EXKIVITY™ (mobocertinib) capsules

EXKIVITY™ (mobocertinib) capsules

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EXKIVITY™ (mobocertinib) capsules

Mobocertinib is a kinase inhibitor. The chemical name for mobocertinib succinate is propan-2-yl 2-[5-(acryloylamino)-4-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxyanilino]-4-(1-methyl-1H-indol-3- yl)pyrimidine-5-carboxylate succinate. The molecular formula is C32H39N7O4 + C4H6O4 (succinate salt) which corresponds to a molecular weight of 703.8 g/mol. Mobocertinib has no chiral centers.

Mobocertinib succinate has a solubility of 152 mg/mL in pH 1.0 and >17.6 mg/mL in pH 6.8 solutions at 37°C.

EXKIVITY capsule for oral administration contains 40 mg mobocertinib equivalent to 48.06 mg mobocertinib succinate, with no inactive ingredients. The capsule shells contain 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.

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)

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).

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.

Dosage and administration

Patient Selection: Select patients with locally advanced or metastatic NSCLC for treatment with EXKIVITY based on the presence of EGFR exon 20 insertion mutations

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, 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.

Contraindications

None

Warnings and precautions

QTc Prolongation and Torsades de Pointes: EXKIVITY can cause life-threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal.

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

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

Interstitial Lung Disease (ILD)/Pneumonitis: EXKIVITY can cause ILD/pneumonitis, which can be fatal. 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: EXKIVITY can cause cardiac toxicity (including decreased ejection fraction, cardiomyopathy, and congestive heart failure) resulting in heart failure which can be fatal. 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

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

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

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

Adverse 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.

Drug interactions

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

Use in specific population

Pregnancy: 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.

Lactation: 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.

Contraception: 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

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: 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)

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)

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