Exkivity Prescribing Information
- 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 (2.4)].
EXKIVITY is 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 [see Dosage and Administration (2.2)], 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 [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Recommended Evaluation and Testing Before Initiating EXKIVITY
Before initiating EXKIVITY, evaluate QTc and electrolytes and correct abnormalities in sodium, potassium, calcium, and magnesium [see Warnings and Precautions (5.1)].
Patient 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.
Recommended 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 a dose is missed by more than 6 hours, skip the dose and take the next dose the following day at its regularly scheduled time.
If a dose is vomited, do not take an additional dose. Take the next dose as prescribed the following day.
Dosage Modifications for Adverse Reactions
EXKIVITY dose reduction levels for adverse reactions are summarized in Table 1.
| Dose Reductions | Dose Level |
|---|---|
| First dose reduction | 120 mg once daily |
| Second dose reduction | 80 mg once daily |
Recommended dosage modifications of EXKIVITY for adverse reactions are provided in Table 2.
| Adverse Reaction | Severity * | EXKIVITY Dosage Modification |
|---|---|---|
| ULN = upper limit of normal | ||
| ||
| QTc Interval Prolongation and Torsades de Pointes [see Warnings and Precautions (5.1)] | Grade 2 (QTc interval 481-500 msec) | First Occurrence
|
| Grade 3 (QTc interval ≥501 msec or QTc interval increase of >60 msec from baseline) | First Occurrence
| |
| Grade 4 (Torsades de Pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia) |
| |
| Interstitial Lung Disease (ILD)/pneumonitis [see Warnings and Precautions (5.2)] | Any grade |
|
| Decreased Ejection Fraction or Heart Failure [see Warnings and Precautions (5.3)] | Grade 2 decreased ejection fraction |
|
| ≥ Grade 2 heart failure or Grade 3 or 4 decreased ejection fraction |
| |
| Diarrhea [see Warnings and Precautions (5.4)] | Intolerable or recurrent Grade 2 or Grade 3 |
|
| Grade 4 | First Occurrence
| |
| Increased Amylase or Lipase [see Adverse Reactions (6.1)] | Grade 3 without signs or symptoms |
|
| Grade 3 with signs or symptoms |
| |
| Grade 4 | First Occurrence
| |
| Other Adverse Reactions [see Adverse Reactions (6.1)] | Intolerable or recurrent Grade 2 or Grade 3 |
|
| Grade 4 | First Occurrence
| |
Dosage Modifications for Moderate CYP3A Inhibitors
Avoid concomitant use of moderate CYP3A inhibitors with EXKIVITY. If concomitant use of a 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 3 to 5 elimination half-lives, resume EXKIVITY at the dose taken prior to initiating the moderate CYP3A inhibitor [see Drug Interactions (7.1)].
2.6 Dosage Modifications for Patients with Severe Renal Impairment
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 for patients with severe renal impairment [see Use in Specific Populations (8.6)].
Capsules: 40 mg, white, size 2, imprinted with "MB788" on the cap and "40mg" on the body in black ink.
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], 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 (see Data). 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.
Data
Animal Data
In 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).
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.
Females and Males of Reproductive Potential
EXKIVITY can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
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 [see Drug Interactions (7.2)].
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 [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of EXKIVITY in pediatric patients have not been established.
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 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.
Renal Impairment
Mobocertinib plasma concentrations are higher in patients with severe renal impairment [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions. Reduce the recommended dosage of EXKIVITY for patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 by Modification of Diet in Renal Disease [MDRD] equation) [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)]. No dosage adjustment of EXKIVITY is recommended for patients with mild-to-moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2 by MDRD equation).
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)-to-severe (total bilirubin >3 times ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)].
None.