XPOVIO
Generic: SELINEXOR
Basic Information
Manufacturer
Karyopharm Therapeutics Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
f6dd2682-75a6-4863-90a8-a3197f6f78a8
Indications & Usage
1 INDICATIONS AND USAGE XPOVIO is a nuclear export inhibitor indicated: In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy ( 1.1 ).
In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody ( 1.1 ).
1.1 Multiple Myeloma XPOVIO in combination with bortezomib and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
XPOVIO in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody ( 1.1 ).
1.1 Multiple Myeloma XPOVIO in combination with bortezomib and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
XPOVIO in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
Adverse Reactions
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 )] .
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, weight decreased, 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, weight decreased, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection ( 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.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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: 1 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, a 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, weight decreased (7% each), and asthenia (6%).
The most common adverse reactions (≥20% with a difference between arms of >5% compared to Vd) were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, weight decreased, cataract, and vomiting.
Grade 3-4 laboratory abnormalities (≥10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia.
Table 6 summarizes the adverse reactions in BOSTON.
Table 6: Adverse Reactions (≥10%) in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) with a Difference Between Arms of >5% Compared to Vd in BOSTON Key: X=XPOVIO, Vd=bortezomib-dexamethasone a.
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 Reaction Weekly XVd (n=195) Twice Weekly Vd (n=204) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal Nausea 50 8 10 0 Diarrhea 32 6 25 <1 Vomiting 21 4.1 4.4 0 General Conditions Fatigue a 59 21 28 5 Pyrexia 15 1.5 11 1 Metabolism and Nutrition Decreased appetite 35 3.6 5 0 Weight decreased 26 2.1 12 1 Nervous System Peripheral neuropathy b 32 4.6 47 9 Dizziness 12 <1 3.9 0 Infections Upper respiratory tract infection c 29 3.6 22 1.5 Eye Disorders Cataract 22 9 6 1.5 Vision blurred d 13 <1 6 0 Clinically 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 7 summarizes selected laboratory abnormalities in BOSTON.
Table 7: Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) in BOSTON Laboratory Abnormality Weekly XVd Twice Weekly Vd All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 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 decrease 92 43 51 19 Lymphocyte count decrease 77 38 70 27 Hemoglobin decrease 71 17 51 a 12 Neutrophil count decrease 48 12 19 7 Chemistry Glucose increase 62 3.8 47 4.1 Phosphate decrease 61 23 42 11 Sodium decrease 58 14 25 3 Calcium decrease 55 2.1 47 1 Blood urea nitrogen increase 41 5 40 5 Creatinine increase 28 3.6 24 1.5 Potassium decrease 27 6 22 3.5 Magnesium decrease 27 <1 23 1.5 Potassium increase 18 4.1 21 2.5 Hepatic ALT increase 33 3.1 30 <1 Albumin decrease 27 <1 35 <1 AST increase 24 1.5 19 <1 Bilirubin increase 16 1 13 2 ALP increase 12 0 16 <1 XPOVIO 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 1 and 3 of every week (n=202).
The median duration of XPOVIO treatment was 8 weeks (range: 1 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 a 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 8 summarizes the adverse reactions in STORM.
Table 8: Adverse Reactions (≥10%) in Patients Who Received XPOVIO in STORM Adverse Reaction XPOVIO 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 (%) Thrombocytopenia a 74 61 Fatigue b 73 22 Nausea 72 9 Anemia c 59 40 Decreased appetite 53 4.5 Weight decreased 47 0.5 Diarrhea 44 6 Vomiting 41 3.5 Hyponatremia 39 22 Neutropenia d 34 21 Leukopenia 28 11 Constipation 25 1.5 Dyspnea e 24 3.5 k Upper respiratory tract infection f 21 3 Cough g 16 0 Mental status changes h 16 7 Pyrexia 16 0.5 Hyperglycemia 15 7 Dizziness 15 0 Insomnia 15 2 Lymphopenia 15 10 Dehydration 14 3.5 Hypercreatininemia i 14 2 Pneumonia j 13 9 k Epistaxis 12 0.5 Hypokalemia 12 3.5 Dysgeusia 11 0 Vision blurred 10 0.5 Headache 10 0
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, weight decreased, 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, weight decreased, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection ( 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.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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: 1 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, a 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, weight decreased (7% each), and asthenia (6%).
The most common adverse reactions (≥20% with a difference between arms of >5% compared to Vd) were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, weight decreased, cataract, and vomiting.
Grade 3-4 laboratory abnormalities (≥10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia.
Table 6 summarizes the adverse reactions in BOSTON.
Table 6: Adverse Reactions (≥10%) in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) with a Difference Between Arms of >5% Compared to Vd in BOSTON Key: X=XPOVIO, Vd=bortezomib-dexamethasone a.
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 Reaction Weekly XVd (n=195) Twice Weekly Vd (n=204) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal Nausea 50 8 10 0 Diarrhea 32 6 25 <1 Vomiting 21 4.1 4.4 0 General Conditions Fatigue a 59 21 28 5 Pyrexia 15 1.5 11 1 Metabolism and Nutrition Decreased appetite 35 3.6 5 0 Weight decreased 26 2.1 12 1 Nervous System Peripheral neuropathy b 32 4.6 47 9 Dizziness 12 <1 3.9 0 Infections Upper respiratory tract infection c 29 3.6 22 1.5 Eye Disorders Cataract 22 9 6 1.5 Vision blurred d 13 <1 6 0 Clinically 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 7 summarizes selected laboratory abnormalities in BOSTON.
Table 7: Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with Multiple Myeloma Who Received XPOVIO in Combination with Bortezomib and Dexamethasone (XVd) in BOSTON Laboratory Abnormality Weekly XVd Twice Weekly Vd All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 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 decrease 92 43 51 19 Lymphocyte count decrease 77 38 70 27 Hemoglobin decrease 71 17 51 a 12 Neutrophil count decrease 48 12 19 7 Chemistry Glucose increase 62 3.8 47 4.1 Phosphate decrease 61 23 42 11 Sodium decrease 58 14 25 3 Calcium decrease 55 2.1 47 1 Blood urea nitrogen increase 41 5 40 5 Creatinine increase 28 3.6 24 1.5 Potassium decrease 27 6 22 3.5 Magnesium decrease 27 <1 23 1.5 Potassium increase 18 4.1 21 2.5 Hepatic ALT increase 33 3.1 30 <1 Albumin decrease 27 <1 35 <1 AST increase 24 1.5 19 <1 Bilirubin increase 16 1 13 2 ALP increase 12 0 16 <1 XPOVIO 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 1 and 3 of every week (n=202).
The median duration of XPOVIO treatment was 8 weeks (range: 1 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 a 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 8 summarizes the adverse reactions in STORM.
Table 8: Adverse Reactions (≥10%) in Patients Who Received XPOVIO in STORM Adverse Reaction XPOVIO 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 (%) Thrombocytopenia a 74 61 Fatigue b 73 22 Nausea 72 9 Anemia c 59 40 Decreased appetite 53 4.5 Weight decreased 47 0.5 Diarrhea 44 6 Vomiting 41 3.5 Hyponatremia 39 22 Neutropenia d 34 21 Leukopenia 28 11 Constipation 25 1.5 Dyspnea e 24 3.5 k Upper respiratory tract infection f 21 3 Cough g 16 0 Mental status changes h 16 7 Pyrexia 16 0.5 Hyperglycemia 15 7 Dizziness 15 0 Insomnia 15 2 Lymphopenia 15 10 Dehydration 14 3.5 Hypercreatininemia i 14 2 Pneumonia j 13 9 k Epistaxis 12 0.5 Hypokalemia 12 3.5 Dysgeusia 11 0 Vision blurred 10 0.5 Headache 10 0