ADVERSE REACTIONS SECTION.

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)].Serious Infection [see Warnings and Precautions (5.5)].Neurological Toxicity [see Warnings and Precautions (5.6)].Cataract [see Warnings and Precautions (5.8)].. 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)].. Serious Infection [see Warnings and Precautions (5.5)].. Neurological Toxicity [see Warnings and Precautions (5.6)].. Cataract [see Warnings and Precautions (5.8)].. The most common adverse reactions (>=20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting. Grade 3-4 laboratory abnormalities (>=10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia (6.1).The most common adverse reactions (>=20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection (6.1).The most common adverse reactions (incidence >=20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3-4 laboratory abnormalities (>=15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1-888-209-9326 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common adverse reactions (>=20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting. Grade 3-4 laboratory abnormalities (>=10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia (6.1).. The most common adverse reactions (>=20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection (6.1).. The most common adverse reactions (incidence >=20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3-4 laboratory abnormalities (>=15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia (6.1).. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Multiple Myeloma. XPOVIO in Combination with Bortezomib and Dexamethasone (XVd)The safety of XPOVIO in combination with bortezomib and dexamethasone was evaluated in BOSTON [see Clinical Studies (14.1)]. Patients were randomized to receive XPOVIO 100 mg orally once weekly in combination with bortezomib and dexamethasone (XVd) (n=195) or bortezomib and dexamethasone (Vd) (n=204). Among patients who received XPOVIO, the median duration of XPOVIO treatment was 29 weeks (range: to 120 weeks) and the median dose was 80 mg (range: 30 to 137 mg) per week.Serious adverse reactions occurred in 52% of patients who received XPOVIO in combination with bortezomib and dexamethasone. Serious adverse reactions in >3% of patients included pneumonia (14%), sepsis, diarrhea and vomiting (4% each). Fatal adverse reactions occurred in 6% of patients within 30 days of last treatment, including pneumonia (n=3) and sepsis (n=3).Grade >=2 peripheral neuropathy, pre-specified key secondary endpoint, was lower in the XVd arm (21%) compared to the Vd arm (34%); odds ratio 0.50 [95% CI: 0.32, 0.79]. The median treatment duration was 30 weeks (range: 1-120 weeks) in patients who received once weekly XVd as compared to 32 weeks (range: 1-122 weeks) in patients who received twice weekly Vd.Permanent discontinuation of XPOVIO due to an adverse reaction occurred in 19% of patients. Adverse reactions which resulted in permanent discontinuation of XPOVIO in >2% of patients included fatigue (3.6%), nausea (3.1%), thrombocytopenia, decreased appetite, peripheral neuropathy, and vomiting (2.1% each).Dosage interruptions of XPOVIO due to an adverse reaction occurred in 83% of patients. Adverse reactions which required dosage interruption in >5% of patients included thrombocytopenia (33%), fatigue (13%), asthenia (12%), pneumonia (11%), upper respiratory tract infection (10%), decreased appetite (9%), neutropenia (8%), pyrexia (8%), nausea (7%), bronchitis (7%), diarrhea (6%), weight decreased (6%), and anemia (5%).Dose reductions of XPOVIO due to an adverse reaction occurred in 64% of patients. Adverse reactions which required dose reductions in >5% of patients included thrombocytopenia (31%), decreased appetite (8%), nausea, fatigue, decreased weight (7% each), and asthenia (6%).The most common adverse reactions (>=20% with difference between arms of >5% compared to Vd) were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, weight decrease, cataract, and vomiting. Grade 3-4 laboratory abnormalities (>=10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia.Table summarizes the adverse reactions in BOSTON.Table 5: Adverse Reactions (>=10%) in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) with Difference Between Arms of >5% Compared to Vd in BOSTONKey: S=selinexor, Vd=bortezomib-dexamethasonea. Fatigue includes fatigue and asthenia.b. Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, polyneuropathy, peripheral sensorimotor neuropathy, toxic neuropathy, and peripheral motor neuropathy.c. Upper respiratory tract infection includes upper respiratory infection, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, and viral upper respiratory tract infection.d. Vision blurred includes blurred vision, visual acuity reduced, and visual impairment.Adverse ReactionWeekly XVd(n=195)Twice Weekly Vd(n=204)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Gastrointestinal Nausea508100 Diarrhea32625<1 Vomiting214.14.40General Conditions Fatiguea 5928215 Pyrexia151.5111Metabolism and Nutrition Appetite decrease353.650 Weight decrease262.1121Nervous System Peripheral neuropathyb 324.6479 Dizziness12<13.90Infections Upper respiratory tract infectionc 293.6221.5Eye Disorders Cataract22961.5 Vision blurredd 13<160Clinically relevant adverse reactions in <10% of patients who received XPOVIO in combination with bortezomib and dexamethasone included:Neurologic disorders: mental status changes (9%) and syncope (3.6%)Table summarizes selected laboratory abnormalities in BOSTON.Table 6: Select Laboratory Abnormalities (>=15%) That Worsened from Baseline in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) in BOSTONLaboratory AbnormalityWeekly XVdTwice Weekly VdAll Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)The denominator used to calculate the rate varied from 91 to 201 based on the number of patients with at least one post-treatment value.a. Includes one fatal anemia.Hematologic Platelet count decrease92435119 Lymphocyte count decrease77387027 Hemoglobin decrease711751a 12 Neutrophil count decrease4812197Chemistry Glucose increase623.8474.1 Phosphate decrease61234211 Sodium decrease5814253 Calcium decrease552.1471 Blood urea nitrogen increase415405 Creatinine increase283.6241.5 Potassium decrease276223.5 Magnesium decrease27<1231.5 Potassium increase184.1212.5Hepatic ALT increase333.130<1 Albumin decrease27<135<1 AST increase241.519<1 Bilirubin increase161132 ALP increase12016<1XPOVIO in Combination with Dexamethasone (Xd)The safety of XPOVIO in combination with dexamethasone was evaluated in STORM [see Clinical Studies (14.1)]. Patients received XPOVIO 80 mg orally with dexamethasone 20 mg on Days and of every week (n=202). The median duration of XPOVIO treatment was weeks (range: to 60 weeks). The median dose was 115 mg (range: 36 to 200 mg) per week.Fatal adverse reactions occurred in 9% of XPOVIO treated patients. Serious adverse reactions occurred in 58% of patients.The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had reduction in the XPOVIO dose, and 65% had the dose of XPOVIO interrupted. Thrombocytopenia was the leading cause of dose modification, resulting in dose reduction and/or interruption in >25% of patients. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia.Table summarizes the adverse reactions in STORM.Table 7: Adverse Reactions (>=10%) in Patients Who Received XPOVIO in STORMAdverse ReactionXPOVIO 80 mg twice weekly Dexamethasone(n=202)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. All Grades(%)Grades >=3(%)Thrombocytopeniaa 7461Fatigueb 7322Nausea729Anemiac 5940Decreased appetite534.5Weight decreased470.5Diarrhea446Vomiting413.5Hyponatremia3922Neutropeniad 3421Leukopenia2811Constipation251.5Dyspneae 243.5k Upper respiratory tract infectionf 213Coughg 160Mental status changesh 167Pyrexia160.5Hyperglycemia157Dizziness150Insomnia152Lymphopenia1510Dehydration143.5Hypercreatininemiai 142Pneumoniaj 139k Epistaxis120.5Hypokalemia123.5Dysgeusia110Vision blurred100.5Headache100. Neurologic disorders: mental status changes (9%) and syncope (3.6%). Diffuse Large B-Cell LymphomaThe safety of XPOVIO was evaluated in SADAL [see Clinical Studies (14.2)]. Patients received XPOVIO 60 mg orally on Days and of every week (n=134). The study required an absolute neutrophil count >=1000/uL, platelet count >=75,000/uL, hepatic transaminases <=2.5 times upper limit of normal (ULN) unless abnormal from lymphoma, and bilirubin <=2 times ULN. The study permitted maximum of prior systemic regimens for DLBCL. Antiemetic prophylaxis with 5HT-3 receptor antagonist was required. The median duration of XPOVIO treatment was 2.1 months (range: week to 3.7 years) with 38% receiving at least months and 22% receiving at least months of treatment. The median exposure was 100 mg per week.Fatal adverse reactions occurred in 3.7% of patients within 30 days and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reaction was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients who received XPOVIO; the most frequent serious adverse reaction was infection (21% of patients).Discontinuation due to adverse reactions occurred in 17% of patients who received XPOVIO. Adverse reactions which results in discontinuation in >=2% of patients included: infection, fatigue, thrombocytopenia, and nausea.Adverse reactions led to XPOVIO dose interruption in 61% of patients and dose reduction in 49%, with 17% of all patients having or more dose reductions. The median time to first dose modification (reduction or interruption) was weeks, with the leading causes being thrombocytopenia (40% of all patients), neutropenia (16%), fatigue (16%), nausea (10%), and anemia (10%). The median time to first dose reduction was weeks, with 83% of first dose reductions occurring within the first months.The most common adverse reactions, excluding laboratory abnormalities, in >=20% of patients were fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Table summarizes selected adverse reactions in SADAL.Table 8: Adverse Reactions (>=10%), Excluding Laboratory Terms, in Patients with DLBCL Who Received XPOVIO in SADALAdverse ReactionXPOVIO 60 mg twice weekly(n=134)All Grades(%)Grade or 4(%)a. Fatigue includes fatigue and asthenia.b. Edema includes edema, swelling, swelling face, edema peripheral, peripheral swelling, acute pulmonary edema.c. Diarrhea includes diarrhea, post-procedural diarrhea, gastroenteritis.d. Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort.e. Appetite decrease includes decreased appetite and hypophagia.f. Cough includes cough and productive cough.g. Dyspnea includes dyspnea and dyspnea exertional.h. Upper respiratory tract infection includes upper respiratory tract infection, sinusitis, nasopharyngitis, pharyngitis, rhinitis, viral upper respiratory infection.i. Urinary tract infection includes urinary tract infection and specific types of urinary tract infection.j. Dizziness includes dizziness and vertigo.k. Taste disorder includes taste disorder, dysgeusia, ageusia.l. Mental status changes include confusional state, amnesia, cognitive disorder, hallucination, delirium, somnolence, depressed level of consciousness, memory impairment.m. Peripheral neuropathy includes peripheral neuropathy, peripheral sensory neuropathy, sensory disturbance, paresthesia, neuralgia.n. Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, pain in extremity, bone pain.o. Hemorrhage includes hemorrhage, hematoma, hematuria, epistaxis, rectal hemorrhage, injection site hematoma, subdural hematoma, upper gastrointestinal hemorrhage, corneal bleeding.p. Vision blurred includes vision blurred, visual acuity reduced, visual impairment.General Conditions Fatiguea 6315 Pyrexia224.5 Edemab 172.2Gastrointestinal Nausea576 Diarrheac 373.0 Constipation290 Vomiting281.5 Abdominal paind 100Metabolism and Nutrition Appetite decreasee 373.7 Weight decrease300Respiratory Coughf 180 Dyspneag 101.5Infections Upper respiratory tract infectionh 171.5 Pneumonia106 Urinary tract infectioni 103Nervous System Dizzinessj 160.7 Taste disorderk 130 Mental status changesl 113.7 Peripheral neuropathy, sensorym 100Musculoskeletal Musculoskeletal painn 152.2Vascular Hypotension133.0 Hemorrhageo 100.7Eye Disorders Vision blurredp 110.7Clinically relevant adverse reactions in <10% of patients who received XPOVIO included:Injury: fall (8%)Metabolic and nutrition disorders: dehydration (7%)Neurologic disorders: headache (4.5%), syncope (2.2%)Infection: sepsis (6%), herpesvirus infection (3%)Eye disorders: cataract (3.7%)Blood and lymphatic disorders: febrile neutropenia (3%)Cardiac disorders: cardiac failure (3%)Table summarizes selected new or worsening laboratory abnormalities in SADAL. Grade 3-4 laboratory abnormalities in >=15% included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade laboratory abnormalities in >=5% were thrombocytopenia (18%), lymphopenia (5%), and neutropenia (9%).Table 9: Select Laboratory Abnormalities (>=15%) Worsening from Baseline in Patients with DLBCL Who Received XPOVIO in SADALLaboratory AbnormalityXPOVIO 60 mg twice weeklyAll Grades(%)Grade or 4(%)Hematologic Platelet count decrease8649 Hemoglobin decrease8225 Lymphocyte count decrease6337 Neutrophil count decrease5831Chemistry Sodium decrease6216 Glucose increase57a Creatinine increase473.9 Phosphate decrease3411 Magnesium decrease302.6 Calcium decrease300.9 Potassium increase263.9 Potassium decrease237 CK increaseb 211.9Hepatic ALT increase290.8 Albumin decrease250 AST increase243.1 Bilirubin increase161.6. Injury: fall (8%). Metabolic and nutrition disorders: dehydration (7%). Neurologic disorders: headache (4.5%), syncope (2.2%). Infection: sepsis (6%), herpesvirus infection (3%). Eye disorders: cataract (3.7%). Blood and lymphatic disorders: febrile neutropenia (3%). Cardiac disorders: cardiac failure (3%).

CLINICAL PHARMACOLOGY SECTION.

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 (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 cell lymphoma. The combination of selinexor and dexamethasone or bortezomib demonstrated synergistic cytotoxic effects in multiple myeloma in vitro and increased anti-tumor activity in murine xenograft multiple myeloma models in vivo, including those resistant to proteasome inhibitors.. 12.2 Pharmacodynamics. An increase in selinexor exposure was associated with an increase in the probability of dose modification and some adverse reactions.. Cardiac ElectrophysiologyThe effect of multiple doses of XPOVIO, up to 175 mg per dose (1.75 times the maximum approved recommended dose), 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 dose range from mg/m2 to 85 mg/m2 (0.05 to 1.44) 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 single dose of XPOVIO in patients with hematologic malignancies are presented in Table 10.Table 10: Selinexor Cmax and AUC After Administration of Single Dose of XPOVIOMean (SD)XPOVIO Dose60 mg80 mg100 mgCmax (ng/mL)442 (188)680 (124)693 (201)AUC0-INF (ng.h/mL)4,096 (1,185)5,386 (1,116)6,998 (818). AbsorptionThe Cmax is reached within hours following oral administration of XPOVIO.. Effect of FoodConcomitant administration of 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 clinically significant extent.. DistributionThe apparent volume of distribution of selinexor is 133 in patients with cancer. The protein binding of selinexor is 95%.. EliminationFollowing single dose of XPOVIO, the mean half-life is to hours. The apparent total clearance of selinexor is 18.6 L/h in patients with cancer.. MetabolismSelinexor is metabolized by CYP3A4, multiple UDP-glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs).. Specific PopulationsNo 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 StudiesAcetaminophen: 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 StudiesCYP Enzymes: Selinexor does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Selinexor is not CYP3A4, CYP1A2, or CYP2B6 inducer.Non-CYP Enzyme Systems: Selinexor is substrate of UGTs and GSTs.Transporter Systems: Selinexor inhibits OATP1B3 but does not inhibit other solute carrier (SLC) transporters. Selinexor is not substrate of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Relapsed or Refractory Multiple Myeloma. XPOVIO Combination with Bortezomib and Dexamethasone (XVd)The efficacy of XPOVIO in combination with bortezomib and dexamethasone was evaluated in BOSTON (NCT03110562). BOSTON was global, randomized, open label, active-controlled trial in adult patients who had received to prior anti-MM regimens. Prior treatment with bortezomib or other PI was allowed. Patients with Grade or higher peripheral neuropathy at study entry were excluded.Patients were randomized to receive one of the following:XPOVIO 100 mg orally once weekly on Days 1, 8, 15, 22, 29 in combination with bortezomib 1.3 mg/m2 administered subcutaneously once weekly on Days 1, 8, 15, 22 and dexamethasone 20 mg taken orally twice weekly on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle [XVd arm] orBortezomib 1.3 mg/m2 administered subcutaneously twice weekly on Days 1, 4, 8, 11 and dexamethasone 20 mg taken orally four times weekly on Days 1, 2, 4, 5, 8, 9, 11, 12 of each 21-day cycle for the first cycles, followed by bortezomib 1.3 mg/m2 administered subcutaneously once weekly on Days 1, 8, 15, 22 and dexamethasone 20 mg taken orally twice weekly on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle (Cycle >=9) [Vd arm].Treatment continued in both arms until disease progression or unacceptable toxicity. Randomization was stratified based on prior proteasome inhibitor therapies exposure (yes versus no), number of prior regimens (1 versus >1), Stage (III versus or II) according to the Revised-International Staging System (R-ISS) and region. Upon confirmed progressive disease (PD), patients in the Vd arm could receive XPOVIO in combination with bortezomib and dexamethasone (XVd) or XPOVIO 100 mg taken orally on Days 1, 8, 15, 22, 29 with dexamethasone 20 mg taken orally on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle.A total of 402 patients were randomized: 195 to XVd arm and 207 to Vd arm. Baseline patient demographics and disease characteristics are summarized in Table 11 and Table 12, respectively.Table 11: Baseline Demographics (BOSTON)CharacteristicXVd(n=195)Vd(n=207)Median age, years (range)66 (40, 87)67 (38, 90)Age distribution, (%) <65 years86 (44)75 (36) 65 74 years75 (38)85 (41) >=75 years34 (17)47 (23)Sex, (%) Male115 (59)115 (56) Female80 (41)92 (44)Race, (%) White161 (83)165 (80) Black or African American4 (2)7 (3) Asian25 (13)25 (12) Other01 (0.5) Missing5 (3)9 (4)Table 12: Disease Characteristics (BOSTON)ParameterXVd(n=195)Vd(n=207)a. Includes any of del (17p)/p53, (14;16), (4;14), 1q21.Median years from diagnosis to randomization (range)3.81 (0.4,23.0)3.59 (0.4, 22.0)ECOG performance status score, (%) 0-1175 (90)191 (92) >=220 (10)16 (8)Creatinine Clearance, (%), mL per minute <303 (1.5)10 (5) 30 to 5953 (27)60 (29) >=60139 (71)137 (66)Revised International Staging System at Baseline, (%) I56 (29)52 (25) II117 (60)125 (60) III12 (6)16 (8) Unknown10 (5)14 (7)Number of Prior Therapies, (%) 2 399 (51)65 (33)31 (16)99 (48)64 (31)44 (21)Type of known prior therapy, (%) Stem Cell transplantation76 (39)63 (30) Lenalidomide77 (39)77 (37) Pomalidomide11 (6)7 (3) Bortezomib134 (69)145 (70) Carfilzomib20 (10)21 (10) Daratumumab11 (6)6 (3)Median weeks since end of last prior therapy, (range)48 (1, 1088)42 (2, 405)Known high-risk cytogeneticsa, (%)97 (50)95 (46)Efficacy was based on progression free survival (PFS) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma, as assessed by an Independent Review Committee (IRC). Efficacy results based on preplanned PFS interim analysis, are shown in Table 13 and Figure 1.Table 13: Efficacy Results per IRC in Multiple Myeloma (BOSTON)XVd(n=195)Vd(n=207)a. Hazard ratio is based on stratified Coxs proportional hazard regression modeling, p-value based on stratified log-rank test. Median follow up of 15.1 months at the time of the analysis.b. The pre-planned PFS interim analysis boundary of statistical significance was defined as p-value <0.0103.c. Includes sCR CR VGPR PR, value based on Cochran-Mantel-Haenszel test.d. Includes sCR CR VGPR, value based on Cochran-Mantel-Haenszel test.Progression Free Survival (PFS)aHazard Ratio [95% CI]0.70 [0.53, 0.93]0.0075 One-sided p-valueb Median PFS in months [95% CI]13.9 (11.7, Not Reached)9.5 (7.6, 10.8)Overall Response Rate (ORR)c, (%)149 (76.4)129 (62.3) 95% CI(69.8, 82.2)(55.3, 68.9) One-sided p-value 0.0012Stringent Complete Response (sCR)19 (10)13 (6)Complete Response (CR)14 (7)9 (4)Very Good Partial Response (VGPR)54 (28)45 (22)Partial Response (PR)62 (32)62 (30)>= VGPR Response Rated, (%)87 (44.6)67 (32.4) 95% CI(37.5, 51.9)(26.0, 39.2) One-sided p-value0.0082Figure 1: Kaplan-Meier Curve of PFS (BOSTON)The median time to response was 1.4 months in the XVd arm and 1.6 months in the Vd arm. The median duration of response, among responding patients, was 20.3 months and 12.9 months in the XVd and Vd arms, respectively.. XPOVIO 100 mg orally once weekly on Days 1, 8, 15, 22, 29 in combination with bortezomib 1.3 mg/m2 administered subcutaneously once weekly on Days 1, 8, 15, 22 and dexamethasone 20 mg taken orally twice weekly on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle [XVd arm] or. Bortezomib 1.3 mg/m2 administered subcutaneously twice weekly on Days 1, 4, 8, 11 and dexamethasone 20 mg taken orally four times weekly on Days 1, 2, 4, 5, 8, 9, 11, 12 of each 21-day cycle for the first cycles, followed by bortezomib 1.3 mg/m2 administered subcutaneously once weekly on Days 1, 8, 15, 22 and dexamethasone 20 mg taken orally twice weekly on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle (Cycle >=9) [Vd arm].Treatment continued in both arms until disease progression or unacceptable toxicity. Randomization was stratified based on prior proteasome inhibitor therapies exposure (yes versus no), number of prior regimens (1 versus >1), Stage (III versus or II) according to the Revised-International Staging System (R-ISS) and region. Upon confirmed progressive disease (PD), patients in the Vd arm could receive XPOVIO in combination with bortezomib and dexamethasone (XVd) or XPOVIO 100 mg taken orally on Days 1, 8, 15, 22, 29 with dexamethasone 20 mg taken orally on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, and 30 of each 35-day cycle.. Figure 1. XPOVIO Combination with Dexamethasone (Xd)The efficacy of XPOVIO plus dexamethasone was evaluated in STORM (KCP-330-012; NCT02336815). STORM was multicenter, single-arm, open-label study of adults with relapsed or refractory multiple myeloma (RRMM). STORM Part 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, proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and to the last line of therapy.In STORM Part 2, total of 122 patients received XPOVIO 80 mg orally in combination with dexamethasone 20 mg orally on Days and of every week. Treatment continued until disease progression or unacceptable toxicity. 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 14 and Table 15, respectively.Efficacy was based on 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 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 16. The median time to first response was weeks (range: to 10 weeks). The median duration of response was 3.8 months (95% CI: 2.3, not estimable).Table 14: Baseline Demographics (STORM)DemographicSTORM(n=83)Median age, years (range)65 (40, 86)Age category, (%) <65 years40 (48) 65 74 years31 (37) >=75 years12 (15)Sex, (%) Male51 (61) Female32 (39)Race, (%) White58 (70) Black or African American13 (16) Asian2 (2) Native Hawaiian or other Pacific Islander1 (1) Other6 (7) Missing3 (4)Table 15: Disease Characteristics (STORM)ParameterSTORM(n=83)a. Includes any of del(17p)/p53, t(14; 16), t(4; 14), 1q21.Median years from diagnosis to start of study treatment (range)7 (1, 23)Prior treatment regimens, median (range)8 (4, 18)Documented refractory status, (%) Lenalidomide83 (100) Pomalidomide83 (100) Bortezomib83 (100) Carfilzomib83 (100) Daratumumab83 (100)Documented refractory status to specific combinations, (%) Bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab83 (100) Daratumumab in any combination57 (69) Daratumumab as single agent (+/- dexamethasone)26 (31)Previous stem cell transplant, (%)67 (81)Revised International Staging System at Baseline, (%) I10 (12) II56 (68) III17 (21) Unknown0High-risk cytogeneticsa, (%)47 (57)Table 16: Efficacy Results per IRC in Relapsed or Refractory Multiple Myeloma (STORM)a. Includes sCR CR VGPR PR.ResponseSTORM(n=83)Overall Response Rate (ORR)a, (%)21 (25.3) 95% CI16.4, 36 Stringent Complete Response (sCR)1 (1) Complete Response (CR)0 Very Good Partial Response (VGPR)4 (5) Partial Response (PR)16 (19). 14.2 Relapsed or Refractory Diffuse Large B-Cell Lymphoma. The efficacy of XPOVIO monotherapy was evaluated in SADAL (KCP-330-009; NCT02227251). SADAL was multicenter, single-arm, open-label study of adults with relapsed or refractory DLBCL, not otherwise specified (NOS), after to systemic regimens. Eligible patients were not candidates for autologous hematopoietic stem cell transplantation (HSCT). The study required minimum of 60 days since last systemic therapy, with minimum of 98 days in patients with refractory disease (defined as less than partial response) to last systemic therapy.Patients received XPOVIO 60 mg orally on Days and of each week. Treatment continued until disease progression or unacceptable toxicity.Of 134 patients evaluated, the median age was 67 years (range: 35-91), 59% were male, 79% were White, and 7% were Asian. Most patients (88%) had an ECOG performance status of or 1. The diagnosis was de novo DLBCL not otherwise specified (NOS) in 75% and transformed DLBCL in 23%. The median number of prior systemic therapies was (range: 1-5), with 63% of patients receiving prior systemic therapies, 24% receiving prior therapies, and 10% receiving or prior therapies. Twenty-eight percent had documented refractory disease to the most recent therapy; 30% had prior autologous HSCT. The median time from last systemic therapy to the start of XPOVIO was 5.4 months overall and 3.6 months in the patients with refractory disease.Efficacy was based on overall response rate (ORR) and duration of response as assessed by an Independent Review Committee (IRC) using Lugano 2014 criteria (Table 17). The median time to first response was 8.1 weeks (range: 6.7-16.4 weeks).Table 17: Efficacy Results per IRC in Relapsed or Refractory DLBCL (SADAL)ParameterXPOVIO 60 mg twice weekly(n=134)ORR per Lugano criteria, (%) 95% CI, %39 (29)22, 38 Complete Response18 (13) Partial Response21 (16)Duration of Response Patients maintaining response at months, n/N (%)22/39 (56) Patients maintaining response at months, n/N (%)15/39 (38) Patients maintaining response at 12 months, n/N (%)6/39 (15).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Multiple Myeloma. XPOVIO in Combination with Bortezomib and Dexamethasone (XVd)The safety of XPOVIO in combination with bortezomib and dexamethasone was evaluated in BOSTON [see Clinical Studies (14.1)]. Patients were randomized to receive XPOVIO 100 mg orally once weekly in combination with bortezomib and dexamethasone (XVd) (n=195) or bortezomib and dexamethasone (Vd) (n=204). Among patients who received XPOVIO, the median duration of XPOVIO treatment was 29 weeks (range: to 120 weeks) and the median dose was 80 mg (range: 30 to 137 mg) per week.Serious adverse reactions occurred in 52% of patients who received XPOVIO in combination with bortezomib and dexamethasone. Serious adverse reactions in >3% of patients included pneumonia (14%), sepsis, diarrhea and vomiting (4% each). Fatal adverse reactions occurred in 6% of patients within 30 days of last treatment, including pneumonia (n=3) and sepsis (n=3).Grade >=2 peripheral neuropathy, pre-specified key secondary endpoint, was lower in the XVd arm (21%) compared to the Vd arm (34%); odds ratio 0.50 [95% CI: 0.32, 0.79]. The median treatment duration was 30 weeks (range: 1-120 weeks) in patients who received once weekly XVd as compared to 32 weeks (range: 1-122 weeks) in patients who received twice weekly Vd.Permanent discontinuation of XPOVIO due to an adverse reaction occurred in 19% of patients. Adverse reactions which resulted in permanent discontinuation of XPOVIO in >2% of patients included fatigue (3.6%), nausea (3.1%), thrombocytopenia, decreased appetite, peripheral neuropathy, and vomiting (2.1% each).Dosage interruptions of XPOVIO due to an adverse reaction occurred in 83% of patients. Adverse reactions which required dosage interruption in >5% of patients included thrombocytopenia (33%), fatigue (13%), asthenia (12%), pneumonia (11%), upper respiratory tract infection (10%), decreased appetite (9%), neutropenia (8%), pyrexia (8%), nausea (7%), bronchitis (7%), diarrhea (6%), weight decreased (6%), and anemia (5%).Dose reductions of XPOVIO due to an adverse reaction occurred in 64% of patients. Adverse reactions which required dose reductions in >5% of patients included thrombocytopenia (31%), decreased appetite (8%), nausea, fatigue, decreased weight (7% each), and asthenia (6%).The most common adverse reactions (>=20% with difference between arms of >5% compared to Vd) were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, weight decrease, cataract, and vomiting. Grade 3-4 laboratory abnormalities (>=10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia.Table summarizes the adverse reactions in BOSTON.Table 5: Adverse Reactions (>=10%) in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) with Difference Between Arms of >5% Compared to Vd in BOSTONKey: S=selinexor, Vd=bortezomib-dexamethasonea. Fatigue includes fatigue and asthenia.b. Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, polyneuropathy, peripheral sensorimotor neuropathy, toxic neuropathy, and peripheral motor neuropathy.c. Upper respiratory tract infection includes upper respiratory infection, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, and viral upper respiratory tract infection.d. Vision blurred includes blurred vision, visual acuity reduced, and visual impairment.Adverse ReactionWeekly XVd(n=195)Twice Weekly Vd(n=204)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Gastrointestinal Nausea508100 Diarrhea32625<1 Vomiting214.14.40General Conditions Fatiguea 5928215 Pyrexia151.5111Metabolism and Nutrition Appetite decrease353.650 Weight decrease262.1121Nervous System Peripheral neuropathyb 324.6479 Dizziness12<13.90Infections Upper respiratory tract infectionc 293.6221.5Eye Disorders Cataract22961.5 Vision blurredd 13<160Clinically relevant adverse reactions in <10% of patients who received XPOVIO in combination with bortezomib and dexamethasone included:Neurologic disorders: mental status changes (9%) and syncope (3.6%)Table summarizes selected laboratory abnormalities in BOSTON.Table 6: Select Laboratory Abnormalities (>=15%) That Worsened from Baseline in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) in BOSTONLaboratory AbnormalityWeekly XVdTwice Weekly VdAll Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)The denominator used to calculate the rate varied from 91 to 201 based on the number of patients with at least one post-treatment value.a. Includes one fatal anemia.Hematologic Platelet count decrease92435119 Lymphocyte count decrease77387027 Hemoglobin decrease711751a 12 Neutrophil count decrease4812197Chemistry Glucose increase623.8474.1 Phosphate decrease61234211 Sodium decrease5814253 Calcium decrease552.1471 Blood urea nitrogen increase415405 Creatinine increase283.6241.5 Potassium decrease276223.5 Magnesium decrease27<1231.5 Potassium increase184.1212.5Hepatic ALT increase333.130<1 Albumin decrease27<135<1 AST increase241.519<1 Bilirubin increase161132 ALP increase12016<1XPOVIO in Combination with Dexamethasone (Xd)The safety of XPOVIO in combination with dexamethasone was evaluated in STORM [see Clinical Studies (14.1)]. Patients received XPOVIO 80 mg orally with dexamethasone 20 mg on Days and of every week (n=202). The median duration of XPOVIO treatment was weeks (range: to 60 weeks). The median dose was 115 mg (range: 36 to 200 mg) per week.Fatal adverse reactions occurred in 9% of XPOVIO treated patients. Serious adverse reactions occurred in 58% of patients.The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had reduction in the XPOVIO dose, and 65% had the dose of XPOVIO interrupted. Thrombocytopenia was the leading cause of dose modification, resulting in dose reduction and/or interruption in >25% of patients. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia.Table summarizes the adverse reactions in STORM.Table 7: Adverse Reactions (>=10%) in Patients Who Received XPOVIO in STORMAdverse ReactionXPOVIO 80 mg twice weekly Dexamethasone(n=202)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. All Grades(%)Grades >=3(%)Thrombocytopeniaa 7461Fatigueb 7322Nausea729Anemiac 5940Decreased appetite534.5Weight decreased470.5Diarrhea446Vomiting413.5Hyponatremia3922Neutropeniad 3421Leukopenia2811Constipation251.5Dyspneae 243.5k Upper respiratory tract infectionf 213Coughg 160Mental status changesh 167Pyrexia160.5Hyperglycemia157Dizziness150Insomnia152Lymphopenia1510Dehydration143.5Hypercreatininemiai 142Pneumoniaj 139k Epistaxis120.5Hypokalemia123.5Dysgeusia110Vision blurred100.5Headache100. Neurologic disorders: mental status changes (9%) and syncope (3.6%). Diffuse Large B-Cell LymphomaThe safety of XPOVIO was evaluated in SADAL [see Clinical Studies (14.2)]. Patients received XPOVIO 60 mg orally on Days and of every week (n=134). The study required an absolute neutrophil count >=1000/uL, platelet count >=75,000/uL, hepatic transaminases <=2.5 times upper limit of normal (ULN) unless abnormal from lymphoma, and bilirubin <=2 times ULN. The study permitted maximum of prior systemic regimens for DLBCL. Antiemetic prophylaxis with 5HT-3 receptor antagonist was required. The median duration of XPOVIO treatment was 2.1 months (range: week to 3.7 years) with 38% receiving at least months and 22% receiving at least months of treatment. The median exposure was 100 mg per week.Fatal adverse reactions occurred in 3.7% of patients within 30 days and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reaction was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients who received XPOVIO; the most frequent serious adverse reaction was infection (21% of patients).Discontinuation due to adverse reactions occurred in 17% of patients who received XPOVIO. Adverse reactions which results in discontinuation in >=2% of patients included: infection, fatigue, thrombocytopenia, and nausea.Adverse reactions led to XPOVIO dose interruption in 61% of patients and dose reduction in 49%, with 17% of all patients having or more dose reductions. The median time to first dose modification (reduction or interruption) was weeks, with the leading causes being thrombocytopenia (40% of all patients), neutropenia (16%), fatigue (16%), nausea (10%), and anemia (10%). The median time to first dose reduction was weeks, with 83% of first dose reductions occurring within the first months.The most common adverse reactions, excluding laboratory abnormalities, in >=20% of patients were fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Table summarizes selected adverse reactions in SADAL.Table 8: Adverse Reactions (>=10%), Excluding Laboratory Terms, in Patients with DLBCL Who Received XPOVIO in SADALAdverse ReactionXPOVIO 60 mg twice weekly(n=134)All Grades(%)Grade or 4(%)a. Fatigue includes fatigue and asthenia.b. Edema includes edema, swelling, swelling face, edema peripheral, peripheral swelling, acute pulmonary edema.c. Diarrhea includes diarrhea, post-procedural diarrhea, gastroenteritis.d. Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort.e. Appetite decrease includes decreased appetite and hypophagia.f. Cough includes cough and productive cough.g. Dyspnea includes dyspnea and dyspnea exertional.h. Upper respiratory tract infection includes upper respiratory tract infection, sinusitis, nasopharyngitis, pharyngitis, rhinitis, viral upper respiratory infection.i. Urinary tract infection includes urinary tract infection and specific types of urinary tract infection.j. Dizziness includes dizziness and vertigo.k. Taste disorder includes taste disorder, dysgeusia, ageusia.l. Mental status changes include confusional state, amnesia, cognitive disorder, hallucination, delirium, somnolence, depressed level of consciousness, memory impairment.m. Peripheral neuropathy includes peripheral neuropathy, peripheral sensory neuropathy, sensory disturbance, paresthesia, neuralgia.n. Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, pain in extremity, bone pain.o. Hemorrhage includes hemorrhage, hematoma, hematuria, epistaxis, rectal hemorrhage, injection site hematoma, subdural hematoma, upper gastrointestinal hemorrhage, corneal bleeding.p. Vision blurred includes vision blurred, visual acuity reduced, visual impairment.General Conditions Fatiguea 6315 Pyrexia224.5 Edemab 172.2Gastrointestinal Nausea576 Diarrheac 373.0 Constipation290 Vomiting281.5 Abdominal paind 100Metabolism and Nutrition Appetite decreasee 373.7 Weight decrease300Respiratory Coughf 180 Dyspneag 101.5Infections Upper respiratory tract infectionh 171.5 Pneumonia106 Urinary tract infectioni 103Nervous System Dizzinessj 160.7 Taste disorderk 130 Mental status changesl 113.7 Peripheral neuropathy, sensorym 100Musculoskeletal Musculoskeletal painn 152.2Vascular Hypotension133.0 Hemorrhageo 100.7Eye Disorders Vision blurredp 110.7Clinically relevant adverse reactions in <10% of patients who received XPOVIO included:Injury: fall (8%)Metabolic and nutrition disorders: dehydration (7%)Neurologic disorders: headache (4.5%), syncope (2.2%)Infection: sepsis (6%), herpesvirus infection (3%)Eye disorders: cataract (3.7%)Blood and lymphatic disorders: febrile neutropenia (3%)Cardiac disorders: cardiac failure (3%)Table summarizes selected new or worsening laboratory abnormalities in SADAL. Grade 3-4 laboratory abnormalities in >=15% included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade laboratory abnormalities in >=5% were thrombocytopenia (18%), lymphopenia (5%), and neutropenia (9%).Table 9: Select Laboratory Abnormalities (>=15%) Worsening from Baseline in Patients with DLBCL Who Received XPOVIO in SADALLaboratory AbnormalityXPOVIO 60 mg twice weeklyAll Grades(%)Grade or 4(%)Hematologic Platelet count decrease8649 Hemoglobin decrease8225 Lymphocyte count decrease6337 Neutrophil count decrease5831Chemistry Sodium decrease6216 Glucose increase57a Creatinine increase473.9 Phosphate decrease3411 Magnesium decrease302.6 Calcium decrease300.9 Potassium increase263.9 Potassium decrease237 CK increaseb 211.9Hepatic ALT increase290.8 Albumin decrease250 AST increase243.1 Bilirubin increase161.6. Injury: fall (8%). Metabolic and nutrition disorders: dehydration (7%). Neurologic disorders: headache (4.5%), syncope (2.2%). Infection: sepsis (6%), herpesvirus infection (3%). Eye disorders: cataract (3.7%). Blood and lymphatic disorders: febrile neutropenia (3%). Cardiac disorders: cardiac failure (3%).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Multiple Myeloma in Combination with Bortezomib and Dexamethasone (XVd): Recommended dosage of XPOVIO is 100 mg taken orally once weekly in combination with bortezomib and dexamethasone (2.1).Multiple Myeloma in Combination with Dexamethasone (Xd): Recommended dosage of XPOVIO is 80 mg taken orally on Days and of each week in combination with dexamethasone (2.1).DLBCL: Recommended dosage of XPOVIO is 60 mg taken orally on Days and of each week (2.2).. Multiple Myeloma in Combination with Bortezomib and Dexamethasone (XVd): Recommended dosage of XPOVIO is 100 mg taken orally once weekly in combination with bortezomib and dexamethasone (2.1).. Multiple Myeloma in Combination with Dexamethasone (Xd): Recommended dosage of XPOVIO is 80 mg taken orally on Days and of each week in combination with dexamethasone (2.1).. DLBCL: Recommended dosage of XPOVIO is 60 mg taken orally on Days and of each week (2.2).. 2.1 Recommended Dosage for Multiple Myeloma. In Combination with Bortezomib and Dexamethasone (XVd)The recommended dosage of XPOVIO is 100 mg taken orally once weekly on Day of each week until disease progression or unacceptable toxicity in combination with:Bortezomib 1.3 mg/m2 administered subcutaneously once weekly on Day of each week for weeks followed by week off.Dexamethasone 20 mg taken orally twice weekly on Days and of each week.Refer to Clinical Studies (14.1) and the prescribing information of bortezomib and dexamethasone for additional dosing information.. Bortezomib 1.3 mg/m2 administered subcutaneously once weekly on Day of each week for weeks followed by week off.. Dexamethasone 20 mg taken orally twice weekly on Days and of each week.. In Combination with Dexamethasone (Xd)The recommended dosage of XPOVIO is 80 mg taken orally on Days and of each week until disease progression or unacceptable toxicity in combination with dexamethasone 20 mg taken orally with each dose of XPOVIO on Days and of each week.For additional information regarding the administration of dexamethasone, refer to its prescribing information.. 2.2 Recommended Dosage for Diffuse Large B-Cell Lymphoma. The recommended dosage of XPOVIO is 60 mg taken orally on Days and of each week until disease progression or unacceptable toxicity.. 2.3 Recommended Monitoring for Safety. Monitor complete blood count (CBC) with differential, standard blood chemistries, body weight, nutritional status, and volume status at baseline and during treatment as clinically indicated. Monitor more frequently during the first three months of treatment [see Warning and Precautions (5.1, 5.2, 5.3, and 5.4)]. Assess the need for dosage modifications of XPOVIO for adverse reactions [see Dosage and Administration (2.5)].. 2.4 Recommended Concomitant Treatments. Advise patients to maintain adequate fluid and caloric intake throughout treatment. Consider intravenous hydration for patients at risk of dehydration [see Warnings and Precautions (5.3, 5.4)].Provide prophylactic antiemetics. Administer 5-HT3 receptor antagonist and other anti-nausea agents prior to and during treatment with XPOVIO [see Warnings and Precautions (5.3)].. 2.5 Dosage Modification for Adverse Reactions. Recommended XPOVIO dosage reduction steps are presented in Table 1.Table 1: XPOVIO Dosage Reduction Steps for Adverse ReactionsRecommended Starting DosageMultiple MyelomaIn Combination with Bortezomib and Dexamethasone (XVd)Multiple MyelomaIn Combination with Dexamethasone (Xd)Diffuse Large B-Cell Lymphoma100 mg once weekly80 mg Days and of each week(160 mg total per week)60 mg Days and of each week(120 mg total per week)First Reduction80 mg once weekly100 mg once weekly40 mg Days and of each week(80 mg total per week)Second Reduction60 mg once weekly80 mg once weekly60 mg once weeklyThird Reduction40 mg once weekly60 mg once weekly40 mg once weeklyFourth ReductionPermanently discontinuePermanently discontinuePermanently discontinueRecommended dosage modifications for hematologic adverse reactions in patients with multiple myeloma and DLBCL are presented in Table and Table 3, respectively. Recommended dosage modifications for non-hematologic adverse reactions are presented in Table 4.Table 2: XPOVIO Dosage Modification Guidelines for Hematologic Adverse Reactions in Patients with Multiple MyelomaAdverse ReactionOccurrenceActionThrombocytopenia[see Warning and Precautions (5.1)]Platelet count 25,000 to less than 75,000/mcLAnyReduce XPOVIO by dose level (see Table 1).Platelet count 25,000 to less than 75,000/mcL with concurrent bleedingAnyInterrupt XPOVIO.Restart XPOVIO at dose level lower (see Table 1) after bleeding has resolved.Administer platelet transfusions per clinical guidelines.Platelet count less than 25,000/mcLAny Interrupt XPOVIO.Monitor until platelet count returns to at least 50,000/mcL.Restart XPOVIO at dose level lower (see Table 1).Neutropenia[see Warning and Precautions (5.2)]Absolute neutrophil count of 0.5 to x 109/L without feverAnyReduce XPOVIO by dose level (see Table 1).Absolute neutrophil count less than 0.5 109/L OR febrile neutropeniaAny Interrupt XPOVIO.Monitor until neutrophil counts return to x 109/L or higher.Restart XPOVIO at dose level lower (see Table 1).AnemiaHemoglobin less than g/dLAnyReduce XPOVIO by dose level (see Table 1).Administer blood transfusions per clinical guidelines.Life-threatening consequences AnyInterrupt XPOVIO.Monitor hemoglobin until levels return to g/dL or higher.Restart XPOVIO at dose level lower (see Table 1).Administer blood transfusions per clinical guidelines.Table 3: XPOVIO Dosage Modification Guidelines for Hematologic Adverse Reactions in Patients with Diffuse Large B-Cell LymphomaAdverse ReactionOccurrenceActionThrombocytopenia[see Warning and Precautions (5.1)]Platelet count 50,000 to less than 75,000/mcLAnyInterrupt one dose of XPOVIO.Restart XPOVIO at the same dose level.Platelet count 25,000 to less than 50,000/mcL without bleeding1stInterrupt XPOVIO.Monitor until platelet count returns to at least 50,000/mcL.Reduce XPOVIO by dose level (see Table 1).Platelet count 25,000 to less than 50,000/mcL with concurrent bleedingAnyInterrupt XPOVIO.Monitor until platelet count returns to at least 50,000/mcL.Restart XPOVIO at dose level lower (see Table 1), after bleeding has resolved.Administer platelet transfusions per clinical guidelines.Platelet count less than 25,000/mcLAnyInterrupt XPOVIO.Monitor until platelet count returns to at least 50,000/mcL.Restart XPOVIO at dose level lower (see Table 1).Administer platelet transfusions per clinical guidelines.Neutropenia[see Warning and Precautions (5.2)]Absolute neutrophil count of 0.5 to less than x 109/L without fever1st occurrenceInterrupt XPOVIO.Monitor until neutrophil counts return to x 109/L or higher.Restart XPOVIO at the same dose level.RecurrenceInterrupt XPOVIO.Monitor until neutrophil counts return to x 109/L or higher.Administer growth factors per clinical guidelines.Restart XPOVIO at dose level lower (see Table 1).Absolute neutrophil count less than 0.5 109/L OR Febrile neutropeniaAnyInterrupt XPOVIO.Monitor until neutrophil counts return to x 109/L or higher.Administer growth factors per clinical guidelines.Restart XPOVIO at dose level lower (see Table 1).AnemiaHemoglobin less than g/dLAnyReduce XPOVIO by dose level (see Table 1).Administer blood transfusions per clinical guidelines.Life-threatening consequencesAnyInterrupt XPOVIO.Monitor hemoglobin until levels return to g/dL or higher.Restart XPOVIO at dose level lower (see Table 1).Administer blood transfusions per clinical guidelines.Table 4: XPOVIO Dosage Modification Guidelines for Non-Hematologic Adverse ReactionsAdverse ReactionOccurrenceActionNausea and Vomiting[see Warning and Precautions (5.3)]Grade or nausea (oral intake decreased without significant weight loss, dehydration or malnutrition) OR Grade or vomiting (5 or fewer episodes per day)AnyMaintain XPOVIO and initiate additional anti-nausea medications.Grade nausea (inadequate oral caloric or fluid intake) OR Grade or higher vomiting (6 or more episodes per day)AnyInterrupt XPOVIO.Monitor until nausea or vomiting has resolved to Grade or lower or baseline.Initiate additional anti-nausea medications.Restart XPOVIO at dose level lower (see Table 1).Diarrhea[see Warning and Precautions (5.3)]Grade (increase of to stools per day over baseline)1st Maintain XPOVIO and institute supportive care.2nd and subsequentReduce XPOVIO by dose level (see Table 1).Institute supportive care.Grade or higher (increase of stools or more per day over baseline; hospitalization indicated)Any Interrupt XPOVIO and institute supportive care.Monitor until diarrhea resolves to Grade or lower.Restart XPOVIO at dose level lower (see Table 1).Weight Loss and Anorexia[see Warning and Precautions (5.3)]Weight loss of 10% to less than 20% OR Anorexia associated with significant weight loss or malnutritionAnyInterrupt XPOVIO and institute supportive care.Monitor until weight returns to more than 90% of baseline weight.Restart XPOVIO at dose level lower (see Table 1).Hyponatremia[see Warning and Precautions (5.4)]Sodium level 130 mmol/L or lessAnyInterrupt XPOVIO, evaluate, and provide supportive care.Monitor until sodium levels return to greater than 130 mmol/L.Restart XPOVIO at dose level lower (see Table 1).FatigueGrade lasting greater than days OR Grade 3Any Interrupt XPOVIO.Monitor until fatigue resolves to Grade or baseline.Restart XPOVIO at dose level lower (see Table 1).Ocular Toxicity[see Warning and Precautions (5.8)]Grade 2, excluding cataractAnyPerform ophthalmologic evaluation.Interrupt XPOVIO and provide supportive care.Monitor until ocular symptoms resolve to Grade or baseline.Restart XPOVIO at dose level lower (see Table 1).Grade >=3, excluding cataractAnyPermanently discontinue XPOVIO.Perform ophthalmologic evaluation.Other Non-Hematologic Adverse Reactions[see Warning and Precautions (5.6)]Grade or 4AnyInterrupt XPOVIO.Monitor until resolved to Grade or lower; restart XPOVIO at dose level lower (see Table 1).. Reduce XPOVIO by dose level (see Table 1).. Interrupt XPOVIO.. Restart XPOVIO at dose level lower (see Table 1) after bleeding has resolved.. Administer platelet transfusions per clinical guidelines.. Interrupt XPOVIO.. Monitor until platelet count returns to at least 50,000/mcL.. Restart XPOVIO at dose level lower (see Table 1).. Reduce XPOVIO by dose level (see Table 1).. Interrupt XPOVIO.. Monitor until neutrophil counts return to x 109/L or higher.. Restart XPOVIO at dose level lower (see Table 1).. Reduce XPOVIO by dose level (see Table 1).. Administer blood transfusions per clinical guidelines.. Interrupt XPOVIO.. Monitor hemoglobin until levels return to g/dL or higher.. Restart XPOVIO at dose level lower (see Table 1).. Administer blood transfusions per clinical guidelines.. Interrupt one dose of XPOVIO.. Restart XPOVIO at the same dose level.. Interrupt XPOVIO.. Monitor until platelet count returns to at least 50,000/mcL.. Reduce XPOVIO by dose level (see Table 1).. Interrupt XPOVIO.. Monitor until platelet count returns to at least 50,000/mcL.. Restart XPOVIO at dose level lower (see Table 1), after bleeding has resolved.. Administer platelet transfusions per clinical guidelines.. Interrupt XPOVIO.. Monitor until platelet count returns to at least 50,000/mcL.. Restart XPOVIO at dose level lower (see Table 1).. Administer platelet transfusions per clinical guidelines.. Interrupt XPOVIO.. Monitor until neutrophil counts return to x 109/L or higher.. Restart XPOVIO at the same dose level.. Interrupt XPOVIO.. Monitor until neutrophil counts return to x 109/L or higher.. Administer growth factors per clinical guidelines.. Restart XPOVIO at dose level lower (see Table 1).. Interrupt XPOVIO.. Monitor until neutrophil counts return to x 109/L or higher.. Administer growth factors per clinical guidelines.. Restart XPOVIO at dose level lower (see Table 1).. Reduce XPOVIO by dose level (see Table 1).. Administer blood transfusions per clinical guidelines.. Interrupt XPOVIO.. Monitor hemoglobin until levels return to g/dL or higher.. Restart XPOVIO at dose level lower (see Table 1).. Administer blood transfusions per clinical guidelines.. Maintain XPOVIO and initiate additional anti-nausea medications.. Interrupt XPOVIO.. Monitor until nausea or vomiting has resolved to Grade or lower or baseline.. Initiate additional anti-nausea medications.. Restart XPOVIO at dose level lower (see Table 1).. Maintain XPOVIO and institute supportive care.. Reduce XPOVIO by dose level (see Table 1).. Institute supportive care.. Interrupt XPOVIO and institute supportive care.. Monitor until diarrhea resolves to Grade or lower.. Restart XPOVIO at dose level lower (see Table 1).. Interrupt XPOVIO and institute supportive care.. Monitor until weight returns to more than 90% of baseline weight.. Restart XPOVIO at dose level lower (see Table 1).. Interrupt XPOVIO, evaluate, and provide supportive care.. Monitor until sodium levels return to greater than 130 mmol/L.. Restart XPOVIO at dose level lower (see Table 1).. Interrupt XPOVIO.. Monitor until fatigue resolves to Grade or baseline.. Restart XPOVIO at dose level lower (see Table 1).. Perform ophthalmologic evaluation.. Interrupt XPOVIO and provide supportive care.. Monitor until ocular symptoms resolve to Grade or baseline.. Restart XPOVIO at dose level lower (see Table 1).. Permanently discontinue XPOVIO.. Perform ophthalmologic evaluation.. Interrupt XPOVIO.. Monitor until resolved to Grade or lower; restart XPOVIO at dose level lower (see Table 1).. 2.6 Administration. 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 dose of XPOVIO is missed or delayed, instruct patients to take their next dose at the next regularly scheduled time.If patient vomits dose of XPOVIO, the patient should not repeat the dose and the patient should take the next dose on the next regularly scheduled day.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. 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 patient misses dose, advise them to take their next dose at its regularly scheduled time. If patient vomits or misses dose of XPOVIO, advise them to take the next dose on the next regularly scheduled day.Advise patients that XPOVIO comes in child-resistant blister pack.Advise patients to take their prescribed dexamethasone (if applicable) and prophylactic anti-nausea medications as directed [see Dosage and Administration (2.1, 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 three months of treatment [see Dosage and Administration (2.3)].Advise patients to maintain appropriate fluid and caloric intake throughout their treatment [see Dosage and Administration (2.4)].. 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 patient misses dose, advise them to take their next dose at its regularly scheduled time. If patient vomits or misses dose of XPOVIO, advise them to take the next dose on the next regularly scheduled day.. Advise patients that XPOVIO comes in child-resistant blister pack.. Advise patients to take their prescribed dexamethasone (if applicable) and prophylactic anti-nausea medications as directed [see Dosage and Administration (2.1, 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 three months of treatment [see Dosage and Administration (2.3)].. Advise patients to maintain appropriate fluid and caloric intake throughout their treatment [see Dosage and Administration (2.4)].. Hematologic Adverse Reactions. ThrombocytopeniaAdvise 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 months of treatment. Advise patients to report signs of bleeding right away [see Warnings and Precautions (5.1)].. AnemiaAdvise 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)].. NeutropeniaAdvise 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 months of treatment.. Gastrointestinal Adverse ReactionsAdvise 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)].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)].. HyponatremiaAdvise 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)]. Serious InfectionAdvise patients of the possibility of serious infections. Instruct patients to immediately report infection-related signs or symptoms (e.g., chills, fever) [see Warnings and Precautions (5.5)].. NeurotoxicityAdvise patients that they may experience confusion and dizziness. Advise patients to report symptoms of neurological toxicity right away. Advise patients not to drive or operate hazardous machinery until the neurological toxicity fully resolves. Advise patients to use fall prevention measures as warranted [see Warnings and Precautions (5.6)].. Embryo-Fetal ToxicityAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to contact their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].Advise females of reproductive potential and males with female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for week after the final dose [see Use in Specific Populations (8.3)].. CataractAdvise patients of the potential risk of worsening or new onset of cataract, that may require surgery. Advise patients to readily inform their healthcare professionals of changes in vision (i.e. blurred vision) and that ophthalmologic evaluation may be performed as clinically indicated [see Warnings and Precautions (5.8)].. FatigueAdvise patients that they may experience fatigue [see Adverse Reactions (6.1)]. LactationAdvise women not to breastfeed during treatment with XPOVIO and for week after the final dose [see Use in Specific Populations (8.2)].. Concomitant MedicationsAdvise patients to take 5-HT3 antagonist prophylactic treatment and other anti-nausea agents prior to and during treatment with XPOVIO [see Dosage and Administration (2.4)].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 registered trademark of Karyopharm Therapeutics Inc.(C)2020-2021 Karyopharm Therapeutics Inc.For more information, call 1-888-209-9326 or go to www.XPOVIO.com.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: August 2021MEDICATION GUIDEXPOVIO(R) (x-PO-Vee-O)(selinexor)tabletsWhat is the most important information should know about XPOVIOXPOVIO can cause serious side effects, including:Low platelet counts. Low platelet counts are common with XPOVIO and can lead to bleeding which can be severe and can sometimes cause death. Your healthcare provider may prescribe platelet transfusions or other treatments for your low platelet counts.Tell your healthcare provider right away if you have any bleeding or easy bruising during treatment with XPOVIO.Low white blood cell counts. Low white blood cell counts are common with XPOVIO and can sometimes be severe. You may have an increased risk of getting bacterial infections during treatment with XPOVIO. Your healthcare provider may prescribe antibiotics if you have signs or symptoms of infection, or certain medicines to help increase your white blood cell count, if needed.Your healthcare provider will do blood tests before you start taking XPOVIO, and often during the first months of treatment, and then as needed during treatment to monitor you for side effects.Your healthcare provider may change your dose of XPOVIO, stop your treatment for period of time, or completely stop your treatment if you have certain side effects during treatment with XPOVIO. See What are the possible side effects of XPOVIO for more information about side effects. What is XPOVIOXPOVIO is prescription medicine used:in combination with the medicines VELCADE(R) (bortezomib) and dexamethasone to treat adults with multiple myeloma (MM) who have received at least one prior treatment for their disease.in combination with dexamethasone to treat adults with multiple myeloma (MM) that has come back (relapsed) or that did not respond to previous treatment (refractory), andwho have received at least prior therapies, and whose disease did not respond to (refractory) to at least proteasome inhibitor medicines, at least immunomodulatory agents, and an anti-CD38 monoclonal antibody medicine. to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL) that has come back (relapsed) or that did not respond to previous treatment (refractory) and who have received at least prior therapies It is not known if XPOVIO is safe and effective in children less than 18 years of age.What should tell my healthcare provider before taking XPOVIOBefore taking XPOVIO, tell your healthcare provider about all of your medical conditions, including if you:have or have had recent or active infectionhave or have had bleeding problemsare pregnant or plan to become pregnant. XPOVIO can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start taking XPOVIO.You should use effective birth control (contraception) during treatment with XPOVIO and for week after your last dose.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with XPOVIO. Males with female partners who are able to become pregnant: You should use effective birth control during treatment with XPOVIO and for week after your last dose. are breastfeeding or plan to breastfeed. It is not known if XPOVIO passes into your breast milk.Do not breastfeed during treatment with XPOVIO and for week after your last dose of XPOVIO. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk with your healthcare provider before taking any new medicines.How should take XPOVIOTake XPOVIO exactly as prescribed by your healthcare provider.If you have multiple myeloma, your healthcare provider will prescribe dexamethasone with your XPOVIO treatment. Take dexamethasone exactly as prescribed.Your healthcare provider will tell you how much XPOVIO to take and when to take it. Do not change your dose or stop taking XPOVIO without talking to your healthcare provider first.Swallow XPOVIO tablets whole with water. Do not break, chew, crush, or divide the tablets. Be sure to take any medicines prescribed by your healthcare provider before and during treatment with XPOVIO to help prevent nausea and vomiting. Tell your healthcare provider if the prescribed medicine does not control your nausea and vomiting.It is important for you to drink enough fluids to help prevent dehydration and to eat enough calories to help prevent weight loss during treatment with XPOVIO. Talk to your healthcare provider if this is problem for you. See What are the possible side effects of XPOVIO If you miss dose of XPOVIO, take your next dose at your next regularly scheduled day and time.If you vomit after taking dose of XPOVIO, do not take an extra dose. Take your next dose at your next regularly scheduled day and time.If you take too much XPOVIO, call your healthcare provider right away.What should avoid while taking XPOVIOXPOVIO can cause neurologic side effects.See What are the possible side effects of XPOVIO below.If you have any neurologic side effects with XPOVIO, do not drive or operate heavy or dangerous machinery until your neurologic side effects go away. Avoid falling. Use care as needed to avoid falling due to neurologic side effects.What are the possible side effects of XPOVIOXPOVIO can cause serious side effects, including:See What is the most important information should know about XPOVIONausea and vomiting. Nausea and vomiting are common with XPOVIO and can sometimes be severe. Nausea and vomiting may affect your ability to eat and drink well. You can lose too much body fluid and body salts (electrolytes) and may be at risk for becoming dehydrated. You may need to receive intravenous (IV) fluids or other treatments to help prevent dehydration. Your healthcare provider will prescribe anti-nausea medicines for you to take before you start and during treatment with XPOVIO. See How should take XPOVIO Diarrhea. Diarrhea is common with XPOVIO and can sometimes be severe. You can lose too much body fluid and body salts (electrolytes) and may be at risk for becoming dehydrated. You may need to receive IV fluids or other treatments to help prevent dehydration. Your healthcare provider will prescribe anti-diarrhea medicine for you as needed.Loss of appetite and weight loss. Loss of appetite and weight loss are common with XPOVIO and can sometimes be severe. Tell your healthcare provider if you have decrease or loss of appetite and if you notice that you are losing weight at any time during treatment. Your healthcare provider may prescribe medicines that can help increase your appetite or prescribe other kinds of nutritional support. Your healthcare provider will monitor your appetite and weight before you start XPOVIO and often during the first months, then as needed during treatment.Decreased sodium levels in your blood. Decreased sodium levels in your blood is common with XPOVIO but can also sometimes be severe. Low sodium levels in your blood can happen if you have nausea, vomiting, or diarrhea, you become dehydrated, or if you have loss of appetite with XPOVIO. You may not have any symptoms of low sodium level. Your healthcare provider may talk with you about your diet and prescribe IV fluids for you based on the sodium levels in your blood. Your healthcare provider will do blood tests before you start taking XPOVIO, and often during the first months of treatment, and then as needed during treatment to monitor the sodium levels in your blood.Serious infections. Infections are common with XPOVIO and can be serious and can sometimes cause death. XPOVIO can cause infections including upper or lower respiratory tract infections, such as pneumonia, and an infection throughout your body (sepsis). Tell your healthcare provider right away if you have any signs or symptoms of an infection such as cough, chills or fever, during treatment with XPOVIO. Neurologic side effects. XPOVIO can cause neurologic side effects that can sometimes be severe and life-threatening.XPOVIO can cause dizziness, fainting, decreased alertness, and changes in your mental status including confusion and decreased awareness of things around you (delirium).In some people, XPOVIO may also cause problems with thinking (cognitive problems), seeing or hearing things that are not really there (hallucinations), and may become very sleepy or drowsy.Taking other medicines that can cause dizziness or mental status changes during treatment with XPOVIO may increase your risk of neurologic side effects. Tell your healthcare provider right away if you get any of these signs or symptoms.New or worsening cataract, cloudy or loss of transparency of the lens in the eye. New or worsening cataract are common with XPOVIO. If cataract forms, your vision may decrease, and you may need eye surgery to remove the cataract and restore your vision. Tell your healthcare provider right away if you have symptoms of cataract such as double vision, blurred vision, sensitivity to light or glare.Your healthcare provider may change your dose of XPOVIO, stop your treatment for period of time, or completely stop your treatment if you have certain side effects during treatment with XPOVIO.Common side effects of XPOVIO include: tirednesslow red blood cell count (anemia). Symptoms may include tiredness and shortness of breath.constipationshortness of breathincreased blood sugarchanges in body salt and mineral levels in your bloodchanges in kidney and liver function blood tests XPOVIO may cause fertility problems in males and females, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.These are not all the possible side effects of XPOVIO.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store XPOVIOStore XPOVIO at or below 86F (30C).XPOVIO comes in child-resistant blister pack.Keep XPOVIO and all medicines out of the reach of children.General information about the safe and effective use of XPOVIO.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use XPOVIO for condition for which it was not prescribed. Do not give XPOVIO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about XPOVIO that is written for health professionals.What are the ingredients in XPOVIOActive ingredient: selinexorInactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, Opadry 200 clear, Opadry II blue, povidone K30, and sodium lauryl sulfate.Manufactured for and marketed by: Karyopharm Therapeutics Inc., 85 Wells Avenue, Newton, MA, 02459XPOVIO is registered trademark of Karyopharm Therapeutics Inc. All other trademarks are the property of their respective owners.(C)2020-2021 Karyopharm Therapeutics Inc.For more information, call 1-888-209-9326 or go to www.XPOVIO.com. Low platelet counts. Low platelet counts are common with XPOVIO and can lead to bleeding which can be severe and can sometimes cause death. Your healthcare provider may prescribe platelet transfusions or other treatments for your low platelet counts.Tell your healthcare provider right away if you have any bleeding or easy bruising during treatment with XPOVIO.. Low white blood cell counts. Low white blood cell counts are common with XPOVIO and can sometimes be severe. You may have an increased risk of getting bacterial infections during treatment with XPOVIO. Your healthcare provider may prescribe antibiotics if you have signs or symptoms of infection, or certain medicines to help increase your white blood cell count, if needed.. in combination with the medicines VELCADE(R) (bortezomib) and dexamethasone to treat adults with multiple myeloma (MM) who have received at least one prior treatment for their disease.. in combination with dexamethasone to treat adults with multiple myeloma (MM) that has come back (relapsed) or that did not respond to previous treatment (refractory), andwho have received at least prior therapies, and whose disease did not respond to (refractory) to at least proteasome inhibitor medicines, at least immunomodulatory agents, and an anti-CD38 monoclonal antibody medicine. who have received at least prior therapies, and whose disease did not respond to (refractory) to at least proteasome inhibitor medicines, at least immunomodulatory agents, and an anti-CD38 monoclonal antibody medicine.. to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL) that has come back (relapsed) or that did not respond to previous treatment (refractory) and who have received at least prior therapies have or have had recent or active infection. have or have had bleeding problems. are pregnant or plan to become pregnant. XPOVIO can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start taking XPOVIO.You should use effective birth control (contraception) during treatment with XPOVIO and for week after your last dose.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with XPOVIO. Males with female partners who are able to become pregnant: You should use effective birth control during treatment with XPOVIO and for week after your last dose. Your healthcare provider will check to see if you are pregnant before you start taking XPOVIO.. You should use effective birth control (contraception) during treatment with XPOVIO and for week after your last dose.. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with XPOVIO.. You should use effective birth control during treatment with XPOVIO and for week after your last dose.. are breastfeeding or plan to breastfeed. It is not known if XPOVIO passes into your breast milk.Do not breastfeed during treatment with XPOVIO and for week after your last dose of XPOVIO. Do not breastfeed during treatment with XPOVIO and for week after your last dose of XPOVIO.. Take XPOVIO exactly as prescribed by your healthcare provider.. If you have multiple myeloma, your healthcare provider will prescribe dexamethasone with your XPOVIO treatment. Take dexamethasone exactly as prescribed.. Your healthcare provider will tell you how much XPOVIO to take and when to take it. Do not change your dose or stop taking XPOVIO without talking to your healthcare provider first.. Swallow XPOVIO tablets whole with water. Do not break, chew, crush, or divide the tablets. Be sure to take any medicines prescribed by your healthcare provider before and during treatment with XPOVIO to help prevent nausea and vomiting. Tell your healthcare provider if the prescribed medicine does not control your nausea and vomiting.. It is important for you to drink enough fluids to help prevent dehydration and to eat enough calories to help prevent weight loss during treatment with XPOVIO. Talk to your healthcare provider if this is problem for you. See What are the possible side effects of XPOVIO If you miss dose of XPOVIO, take your next dose at your next regularly scheduled day and time.. If you vomit after taking dose of XPOVIO, do not take an extra dose. Take your next dose at your next regularly scheduled day and time.. If you take too much XPOVIO, call your healthcare provider right away.. See What are the possible side effects of XPOVIO below.. If you have any neurologic side effects with XPOVIO, do not drive or operate heavy or dangerous machinery until your neurologic side effects go away. Avoid falling. Use care as needed to avoid falling due to neurologic side effects.. See What is the most important information should know about XPOVIO. Nausea and vomiting. Nausea and vomiting are common with XPOVIO and can sometimes be severe. Nausea and vomiting may affect your ability to eat and drink well. You can lose too much body fluid and body salts (electrolytes) and may be at risk for becoming dehydrated. You may need to receive intravenous (IV) fluids or other treatments to help prevent dehydration. Your healthcare provider will prescribe anti-nausea medicines for you to take before you start and during treatment with XPOVIO. See How should take XPOVIO Diarrhea. Diarrhea is common with XPOVIO and can sometimes be severe. You can lose too much body fluid and body salts (electrolytes) and may be at risk for becoming dehydrated. You may need to receive IV fluids or other treatments to help prevent dehydration. Your healthcare provider will prescribe anti-diarrhea medicine for you as needed.. Loss of appetite and weight loss. Loss of appetite and weight loss are common with XPOVIO and can sometimes be severe. Tell your healthcare provider if you have decrease or loss of appetite and if you notice that you are losing weight at any time during treatment. Your healthcare provider may prescribe medicines that can help increase your appetite or prescribe other kinds of nutritional support. Your healthcare provider will monitor your appetite and weight before you start XPOVIO and often during the first months, then as needed during treatment.. Decreased sodium levels in your blood. Decreased sodium levels in your blood is common with XPOVIO but can also sometimes be severe. Low sodium levels in your blood can happen if you have nausea, vomiting, or diarrhea, you become dehydrated, or if you have loss of appetite with XPOVIO. You may not have any symptoms of low sodium level. Your healthcare provider may talk with you about your diet and prescribe IV fluids for you based on the sodium levels in your blood. Your healthcare provider will do blood tests before you start taking XPOVIO, and often during the first months of treatment, and then as needed during treatment to monitor the sodium levels in your blood.. Serious infections. Infections are common with XPOVIO and can be serious and can sometimes cause death. XPOVIO can cause infections including upper or lower respiratory tract infections, such as pneumonia, and an infection throughout your body (sepsis). Tell your healthcare provider right away if you have any signs or symptoms of an infection such as cough, chills or fever, during treatment with XPOVIO. Neurologic side effects. XPOVIO can cause neurologic side effects that can sometimes be severe and life-threatening.XPOVIO can cause dizziness, fainting, decreased alertness, and changes in your mental status including confusion and decreased awareness of things around you (delirium).In some people, XPOVIO may also cause problems with thinking (cognitive problems), seeing or hearing things that are not really there (hallucinations), and may become very sleepy or drowsy.Taking other medicines that can cause dizziness or mental status changes during treatment with XPOVIO may increase your risk of neurologic side effects. XPOVIO can cause dizziness, fainting, decreased alertness, and changes in your mental status including confusion and decreased awareness of things around you (delirium).. In some people, XPOVIO may also cause problems with thinking (cognitive problems), seeing or hearing things that are not really there (hallucinations), and may become very sleepy or drowsy.. Taking other medicines that can cause dizziness or mental status changes during treatment with XPOVIO may increase your risk of neurologic side effects. Tell your healthcare provider right away if you get any of these signs or symptoms.. New or worsening cataract, cloudy or loss of transparency of the lens in the eye. New or worsening cataract are common with XPOVIO. If cataract forms, your vision may decrease, and you may need eye surgery to remove the cataract and restore your vision. Tell your healthcare provider right away if you have symptoms of cataract such as double vision, blurred vision, sensitivity to light or glare.. tiredness. low red blood cell count (anemia). Symptoms may include tiredness and shortness of breath.. constipation. shortness of breath. increased blood sugar. changes in body salt and mineral levels in your blood. changes in kidney and liver function blood tests. Store XPOVIO at or below 86F (30C).. XPOVIO comes in child-resistant blister pack.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed (8.2).. 8.1 Pregnancy. Risk SummaryBased on findings in animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], XPOVIO can cause fetal harm when administered to 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 dataIn an embryo-fetal development study in pregnant rats, daily oral administration of selinexor at 0, 0.25, 0.75, or mg/kg throughout organogenesis caused incomplete or delayed ossification, skeletal variations, and reduced fetal weight compared with controls at 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 mg/kg, including microphthalmia, fetal edema, malpositioned kidney, and persistent truncus arteriosus.. 8.2 Lactation. Risk SummaryThere 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 breastfed child, advise women not to breastfeed during treatment with XPOVIO and for week after the last dose.. 8.3 Females and Males of Reproductive Potential. XPOVIO can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating XPOVIO [see Use in Specific Populations (8.1)].. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with XPOVIO and for week after the last dose.. MalesAdvise males with female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for week after the last dose.. Infertility. Females and MalesBased 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. In BOSTON, of the 195 patients with multiple myeloma who received XPOVIO in combination with bortezomib and dexamethasone, 56% were 65 years of age and older, while 17% were 75 years of age and older. No overall differences in effectiveness were observed between these patients and younger patients. When comparing patients 65 years of age and older to younger patients, older patients had higher incidence of discontinuation due to an adverse reaction (28% vs 13%) and higher incidence of serious adverse reactions (56% vs 47%).In STORM, of the 202 patients with multiple myeloma who received XPOVIO, 49% were 65 years of age and older, while 11% were 75 years of age and older. 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Thrombocytopenia: Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care (2.5, 5.1).Neutropenia: Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony-stimulating factors (2.5, 5.2).Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care (2.5, 5.3).Hyponatremia: Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care (2.5, 5.4).Serious Infection: Monitor for infection and treat promptly (5.2, 5.5).Neurological Toxicity: Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes (5.6).Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partner of reproductive potential, of the potential risk to fetus and use of effective contraception (5.7, 8.1, 8.3).Cataract: Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract (5.8).. Thrombocytopenia: Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care (2.5, 5.1).. Neutropenia: Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony-stimulating factors (2.5, 5.2).. Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care (2.5, 5.3).. Hyponatremia: Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care (2.5, 5.4).. Serious Infection: Monitor for infection and treat promptly (5.2, 5.5).. Neurological Toxicity: Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes (5.6).. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partner of reproductive potential, of the potential risk to fetus and use of effective contraception (5.7, 8.1, 8.3).. Cataract: Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract (5.8).. 5.1 Thrombocytopenia. XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia is the leading cause of dosage modifications [see Adverse Reactions (6.1)].In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), thrombocytopenia was reported in 92% of patients and severe (Grade 3-4) thrombocytopenia was reported in 43% of patients. The median time to first onset was 22 days for any grade thrombocytopenia and 43 days for Grade or thrombocytopenia. Bleeding occurred in 16% of patients with thrombocytopenia, clinically significant bleeding (Grade >=3 bleeding) occurred in 4% of patients with thrombocytopenia, and fatal hemorrhage occurred in 2% of patients with thrombocytopenia. Permanent discontinuations of XPOVIO due to thrombocytopenia occurred in 2% of patients.In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), thrombocytopenia was reported as an adverse reaction in 74% of patients and severe (Grade 3-4) thrombocytopenia was reported in 61% of patients. 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.In patients with DLBCL who received XPOVIO 60 mg twice weekly (SADAL, n=134), thrombocytopenia developed or worsened in 86% of patients, including Grade 3-4 thrombocytopenia in 49% of patients (Grade 4, 18%). The median time to first onset was 28 days for any grade thrombocytopenia and 33 days for Grade or thrombocytopenia.Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during the first three 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, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5)].. 5.2 Neutropenia. XPOVIO can cause life-threatening neutropenia, potentially increasing the risk of infection [see Adverse Reactions (6.1)].In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), neutropenia was reported in 48% of patients and severe neutropenia (Grade 3-4) was reported in 12% of patients. The median time to onset of the first event was 23 days for any grade neutropenia and 40 days for Grade 3-4 neutropenia. Febrile neutropenia was reported in <1% of patients.In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), neutropenia was reported as an adverse reaction in 34% of patients and severe (Grade 3-4) neutropenia was reported in 21% of patients. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.In patients with DLBCL (SADAL, n=134), Grade neutropenia developed in 21% of patients and Grade neutropenia developed in 9% of patients. The median time to first onset of Grade or neutropenia was 32 days. Febrile neutropenia was reported in 3% of patients.Obtain white blood cell counts with differential at baseline and throughout treatment. Monitor more frequently during the first three months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5)].. 5.3 Gastrointestinal Toxicity. XPOVIO can cause severe gastrointestinal toxicities [see Adverse Reactions (6.1)]. In patients with DLBCL (n=134), gastrointestinal toxicity occurred in 80% of patients with Grade or in 13%.. Nausea/VomitingIn patients with multiple myeloma who received XPOVIO once weekly (BOSTON, n=195) with use of antiemetic prophylaxis (88% of patients), nausea was reported in 50% of patients and Grade nausea was reported in 8% of patients. The median time to onset of the first event was days. Vomiting was reported in 21% of patients and Grade vomiting was reported in 4.1% of patients. The median time to onset of the first event was days. Permanent discontinuation due to nausea occurred in 3.1% of patients and due to vomiting occurred in 2.1% of patients.In patients with multiple myeloma receiving XPOVIO 80 mg twice weekly (STORM, n=202) with use of antiemetic prophylaxis, nausea was reported as an adverse reaction in 72% of patients and Grade nausea occurred in 9%. The median time to first onset of nausea was days. Vomiting was reported in 41% of patients and Grade vomiting occurred in 4% of patients. The median time to first onset of vomiting was days.In patients with DLBCL (SADAL, n=134) with use of antiemetic prophylaxis, nausea occurred in 57% of patients and Grade nausea occurred in 6% of patients. Vomiting occurred in 28% of patients and Grade vomiting occurred in 1.5% of patients. The median time to first onset was days for nausea and days for vomiting.Provide prophylactic antiemetics. Administer 5-HT3 receptor antagonists and other anti-nausea agents prior to and during treatment with XPOVIO. Interrupt, reduce dose or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5)]. Administer intravenous fluids to prevent dehydration and replace electrolytes as clinically indicated.. DiarrheaIn patients with multiple myeloma who received XPOVIO once weekly (BOSTON, n=195), diarrhea was reported in 32% of patients and Grade diarrhea was reported in 6% of patients. The median time to onset of the first event was 50 days. Permanent discontinuation due to diarrhea occurred in 1% of patients.In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), diarrhea was reported as an adverse reaction in 44% of patients and Grade diarrhea occurred in 6% of patients. The median time to onset of diarrhea was 15 days.In patients with DLBCL (SADAL, n=134), diarrhea occurred in 37% of patients and Grade diarrhea occurred in 3% of patients treated with XPOVIO. The median time to onset of the first event was 12 days.Interrupt, reduce dose or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5)]. Provide standard anti-diarrheal agents, administer intravenous fluids to prevent dehydration and replace electrolytes as clinically indicated.. Anorexia/Weight LossIn patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), anorexia was reported in 35% of patients and Grade anorexia was reported in 3.6% of patients. The median time to onset of the first event was 35 days. Permanent discontinuations due to anorexia occurred in 2.1% of patients. Weight loss was reported in 26% of patients and Grade weight loss was reported in 2.1% of patients. The median time to onset of the first event was 58 days. Permanent discontinuation due to weight loss occurred in 1% of patients.In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM n=202), anorexia was reported as an adverse reaction in 53% of patients and Grade anorexia occurred in 5% of patients. The median time to onset of anorexia was days. Weight loss was reported as an adverse reaction in 47% of patients and Grade weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.In patients with DLBCL (SADAL, n=134), anorexia was reported as an adverse reaction in 37% of patients and Grade anorexia occurred in 3.7% of patients treated with XPOVIO. Weight loss (Grade 1-2) was reported as an adverse reaction in 30% of patients.Monitor weight, nutritional status, and volume status at baseline and throughout treatment. Monitor more frequently during the first three months of treatment. Interrupt, reduce dose or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5)]. Provide nutritional support, fluids, and electrolyte repletion as clinically indicated.. 5.4 Hyponatremia. XPOVIO can cause severe or life-threatening hyponatremia [see Adverse Reactions (6.1)].In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), hyponatremia was reported in 58% of patients and Grade 3-4 hyponatremia was reported in 14% of patients. The median time to first onset was 21 days for any grade hyponatremia and the median time to first onset for Grade or hyponatremia was 22 days.In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), hyponatremia was reported as an adverse reaction in 39% of patients and Grade or hyponatremia was reported in 22% of patients. The median time to onset of the first event was days.In patients with DLBCL (SADAL, n=134), hyponatremia developed in 62% of patients and Grade hyponatremia developed in 16% of patients treated with XPOVIO. In approximately 63% of cases, hyponatremia occurred in the context of gastrointestinal toxicity such as nausea, vomiting, diarrhea, dehydration, and anorexia.Monitor sodium level at baseline and throughout treatment. 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. Assess hydration status and manage hyponatremia per clinical guidelines, including intravenous saline and/or salt tablets as appropriate and dietary review. Interrupt, reduce dose or permanently discontinue based on severity of the adverse reaction [see Dosage and Administration (2.5)]. 5.5 Serious Infection. XPOVIO can cause serious and fatal infections. Most of these infections were not associated with Grade or higher neutropenia [see Adverse Reactions (6.1)]. In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), 69% of patients experienced any grade of infection. Grade >=3 infections were reported in 32% of patients, and deaths from infections occurred in 3.1% of patients. The most frequently reported Grade >=3 infection was pneumonia in 14% of patients, followed by sepsis in 4.1% and upper respiratory tract infection in 3.6% of patients.In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), 52% of patients experienced any grade of infection. Grade >=3 infections were reported in 25% of patients, and deaths from infections occurred in 4% of patients within 30 days of last treatment. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. The most frequently 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.In patients with DLBCL (SADAL, n=134), 25% of patients experienced Grade or higher infection and 21% had an infection-related serious adverse reaction; 49% developed an infection of any grade, most frequently involving the upper or lower respiratory tract. The most frequently reported Grade >=3 infections were lower respiratory tract infections in 9% of patients (including pneumonia in 6%), followed by sepsis (6%). The median time to onset of Grade >=3 infection was 42 days.Atypical infections reported after XPOVIO include, but are not limited to, fungal pneumonia and herpes virus infection.Monitor for signs and symptoms of infection, evaluate and treat promptly.. 5.6 Neurological Toxicity. XPOVIO can cause life-threatening neurological toxicities [see Adverse Reactions (6.1)].In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), neurological adverse reactions (excluding peripheral neuropathy) including dizziness, syncope, depressed level of consciousness, vertigo, amnesia, and mental status changes (including delirium and confusional state) occurred in 26% of patients and severe events (Grade 3-4) occurred in 3.6% of patients. The median time to the first event was 29 days. Permanent discontinuation due to neurological adverse reactions occurred in 2.1% of patients.In patients with multiple myeloma who received XPOVIO 80 mg twice weekly (STORM, n=202), 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. The median time to the first event was 15 days.In patients with DLBCL (SADAL, n=134), neurological adverse reactions occurred in 25% of patients and severe events (Grade 3-4) occurred in 6% of patients treated with XPOVIO. The most frequent manifestations were dizziness (16%) and mental status changes (11%), including confusion, cognitive disorders, somnolence, hallucination, delirium, and depressed level of consciousness. Syncope occurred in 2.2% of patients. The median time to the first event was 28 days. Among patients with such neurological adverse reactions, 68% recovered with median time to recovery of 14 days.Coadministration of XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurological toxicity fully resolves. Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes. Institute fall precautions as appropriate.. 5.7 Embryo-Fetal Toxicity. Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential and males with female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for week after the last dose [see Use in Specific Populations (8.1, 8.3)].. 5.8 Cataract. New onset or exacerbation of cataract has occurred during treatment with XPOVIO [see Adverse Reactions (6.1)]. In patients with multiple myeloma who received XPOVIO 100 mg once weekly (BOSTON, n=195), the incidence of new onset or worsening cataracts requiring clinical intervention was reported in 22% of patients. The median time to new onset of cataract was 228 days and was 237 days for worsening of cataract in patients presenting with cataract at start of XPOVIO therapy. Treatment of cataracts usually requires surgical removal of the cataract.