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)].

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 5 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 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)
Adverse Reaction	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 Fatiguea	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 neuropathyb	32	4.6	47	9
Dizziness	12	<1	3.9	0
Infections Upper respiratory tract infectionc	29	3.6	22	1.5
Eye Disorders Cataract	22	9	6	1.5
Vision blurredd	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 6 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 BOSTON
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.
Laboratory Abnormality	Weekly XVd		Twice Weekly Vd
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematologic Platelet count decrease	92	43	51	19
Lymphocyte count decrease	77	38	70	27
Hemoglobin decrease	71	17	51a	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 7 summarizes the adverse reactions in STORM.

Table 7: Adverse Reactions (≥10%) in Patients Who Received XPOVIO in STORM
a. Thrombocytopenia includes thrombocytopenia and platelet count decreased.
b. Fatigue includes fatigue and asthenia.
c. Anemia includes anemia and hematocrit decreased.
d. Neutropenia includes neutropenia and neutrophil count decreased.
e. Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest.
f. Upper respiratory tract infection includes upper respiratory tract infection, respiratory tract infection, pharyngitis, nasopharyngitis, bronchitis, bronchiolitis, respiratory syncytial virus infection, parainfluenza virus infection, rhinitis, rhinovirus infection, and adenovirus infection.
g. Cough includes cough, productive cough, and upper-airway cough syndrome.
h. Mental status changes includes mental status changes, confusional state, and delirium.
i. Hypercreatininemia includes hypercreatininemia and hypercreatinemia.
j. Pneumonia includes pneumonia, atypical pneumonia, lung infection, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumonia influenzal, and pneumonia viral.
k. Includes fatal event.
Adverse Reaction	XPOVIO 80 mg twice weekly + Dexamethasone (n=202)
Adverse Reaction	All Grades (%)	Grades ≥3 (%)
Thrombocytopeniaa	74	61
Fatigueb	73	22
Nausea	72	9
Anemiac	59	40
Decreased appetite	53	4.5
Weight decreased	47	0.5
Diarrhea	44	6
Vomiting	41	3.5
Hyponatremia	39	22
Neutropeniad	34	21
Leukopenia	28	11
Constipation	25	1.5
Dyspneae	24	3.5k
Upper respiratory tract infectionf	21	3
Coughg	16	0
Mental status changesh	16	7
Pyrexia	16	0.5
Hyperglycemia	15	7
Dizziness	15	0
Insomnia	15	2
Lymphopenia	15	10
Dehydration	14	3.5
Hypercreatininemiai	14	2
Pneumoniaj	13	9k
Epistaxis	12	0.5
Hypokalemia	12	3.5
Dysgeusia	11	0
Vision blurred	10	0.5
Headache	10	0

Diffuse Large B-Cell Lymphoma

The safety of XPOVIO was evaluated in SADAL [see Clinical Studies (14.2)]. Patients received XPOVIO 60 mg orally on Days 1 and 3 of every week (n=134). The study required an absolute neutrophil count ≥1000/μL, platelet count ≥75,000/μL, hepatic transaminases ≤2.5 times upper limit of normal (ULN) unless abnormal from lymphoma, and bilirubin ≤2 times ULN. The study permitted a maximum of 5 prior systemic regimens for DLBCL. Antiemetic prophylaxis with a 5HT-3 receptor antagonist was required. The median duration of XPOVIO treatment was 2.1 months (range: 1 week to 3.7 years) with 38% receiving at least 3 months and 22% receiving at least 6 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 2 or more dose reductions. The median time to first dose modification (reduction or interruption) was 4 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 6 weeks, with 83% of first dose reductions occurring within the first 3 months.

The most common adverse reactions, excluding laboratory abnormalities, in ≥20% of patients were fatigue, nausea, diarrhea, decreased appetite, weight decreased, constipation, vomiting, and pyrexia. Table 8 summarizes selected adverse reactions in SADAL.

Table 8: Adverse Reactions (≥10%), Excluding Laboratory Terms, in Patients with DLBCL Who Received XPOVIO in SADAL
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. Decreased appetite 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.
Adverse Reaction	XPOVIO 60 mg twice weekly (n=134)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
General Conditions Fatiguea	63	15
Pyrexia	22	4.5
Edemab	17	2.2
Gastrointestinal Nausea	57	6
Diarrheac	37	3.0
Constipation	29	0
Vomiting	28	1.5
Abdominal paind	10	0
Adverse Reaction	XPOVIO 60 mg twice weekly (n=134)
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Metabolism and Nutrition Decreased appetitee	37	3.7
Weight decreased	30	0
Respiratory Coughf	18	0
Dyspneag	10	1.5
Infections Upper respiratory tract infectionh	17	1.5
Pneumonia	10	6
Urinary tract infectioni	10	3
Nervous System Dizzinessj	16	0.7
Taste disorderk	13	0
Mental status changesl	11	3.7
Peripheral neuropathy, sensorym	10	0
Musculoskeletal Musculoskeletal painn	15	2.2
Vascular Hypotension	13	3.0
Hemorrhageo	10	0.7
Eye Disorders Vision blurredp	11	0.7

Clinically 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%), herpes virus infection (3%)
Eye disorders: cataract (3.7%)
Blood and lymphatic disorders: febrile neutropenia (3%)
Cardiac disorders: cardiac failure (3%)

Table 9 summarizes selected new or worsening laboratory abnormalities in SADAL. Grade 3-4 laboratory abnormalities in ≥15% included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade 4 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 SADAL
The denominator used to calculate the rate varied from 107 to 128 based on the number of patients with at least one post-treatment value.
a. Not fasting.
b. CK increase was not associated with reports of myopathy or myalgia.
Laboratory Abnormality	XPOVIO 60 mg twice weekly
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
Hematologic Platelet count decrease	86	49
Hemoglobin decrease	82	25
Lymphocyte count decrease	63	37
Neutrophil count decrease	58	31
Chemistry Sodium decrease	62	16
Glucose increase	57a	5
Creatinine increase	47	3.9
Phosphate decrease	34	11
Magnesium decrease	30	2.6
Calcium decrease	30	0.9
Potassium increase	26	3.9
Potassium decrease	23	7
CK increaseb	21	1.9
Hepatic ALT increase	29	0.8
Albumin decrease	25	0
AST increase	24	3.1
Bilirubin increase	16	1.6