades de Pointes occurred in 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 [see Drug Interactions (7.1)], which may further prolong the QTc [see Drug Interactions (7.3)].Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of the QTc prolongation [see Dosage and Administration (2.3)]. 5.2Interstitial Lung Disease (ILD)/Pneumonitis. EXKIVITY can cause ILD/pneumonitis, which can be fatal. In the pooled EXKIVITY safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 4.3% of patients including 0.8% Grade 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 [see Dosage and Administration (2.3)].. 5.3Cardiac 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 [see Adverse Reactions (6.1)], heart failure occurred in 2.7% of patients including 1.2% Grade reactions, 0.4% Grade reactions, and one (0.4%) fatal case of heart failure.EXKIVITY can cause QTc prolongation resulting in Torsades de Pointes [see Warnings and Precautions (5.1)]. 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 [see Dosage and Administration (2.3)].. 5.4Diarrhea. EXKIVITY can cause diarrhea, which can be severe. In the pooled EXKIVITY safety population [see Adverse Reactions (6.1)], diarrhea occurred in 93% of patients, including 20% Grade and 0.4% Grade 4. The median time to first onset of diarrhea was 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 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 [see Dosage and Administration (2.3)].. 5.5Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, EXKIVITY can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with EXKIVITY [see Drug Interactions (7.2)] and for month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with EXKIVITY and for week after the last dose of EXKIVITY [see Use in Specific Populations (8.1, 8.3)].