XPOVIO (Page 4 of 6)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings in animal studies and its mechanism of action [see Clinical Pharmacology (12.1)] , XPOVIO can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of selinexor to pregnant rats during organogenesis resulted in structural abnormalities and alterations to growth at exposures that were below those occurring clinically at the recommended dose (see Data). Advise pregnant women of the risks to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 in pregnant rats, daily oral administration of selinexor at 0, 0.25, 0.75, or 2 mg/kg throughout organogenesis caused incomplete or delayed ossification, skeletal variations, and reduced fetal weight compared with controls at a dose of 0.75 mg/kg (approximately 0.08-fold of human area under the curve [AUC] at the recommended dose). Malformations were observed at 2 mg/kg, including microphthalmia, fetal edema, malpositioned kidney, and persistent truncus arteriosus.

8.2 Lactation

Risk Summary

There is no information regarding the presence of selinexor or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with XPOVIO and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

XPOVIO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating XPOVIO [see Use in Specific Populations ( 8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

Males

Advise males with a female partner of reproductive potential to use effective contraception during treatment with 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 [see Nonclinical 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 multiple myeloma who received XPOVIO, 49% were 65 years of age and over, while 11% were 75 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 to an adverse reaction (44% vs 27%), higher incidence of serious adverse reactions (70% vs 58%), and higher incidence of fatal adverse reactions (17% vs 9%).

Among 134 patients with DLBCL who received XPOVIO in SADAL, 61% were 65 years of age and older, while 25% were 75 years of age and older. Clinical studies of XPOVIO in patients with relapsed or refractory DLBCL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

11 DESCRIPTION

Selinexor is a 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 C17 H11 F6 N7 O and a molecular mass of 443.31 g/mol. The molecular structure is shown below:

Molecular Structure

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 nothing on the other side. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, 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), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). XPO1 inhibition by selinexor leads to accumulation of TSPs in the nucleus and 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 multiple myeloma cells and showed anti-tumor activity in murine xenograft models of multiple myeloma and diffuse large B cell lymphoma.

12.2 Pharmacodynamics

An increase in selinexor exposure was associated with an increase in the probability of dose modification and some adverse reactions.

Cardiac Electrophysiology

The effect of multiple doses of XPOVIO, up to 175 mg (2.2 times the maximum approved recommended dose) twice weekly, on the QTc interval was evaluated 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

Selinexor Cmax and AUC increased proportionally over a dose range from 3 mg/m2 to 85 mg/m2 (0.06 to 1.8 times the maximum approved recommended dose, based on 1.7 m2 body surface area). No clinically relevant accumulation at steady state was observed. Selinexor Cmax and AUC0-INF after administration of a single dose of XPOVIO in patients with hematologic malignancies are presented in Table 8.

Table 8: Selinexor Cmax and AUC After Administration of a Single Dose of XPOVIO
Mean (SD) XPOVIO Dose
60 mg 80 mg
Cmax (ng/mL) 442 (188) 680 (124)
AUC0-INF (ng·h/mL) 4,096 (1,185) 5,386 (1,116)

Absorption

The Cmax is reached within 4 hours following oral administration of XPOVIO.

Effect of Food

Concomitant administration of a high-fat meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) did not affect the pharmacokinetics of selinexor to a clinically significant extent.

Distribution

The apparent volume of distribution of selinexor is 133 L in patients with cancer. The protein binding of selinexor is 95%.

Elimination

Following a single dose of XPOVIO, the mean half-life is 6 to 8 hours. The apparent total clearance of selinexor is 18.6 L/h in patients with cancer.

Metabolism

Selinexor is metabolized by CYP3A4, multiple UDP-glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs).

Specific Populations

No clinically significant differences in the pharmacokinetics of selinexor were observed based on age (18 to 94 years old), sex, body weight (36 to 168 kg), ethnicity, mild to severe renal impairment (CLCR : 15 to 89 mL/min, estimated by the Cockcroft-Gault equation), and disease type (hematological non-DLBCL, solid tumor, DLBCL). The effect of end-stage renal disease (CLCR <15 mL/min) or hemodialysis on selinexor pharmacokinetics is unknown. Mild hepatic impairment had no clinically significant effect on the pharmacokinetics of selinexor. The effect of moderate and severe hepatic impairment on selinexor pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies

Acetaminophen: No clinically significant differences in selinexor pharmacokinetics were observed when co-administered with acetaminophen (up to 1,000 mg daily dose of acetaminophen).

In vitro Studies

CYP Enzymes: Selinexor does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Selinexor is not a CYP3A4, CYP1A2, or CYP2B6 inducer.

Non-CYP Enzyme Systems: Selinexor is a substrate of UGTs and GSTs.

Transporter Systems: Selinexor inhibits OATP1B3 but does not inhibit other solute carrier (SLC) transporters. Selinexor is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K.

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