DRUG INTERACTIONS- summary

­ • CYP3A Inhibitors: Avoid concomitant use of EXKIVITY with strong or moderate CYP3A inhibitors. If concomitant use of a moderate CYP3A inhibitor is unavoidable, reduce the dose of EXKIVITY.

 • CYP3A Inducers: Avoid concomitant use of EXKIVITY with strong or moderate CYP3A inducers.

U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 38

Name of the Drug-    EXKIVITY

Active Ingredient -   Mobocertinib

Pharmacological Classification- To treat advances on metastatic non-small lung                                                              cancer with certain epidermal growth factor                                                                    receptor Exonzo insertion mutation                                                                                                                                                                                                                                                                                                                                                                             

 Date of Approval-          9/15/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                               EXKIVITY safely and effectively.

See full prescribing information for EXKIVITY. EXKIVITY™ (mobocertinib) capsules, for oral use

Initial U.S. Approval: 2021

WARNING: QTc PROLONGATION AND TORSADES DE POINTES                             See 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

 • 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

 • Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of QTc prolongation

INDICATIONS AND USAGE-

­ EXKIVITY is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

DOSAGE AND ADMINISTRATION-

­ • Recommended Dosage: 160 mg orally once daily, with or without food.

DOSAGE FORMS AND STRENGTHS-

­ Capsules: 40 mg. 

CONTRAINDICATIONS-

­ None.

ADVERSE REACTIONS-

­ 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 3 or 4 laboratory abnormalities were decreased lymphocytes, increased amylase, increased lipase, decreased potassium, decreased hemoglobin, increased creatinine, and decreased magnesium.

CONTRAINDICATIONS-                                                                                               ­ None.

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.

 • 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.

 • 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.

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception.

DOSAGE AND ADMINISTRATION-

­ • Recommended Dosage: 160 mg orally once daily, with or without food.

DOSAGE FORMS AND STRENGTHS-

­ Capsules: 40 mg. 

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Patient Information).

QTc Interval Prolongation and Torsades de Pointes-                                            Inform 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

Interstitial Lung Disease (ILD)/Pneumonitis -                                                                 Inform 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 .

Cardiac Toxicity-                                                                                                        Inform 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

Diarrhea -                                                                                                                           Inform 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

Embryo-Fetal Toxicity-                                                                                                      Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy.

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 .

Lactation-                                                                                                                       Advise women not to breastfeed during treatment with EXKIVITY and for 1 week after the last dose 

Infertility-                                                                                                                          Advise females and males of reproductive potential that EXKIVITY may impair fertility 

Drug Interactions-                                                                                                     Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products 

Inform patients to avoid grapefruit or grapefruit juice while taking EXKIVITY.

Missed Dose -                                                                                                               Advise patients that if a dose of EXKIVITY is missed by 6 hours or if vomiting occurs, resume treatment as prescribed the next day 

Distributed by: Takeda Pharmaceuticals America, Inc. Lexington, MA 02421 EXKIVITY™ is a trademark of Takeda Pharmaceuticals International AG. TAKEDA® and the TAKEDA Logo® are registered trademarks of Takeda Pharmaceutical Company Limited. ©2021 Takeda Pharmaceuticals U.S.A., Inc. All right reserved. EXK366 R1

CLINICAL PHARMACOLOGY -

1. Mechanism of Action-                                                                                    Mobocertinib is a 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).

2 Pharmacodynamics-                                                                                                 Mobocertinib exposure-response relationships and the time course of pharmacodynamic response are unknown.

Cardiac Electrophysiology- The 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.

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 5 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.

Absorption-                                                                                                                     The median (min, max) time to peak concentration (Tmax) of mobocertinib is 4 hours (1, 8 hours). The mean (%CV) absolute bioavailability is 37% (50%).

Effect of Food-                                                                                                                 No clinically meaningful differences in the combined molar AUC and Cmax of mobocertinib, AP32960, and AP32914 were observed following administration of a 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 a 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. 

Distribution-                                                                                                              Mobocertinib was bound to human plasma proteins in a concentration independent manner in vitro from 0.5 to 5.0 µM. 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 L (38%) at steady-state.

Elimination-                                                                                                                    The 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.

Metabolism-                                                                                                                Mobocertinib 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.

Excretion-                                                                                                                   Following administration of a 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 Populations-                                                                                                           No 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 3 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 a 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 a substrate of P-gp. Mobocertinib is not a substrate of BCRP, OATP1B1, and OATP1B3.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                          Based 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.

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 

Advise pregnant women of the potential risk to a 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.

2. Lactation Risk Summary -                                                                                       There 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.

3. Females and Males of Reproductive Potential-                                                        EXKIVITY can cause fetal harm when administered to pregnant women

Pregnancy Testing- Verify pregnancy status in females of reproductive potential prior to initiating EXKIVITY.

Contraception -                                                                                                            Females -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

Males- Advise males with female partners of reproductive potential to use effective contraception during treatment with EXKIVITY and for 1 week after the last dose.

Infertility- Based on animal studies, EXKIVITY may impair fertility in males and females of reproductive potential 

4. Pediatric Use-                                                                                                            The safety and effectiveness of EXKIVITY in pediatric patients have not been established.

5. Geriatric Use-                                                                                                               Of 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 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.

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)

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 3 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)