ast dose.
Males
Advise males with a female partner of reproductive potential to use effective contraception during treatmentwith XPOVIO and for 1 week after the last dose.
Infertility
Females and Males
Based on findings in animals, XPOVIO may impair fertility in females and males of reproductive potential [seeNonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of XPOVIO have not been established in pediatric patients.
8.5 Geriatric Use
Of the 202 patients with RRMM who received XPOVIO, 49% were 65 years of age and over, while 11% were75 years of age and over. No overall difference in effectiveness was observed in patients over 65 years of age,including patients over 75 years of age, when compared with younger patients. When comparing patients
75 years of age and older to younger patients, older patients had a higher incidence of discontinuation due toan adverse reaction (44% vs 27%), higher incidence of serious adverse reactions (70% vs 58%), and higherincidence of fatal adverse reactions (17% vs 9%).
11 DESCRIPTION
XPOVIO (selinexor) is an orally available nuclear export inhibitor.
Selinexor is (2Z)‐3‐{3‐[3,5‐bis(trifluoromethyl)phenyl]‐1H‐1,2,4‐triazol‐1‐yl}‐N'‐(pyrazin‐2‐yl)prop‐2‐enehydrazide. It is a white to off‐white powder and has the molecular formula C17H11F6N7O and a molecularmass of 443.31 g/mol.
The molecular structure is shown below:
Each XPOVIO (selinexor) tablet contains 20 mg of selinexor as the active ingredient.
XPOVIO tablets are blue, round, bi‐convex, film‐coated tablets with “K20” debossed on one side and nothingon the other side. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, magnesiumstearate, microcrystalline cellulose, Opadry 200 clear, Opadry II blue, povidone K30, and sodium lauryl sulfate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
In nonclinical studies, selinexor reversibly inhibits nuclear export of tumor suppressor proteins (TSPs), growthregulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). XPO1 inhibition by selinexor leadsto accumulation of TSPs in the nucleus, reductions in several oncoproteins, such as c‐myc and cyclin D1, cell
cycle arrest, and apoptosis of cancer cells. Selinexor demonstrated pro‐apoptotic activity in vitro in multiplemyeloma cell lines and patient tumor samples, and in murine xenograft models.
12.2 Pharmacodynamics
XPOVIO exposure‐response relationships and the time course of pharmacodynamic responses are unknown.
Cardiac Electrophysiology
The effect of multiple doses of XPOVIO, up to 175 mg (2.2 times the approved recommended dose) twiceweekly, on the QTc interval was eva luated in patients with heavily pretreated hematologic malignancies.
XPOVIO had no large effect (i.e. no greater than 20 ms) on QTc interval at the therapeutic dose level.
12.3 Pharmacokinetics
Following a single‐dose administration of XPOVIO 80 mg, the mean (standard deviation) peak plasmaconcentration (Cmax) was 680 (124) ng/mL and the mean AUC was 5386 (1116) ng•h/mL. Selinexor Cmax andAUC increased proportionally over doses from 3 mg/m2 to 85 mg/m2 (0.06 to 1.8 times the approvedrecommended dose based on 1.7 m2 body surface area). No clinically relevant accumulation at steady statewas observed.
Absorption
The Cmax is reached within 4 hours following oral administration of XPOVIO.
Effect of Food
Concomitant administration of a hig |
