Xpovio Tablet, Film Coated
FDA Label NDC 72237-102

Full FDA labeling including Indications, Dosage, Usage, and Precautions

Structured Product Label

The following Structured Product Label (SPL) was submitted to the FDA by Karyopharm Therapeutics Inc. for the product Xpovio (NDC 72237-102). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.

This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 recommended dosage, 2.2 recommended monitoring for safety, 2.3 recommended concomitant treatments, 2.4 dosage modification for adverse reactions, 3 dosage forms and strengths, 4 contraindications, 5.1 thrombocytopenia, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.

Label Section Quick Index

1 Indications And Usage

XPOVIO is indicated in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

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

2.1 Recommended Dosage

The recommended starting dosage of XPOVIO is 80 mg (four 20 mg tablets) taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity [see Clinical Studies (14.1)].

The recommended starting dosage of dexamethasone is 20 mg taken orally with each dose of XPOVIO on Days 1 and 3 of each week. For additional information regarding the administration of dexamethasone, refer to its prescribing information.

Each XPOVIO dose should be taken at approximately the same time of day, and each tablet should be swallowed whole with water. Do not break, chew, crush, or divide the tablets.

If a dose of XPOVIO is missed or delayed, instruct patients to take their next dose at the next regularly scheduled time. If a patient vomits a dose of XPOVIO, the patient should not repeat the dose and the patient should take the next dose on the next regularly scheduled day.

2.2 Recommended Monitoring For Safety

Monitor complete blood count (CBC), standard blood chemistry, and body weight at baseline and during treatment as clinically indicated. Monitor more frequently during the first two months of treatment [see Warning and Precautions (5.1, 5.2, 5.3, and 5.4)].

2.3 Recommended Concomitant Treatments

Advise patients to maintain adequate fluid and caloric intake throughout treatment.

Consider intravenous hydration for patients at risk of dehydration.

Provide prophylactic concomitant treatment with a 5-HT3 antagonist and/or other anti-nausea agents prior to and during treatment with XPOVIO [see Warnings and Precautions (5.3)].

2.4 Dosage Modification For Adverse Reactions

Recommended XPOVIO dosage reductions and dosage modifications for adverse reactions are presented in Table 1 and Table 2, respectively.

Refer to the dexamethasone prescribing information for dexamethasone dosage modifications due to adverse reactions.

Table 1: XPOVIO Dosage Reduction Steps for Adverse Reactions
Recommended Starting DosageFirst ReductionSecond ReductionThird ReductionDiscontinue
80 mg
Days 1 and 3 of each week
(160 mg total per week) 		100 mg
once weekly 		80 mg
once weekly 		60 mg
once weekly
Table 2: XPOVIO Dosage Modification Guidelines for Adverse Reactions

a. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Adverse ReactionaOccurrenceAction
Hematologic Adverse Reactions
Thrombocytopenia
Platelet count 25,000 to less than 75,000/mcL Any
  • Reduce XPOVIO by 1 dose level (see Table 1).
Platelet count 25,000 to less than 75,000/mcL with concurrent bleeding Any
  • Interrupt XPOVIO.
  • Restart XPOVIO at 1 dose level lower (see Table 1), after bleeding has resolved.
Platelet count less than 25,000/mcL Any
  • Interrupt XPOVIO.
  • Monitor until platelet count returns to at least 50,000/mcL.
  • Restart XPOVIO at 1 dose level lower (see Table 1).
Neutropenia
Absolute neutrophil count of 0.5 to 1.0 x 109/L without fever Any
  • Reduce XPOVIO by 1 dose level (see Table 1).
Absolute neutrophil count less than 0.5 x 109/L
OR febrile neutropenia 		Any
  • Interrupt XPOVIO.
  • Monitor until neutrophil counts return to 1.0 x 109/L or higher.
  • Restart XPOVIO at 1 dose level lower (see Table 1).
Anemia
Hemoglobin less than 8.0 g/dL Any
  • Reduce XPOVIO by 1 dose level (see Table 1).
  • Administer blood transfusions and/or other treatments per clinical guidelines.
Life-threatening consequences
(urgent intervention indicated) 		Any
  • Interrupt XPOVIO.
  • Monitor hemoglobin until levels return to 8 g/dL or higher.
  • Restart XPOVIO at 1 dose level lower (see Table 1).
  • Administer blood transfusions and/or other treatments per clinical guidelines.
Non-Hematologic Adverse Reactions
Hyponatremia
Sodium level 130 mmol/L or less Any
  • Interrupt XPOVIO and provide appropriate supportive care.
  • Monitor until sodium levels return to 130 mmol/L or higher.
  • Restart XPOVIO at 1 dose level lower (see Table 1).
Fatigue
Grade 2 lasting greater than 7 days
OR Grade 3 		Any
  • Interrupt XPOVIO.
  • Monitor until fatigue resolves to Grade 1 or baseline.
  • Restart XPOVIO at 1 dose level lower (see Table 1).
Nausea and Vomiting
Grade 1 or 2 nausea (oral intake decreased without significant weight loss, dehydration or malnutrition)
OR Grade 1 or 2 vomiting (5 or fewer episodes per day) 		Any
  • Maintain XPOVIO and initiate additional anti-nausea medications.
Grade 3 nausea (inadequate oral caloric or fluid intake)
OR Grade 3 or higher vomiting (6 or more episodes per day) 		Any
  • Interrupt XPOVIO.
  • Monitor until nausea or vomiting has resolved to Grade 2 or lower or baseline.
  • Initiate additional anti-nausea medications.
  • Restart XPOVIO at 1 dose level lower (see Table 1).
Diarrhea
Grade 2 (increase of 4 to 6 stools per day over baseline) 1st
  • Maintain XPOVIO and institute supportive care.
2nd and subsequent
  • Reduce XPOVIO by 1 dose level (see Table 1).
  • Institute supportive care.
Grade 3 or higher (increase of 7 stools or more per day over baseline; hospitalization indicated) Any
  • Interrupt XPOVIO and institute supportive care.
  • Monitor until diarrhea resolves to Grade 2 or lower.
  • Restart XPOVIO at 1 dose level lower (see Table 1).
Weight Loss and Anorexia
Weight loss of 10% to less than 20% OR anorexia associated with significant weight loss or malnutrition Any
  • Interrupt XPOVIO and institute supportive care.
  • Monitor until weight returns to more than 90% of baseline weight.
  • Restart XPOVIO at 1 dose level lower (see Table 1).
Other Non-Hematologic Adverse Reactions
Grade 3 or 4 (life threatening) Any
  • Interrupt XPOVIO.
  • Monitor until resolved to Grade 2 or lower, restart XPOVIO at 1 dose level lower (see Table 1).

3 Dosage Forms And Strengths

Tablets: 20 mg, blue, round, bi-convex, film-coated tablets with “K20” debossed on one side and nothing on the other side.

4 Contraindications

None.

5.1 Thrombocytopenia

XPOVIO can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with XPOVIO. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in <1% of patients.

Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].

5.2 Neutropenia

XPOVIO can cause neutropenia, potentially increasing the risk of infection. Neutropenia was reported as an adverse reaction in 34% of patients, and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.

Obtain neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].

5.3 Gastrointestinal Toxicity

Gastrointestinal toxicities occurred in patients treated with XPOVIO [see Adverse Reactions (6.1)].

Other

Nausea/Vomiting

Nausea was reported as an adverse reaction in 72% of patients, and Grade 3 nausea occurred in 9% of patients treated with XPOVIO. The median time to onset of the first nausea event was 3 days.

Vomiting was reported in 41% of patients, and Grade 3 vomiting occurred in 4% of patients treated with XPOVIO. The median time to onset of the first vomiting event was 5 days.

Provide prophylactic 5-HT3 antagonists and/or other anti-nausea agents, prior to and during treatment with XPOVIO. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated [see Dosage and Administration (2.4)].

Diarrhea

Diarrhea was reported as an adverse reaction in 44% of patients, and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.

Manage diarrhea by dose modifications and/or standard anti-diarrheal agents; administer intravenous fluids to prevent dehydration in patients at risk [see Dosage and Administration (2.4)].

Anorexia/Weight Loss

Anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. The median time to onset of anorexia was 8 days.

Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.

Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support [see Dosage and Administration (2.4)].

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.

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.

Pregnancy Testing

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

Contraception

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

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)].

Cardiac Electrophysiology

The effect of multiple doses of XPOVIO, up to 175 mg (2.2 times the 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.

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 125 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 17.9 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, ethnicity, mild to severe renal impairment (CLCR: 15 to 89 mL/min, estimated by the Cockcroft-Gault equation). 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

No dedicated drug interaction studies have been performed with XPOVIO.

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. Selinexor is a substrate of CYP3A4.

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.

Dosing Instructions [see Dosage and Administration (2)]:

  • Instruct patients to take XPOVIO exactly as prescribed.
  • Advise patients to swallow the tablet whole with water. The tablet should not be broken, chewed, crushed, or divided.
  • If a patient misses a dose, advise them to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose of XPOVIO, advise them to take the next dose on the next regularly scheduled day.
  • Advise patients that XPOVIO comes in a child-resistant blister pack.
  • Advise patients to take their prescribed dexamethasone and prophylactic anti-nausea medications exactly as prescribed [see Dosage and Administration (2.3)].
  • Advise patients that blood tests and body weight will be monitored at baseline and during treatment as clinically indicated, with more frequent monitoring during the first two months of treatment [see Dosage and Administration (2.2)].
  • Advise patients to maintain appropriate fluid and caloric intake throughout their treatment [see Dosage and Administration (2.3)].

    • Hematologic Adverse Reactions

    Thrombocytopenia

    Advise patients that they may develop low platelet counts (thrombocytopenia). Symptoms of thrombocytopenia may include bleeding and easy bruising. Advise patients that platelet counts will be monitored at baseline, during treatment, and as clinically indicated, with more frequent monitoring during the first 2 months of treatment. Advise patients to report signs of bleeding right away [see Warnings and Precautions (5.1)].

    Anemia

    Advise patients that they may develop anemia. Symptoms of anemia may include fatigue and shortness of breath. Advise patients to report signs or symptoms of anemia [see Adverse Reactions (6.1)].

    Neutropenia

    Advise patients that they may develop low neutrophil counts which may increase their susceptibility to infection [see Warnings and Precautions (5.2)]. Advise patients that neutrophil counts will be monitored at baseline, during treatment, and as clinically indicated, with more frequent monitoring during the first 2 months of treatment.

    Gastrointestinal Adverse Reactions

    Advise patients they may experience nausea/vomiting or diarrhea and to contact their physician if these adverse reactions occur or persist [see Warnings and Precautions (5.3)].

    Fatigue

    Advise patients that they may experience fatigue [see Adverse Reactions (6.1)].

    Anorexia/Weight Loss

    Advise patients that they may experience weight loss or decreased appetite. Advise patients to report decreased appetite and weight loss [see Warnings and Precautions (5.3)].

    Confusional State and Dizziness

    Advise patients that they may experience confusion and dizziness. Advise patients not to operate motorized vehicles until they know how XPOVIO affects their abilities. Advise patients to report symptoms of neurological toxicity right away. Advise patients to avoid driving or operating machinery until they know how XPOVIO affects their abilities [see Adverse Reactions (6.1)].

    Hyponatremia

    Advise patients that they may develop low sodium levels (hyponatremia). Most cases of hyponatremia were not associated with specific symptoms. Advise patients that levels of sodium will be monitored at baseline and during treatment as clinically indicated, with more frequent monitoring during the first two months of treatment [see Warnings and Precautions (5.4)].

    Infections

    Advise patients of the possibility of serious infections. Instruct patients to report infection-related signs or symptoms (e.g., chills, fever) [see Warnings and Precautions (5.5)].

    Embryo-Fetal Toxicity

    Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with XPOVIO [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].

    Females and Males of Reproductive Potential

    Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the final dose of XPOVIO [see Use in Specific Populations (8.3)].

    Lactation

    Advise women not to breastfeed during treatment with XPOVIO and for 1 week after the final dose of XPOVIO [see Use in Specific Populations (8.2)].

    Concomitant Medications

    Advise patients to take 5-HT3 antagonist prophylactic treatment and/or other anti-nausea agents prior to and during treatment with XPOVIO [see Dosage and Administration (2.3)].

    Advise patients to speak with their physician about other medications they are currently taking and before starting any new medication.

    Manufactured for and marketed by: Karyopharm Therapeutics Inc., 85 Wells Avenue, Newton, MA, 02459.
    XPOVIO is a trademark of Karyopharm Therapeutics Inc.
    ©2019 Karyopharm Therapeutics Inc.
    For more information, call 1-888-209-9326 or go to www.XPOVIO.com.

5.4 Hyponatremia

XPOVIO can cause hyponatremia; 39% of patients treated with XPOVIO experienced hyponatremia, 22% of patients experienced Grade 3 or 4 hyponatremia. The median time to onset of the first event was 8 days.

Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].

5.5 Infections

In patients receiving XPOVIO, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade ≥3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms [see Adverse Reactions (6.1)].

5.6 Neurological Toxicity

Neurological toxicities occurred in patients treated with XPOVIO [see Adverse Reactions (6.1)].

Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with XPOVIO. Median time to the first event was 15 days.

Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.

5.7 Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

The following clinically significant adverse reactions are described in detail in other labeling sections:

  • Thrombocytopenia [see Warnings and Precautions (5.1)].
  • Neutropenia [see Warnings and Precautions (5.2)].
  • Gastrointestinal Toxicity [see Warnings and Precautions (5.3)].
  • Hyponatremia [see Warnings and Precautions (5.4)].
  • Infections [see Warnings and Precautions (5.5)].
  • Neurological Toxicity [see Warnings and Precautions (5.6)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to XPOVIO plus dexamethasone in 202 patients with RRMM who received XPOVIO 80 mg in combination with dexamethasone 20 mg on Days 1 and 3 of every week.

The median duration of XPOVIO treatment was 8 weeks (range: 1 to 60 weeks). The median dose was 115.4 mg (range: 36 to 200 mg) per week.

The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65.3% had the dose of XPOVIO interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.

The population had a median age of 64 years (range: 35 to 86 years), 54% were male, and the majority (73%) were White (17% were Black or African American).

Table 3 summarizes the most common (≥10% of patients) adverse reactions reported in patients with RRMM who received XPOVIO and dexamethasone.

Table 3: Adverse Reactions with XPOVIO 80 mg and Dexamethasone 20 mg Administered Twice Weekly

a. Thrombocytopenia includes thrombocytopenia and platelet count decreased.

b. Fatigue includes fatigue and asthenia.

c. Anemia includes anemia and hematocrit decreased.

d. Neutropenia includes neutropenia and neutrophil count decreased.

e. Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest.

f. Upper respiratory tract infection includes upper respiratory tract infection, respiratory tract infection, pharyngitis, nasopharyngitis, bronchitis, bronchiolitis, respiratory syncytial virus infection, parainfluenza virus infection, rhinitis, rhinovirus infection, and adenovirus infection.

g. Cough includes cough, productive cough, and upper-airway cough syndrome.

h. Mental status changes includes mental status changes, confusional state, and delirium.

i. Hypercreatininemia includes hypercreatininemia and hypercreatinemia.

j. Pneumonia includes pneumonia, atypical pneumonia, lung infection, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumonia influenzal, and pneumonia viral.

k. Includes fatal event.

Adverse ReactionAny Grade
(N = 202)
n (%)		Grade ≥3
(N = 202)
n (%)
Thrombocytopeniaa149 (74) 124 (61)
Fatigueb147 (73) 44 (22)
Nausea 146 (72) 18 (9)
Anemiac119 (59) 81 (40)
Decreased appetite 108 (53) 9 (4.5)
Weight decreased 95 (47) 1 (0.5)
Diarrhea 89 (44) 13 (6)
Vomiting 82 (41) 7 (3.5)
Hyponatremia 78 (39) 44 (22)
Neutropeniad68 (34) 43 (21)
Leukopenia 57 (28) 23 (11)
Constipation 50 (25) 3 (1.5)
Dyspneae48 (24) 7 (3.5)k
Upper respiratory tract infectionf42 (21) 6 (3)
Coughg33 (16) 0
Mental status changesh33 (16) 14 (7)
Pyrexia 32 (16) 1 (0.5)
Hyperglycemia 31 (15) 15 (7)
Dizziness 30 (15) 0
Insomnia 30 (15) 4 (2)
Lymphopenia 30 (15) 20 (10)
Dehydration 28 (14) 7 (3.5)
Hypercreatininemiai28 (14) 4 (2)
Pneumoniaj26 (13) 18 (9)k
Epistaxis 25 (12) 1 (0.5)
Hypokalemia 25 (12) 7 (3.5)
Dysgeusia 22 (11) 0
Vision blurred 21 (10) 1 (0.5)
Headache 20 (10) 0

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% 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%).

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 molecular mass 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 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.

12.1 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, 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 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.

12.3 Pharmacokinetics

Following a single-dose administration of XPOVIO 80 mg, the mean (standard deviation) peak plasma concentration (Cmax) was 680 (124) ng/mL and the mean AUC was 5386 (1116) ng•h/mL. Selinexor Cmax and AUC increased proportionally over doses from 3 mg/m2 to 85 mg/m2 (0.06 to 1.8 times the approved recommended dose based on 1.7 m2 body surface area). No clinically relevant accumulation at steady state was observed.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with selinexor.

Selinexor was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in either the in vitro cytogenetic assay in human lymphocytes or in the in vivo rat micronucleus assay.

Fertility studies in animals have not been conducted with selinexor. In repeat-dose oral toxicity studies, selinexor was administered for up to 13 weeks in rats and monkeys. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed in rats at ≥1 mg/kg, decreased ovarian follicles were observed in rats at ≥2 mg/kg, and single cell necrosis of testes was observed in monkeys at ≥1.5 mg/kg. These dose levels resulted in systemic exposures approximately 0.11, 0.28, and 0.53 times, respectively, the exposure (AUClast) in humans at the recommended human dose of 80 mg.

14.1 Relapsed Refractory Multiple Myeloma

The efficacy of XPOVIO plus dexamethasone was evaluated in STORM (KCP-330-012; NCT02336815). STORM was a multicenter, single-arm, open-label study of patients with RRMM. STORM Part 2 included 122 patients with RRMM who had previously received three or more anti-myeloma treatment regimens including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and an anti-CD38 monoclonal antibody; and whose myeloma was documented to be refractory to glucocorticoids, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy.

In STORM Part 2, a total of 122 patients were treated with XPOVIO (80 mg) in combination with dexamethasone (20 mg) on Days 1 and 3 of every week. Eighty-three patients had RRMM that was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab. Baseline patient demographics and disease characteristics of these 83 patients are summarized in Table 4 and Table 5, respectively. Treatment continued until disease progression, death, or unacceptable toxicity.

The major efficacy outcome measure was overall response rate (ORR), as assessed by an Independent Review Committee (IRC) based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma. The approval of XPOVIO was based upon the efficacy and safety in a prespecified subgroup analysis of the 83 patients whose disease was refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab, as the benefit-risk ratio appeared to be greater in this more heavily pretreated population than in the overall trial population. Overall response rate results are presented in Table 6. The median time to first response was 4 weeks (range: 1 to 10 weeks). The median duration of response was 3.8 months (95% CI: 2.3, not estimable).

Table 4: Baseline Demographics (STORM)
DemographicSTORM
(N = 83)
Median age, years (range) 65 (40, 86)
Age category, n (%)
     <65 years 40 (48)
     65 – 74 years 31 (37)
     ≥75 years 12 (15)
Sex, n (%)
     Male 51 (61)
     Female 32 (39)
Race, n (%)
     White 58 (70)
     Black or African American 13 (16)
     Asian 2 (2)
     Native Hawaiian or other Pacific Islander 1 (1)
     Other 6 (7)
     Missing 3 (4)
Table 5: Disease Characteristics (STORM)

a. Includes any of del(17p)/p53, t(14; 16), t(4; 14), 1q21.

ParameterSTORM
(N = 83)
Median years from diagnosis to start of study treatment (range) 7 (1, 23)
Prior treatment regimens, median (range) 8 (4, 18)
Documented refractory status, n (%)
     Lenalidomide 83 (100)
     Pomalidomide 83 (100)
     Bortezomib 83 (100)
     Carfilzomib 83 (100)
     Daratumumab 83 (100)
Documented refractory status to specific combinations, n (%)
     Bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab 83 (100)
     Daratumumab in any combination 57 (69)
     Daratumumab as single agent (+/- dexamethasone) 26 (31)
Previous stem cell transplant, n (%) 67 (81)
Revised International Staging System at Baseline, n (%)
     I 10 (12)
     II 56 (68)
     III 17 (21)
     Unknown 0
High-risk cytogeneticsa, n (%) 47 (57)
Table 6: Overall Response (STORM) as Assessed by the IRC per IMWG Criteria

a. Includes sCR + CR + VGPR + PR.

ResponseSTORM
(N = 83)
Overall Response Rate (ORR)a, n (%)21 (25.3)
     95% CI 16.4, 36
     Stringent Complete Response (sCR) 1 (1)
     Complete Response (CR) 0
     Very Good Partial Response (VGPR) 4 (5)
     Partial Response (PR) 16 (19)

16.1 How Supplied

XPOVIO (selinexor) are blue, round, bi-convex, and film-coated 20 mg tablets with “K20” debossed on one side and nothing on the other side. Tablets are packaged in a child-resistant blister pack. Four blister packs are supplied per carton. The following four dose presentations are available:

Weekly doseStrength per tabletCartonBlister PackNDC
80 mg twice weekly 20 mg 4 blister packs (32 tablets total in the carton) Each blister has eight 20 mg tablets Outer carton NDC 72237-101-04

Blister pack NDC 72237-101-14
100 mg once weekly 20 mg 4 blister packs (20 tablets total in the carton) Each blister has five 20 mg tablets Outer carton NDC 72237-101-05

Blister pack NDC 72237-101-15
80 mg once weekly 20 mg 4 blister packs (16 tablets total in the carton) Each blister has four 20 mg tablets Outer carton NDC 72237-101-02

Blister pack NDC 72237-101-12
60 mg once weekly 20 mg 4 blister packs (12 tablets total in the carton) Each blister has three 20 mg tablets Outer carton NDC 72237-101-01

Blister pack NDC 72237-101-11

16.2 Storage

Store at or below 30°C (86°F).

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Package Label.Principal Display Panel

Principal Display Panel – 60 mg Carton Label

NDC 72237-101-01

Rx ONLY

60 mg
Once
Weekly
Blister Packs

XPOVIO™

(selinexor) tablets

Contents: 4 individual weekly
blister packs. Each blister pack
contains 3 tablets (20 mg per tablet).

12 film-coated tablets

Dispense enclosed Medication Guide
to each patient.

Karyopharm®
Therapeutics

Principal Display Panel – 60 mg Blister Sleeve Label

NDC 72237-101-11

Rx ONLY

1 PRESS
& HOLD
HERE

60 mg
Once
Weekly
Blister Pack

1. PRESS 2. PULL

XPOVIO™

(selinexor) tablets

TO OPEN

Step 1: Press and
hold button gently.

Step 2: Pull out
medication card.

Blister pack contains
3 tablets (20 mg per tablet).

Refer to Prescribing
Information for dosing
instructions.

Do not break, chew, crush,
or divide the tablets.

Dispense enclosed Medication
Guide to each patient.

Karyopharm®
Therapeutics

Principal Display Panel – 60 mg Blister Pack Label

XPOVIO™(selinexor tablets)

60 mg
Dose
(entire pack)

Push tablets through foil.

Swallow whole with water.

IMPORTANT: Take each dose as prescribed by your physician.

Take only one dose in a single day. Take only one dose per week.

Refer to Prescribing Information for dosing instructions.

Principal Display Panel – 80 mg Carton Label

NDC 72237-101-02

Rx ONLY

80 mg
Once
Weekly
Blister Packs

XPOVIO™

(selinexor) tablets

Contents: 4 individual weekly
blister packs. Each blister pack
contains 4 tablets (20 mg per tablet).

16 film-coated tablets

Dispense enclosed Medication Guide
to each patient.

Karyopharm®
Therapeutics

Principal Display Panel – 80 mg Blister Sleeve Label

NDC 72237-101-12

Rx ONLY

1 PRESS
& HOLD
HERE

80 mg
Once
Weekly
Blister Pack

1. PRESS 2. PULL

XPOVIO™

(selinexor) tablets

TO OPEN

Step 1: Press and
hold button gently.

Step 2: Pull out
medication card.

Blister pack contains
4 tablets (20 mg per tablet).

Refer to Prescribing
Information for dosing
instructions.

Do not break, chew, crush,
or divide the tablets.

Dispense enclosed Medication
Guide to each patient.

Karyopharm®
Therapeutics

Principal Display Panel – 80 mg Blister Pack Label

XPOVIO™(selinexor tablets)

80 mg
Dose
(entire pack)

Push tablets
through foil.

Swallow
whole with
water.

IMPORTANT: Take each dose as prescribed by your physician.

Take only one dose in a single day. Take only one dose per week.

Refer to Prescribing Information for dosing instructions.

Principal Display Panel – 100 mg Carton Label

NDC 72237-101-05

Rx ONLY

100 mg
Once
Weekly
Blister Packs

XPOVIO™

(selinexor) tablets

Contents: 4 individual weekly
blister packs. Each blister pack
contains 5 tablets (20 mg per tablet).

20 film-coated tablets

Dispense enclosed Medication Guide
to each patient.

Karyopharm®
Therapeutics

Principal Display Panel – 100 mg Blister Sleeve Label

NDC 72237-101-15

Rx ONLY

1 PRESS
& HOLD
HERE

100 mg
Once
Weekly
Blister Pack

1. PRESS 2. PULL

XPOVIO™

(selinexor) tablets

TO OPEN

Step 1: Press and
hold button gently.

Step 2: Pull out
medication card.

Blister pack contains
5 tablets (20 mg per tablet).

Refer to Prescribing
Information for dosing
instructions.

Do not break, chew, crush,

or divide the tablets.

Dispense enclosed Medication
Guide to each patient.

Karyopharm®
Therapeutics

Principal Display Panel – 100 mg Blister Pack Label

XPOVIO™(selinexor tablets)

100 mg
Dose
(entire pack)

Push tablets
through foil.

Swallow
whole with
water.

IMPORTANT: Take each dose as prescribed by your physician.

Take only one dose in a single day. Take only one dose per week.

Refer to Prescribing Information for dosing instructions.

Principal Display Panel – 160 mg Carton Label

NDC 72237-101-04

Rx ONLY

80 mg
Twice
Weekly
Blister Packs

(160 mg total
weekly dose)

XPOVIO™

(selinexor) tablets

Contents: 4 individual weekly
blister packs. Each blister pack
contains 8 tablets (20 mg per tablet).

32 film-coated tablets

Dispense enclosed Medication Guide
to each patient.

Karyopharm®
Therapeutics

Principal Display Panel – 160 mg Blister Sleeve Label

NDC 72237-101-14

Rx ONLY

1 PRESS
& HOLD
HERE

80 mg
Twice
Weekly
Blister Pack

1. PRESS 2. PULL

(160 mg total
weekly dose)

XPOVIO™

(selinexor) tablets

TO OPEN

Step 1: Press and
hold button gently.

Step 2: Pull out
medication card.

Blister pack contains
8 tablets (20 mg per tablet).

Refer to Prescribing
Information for dosing
instructions.

Do not break, chew, crush,
or divide the tablets.

Dispense enclosed Medication
Guide to each patient.

Karyopharm®
Therapeutics

Principal Display Panel – 160 mg Blister Pack Label

XPOVIO™(selinexor tablets)

80 mg
Dose

Push tablets through foil.

Swallow whole with water.

80 mg
Dose

IMPORTANT: Take each dose as prescribed by your physician. Take only
one dose in a single day. Doses should be administered on Day 1 and
Day 3 of the week. Refer to Prescribing Information for dosing instructions.

* Please review the disclaimer below.