XPOVIO (Page 3 of 6)

5.6 Neurological Toxicity

XPOVIO can cause life-threatening neurological toxicities [see Adverse Reactions (6.1)].

In patients with multiple myeloma (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 treated with XPOVIO. The median time to the first event was 15 days.

In patients with DLBCL (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 a 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 a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.

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

6 ADVERSE REACTIONS

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

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

6.1 Clinical Trials Experience

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

Multiple Myeloma

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 5 summarizes the adverse reactions in STORM.

Table 5: 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 (%)
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, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Table 6 summarizes selected adverse reactions in SADAL.

Table 6: Adverse Reactions (≥10%), Excluding Laboratory Terms, in Patients with DLBCL Who Received XPOVIO in SADAL
Adverse Reaction XPOVIO 60 mg twice weekly (n=134)
All Grades (%) Grade 3 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 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
Metabolism and Nutrition
Appetite decreasee 37 3.7
Weight decrease 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%), herpesvirus infection (3%)
  • Eye disorders: cataract (3.7%)
  • Blood and lymphatic disorders: febrile neutropenia (3%)
  • Cardiac disorders: cardiac failure (3%)

Table 7 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 7: Select Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients with DLBCL Who Received XPOVIO in SADAL
Laboratory Abnormality XPOVIO 60 mg twice weekly
All Grades (%) Grade 3 or 4 (%)

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.

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 increase b 21 1.9
Hepatic
ALT increase 29 0.8
Albumin decrease 25 0
AST increase 24 3.1
Bilirubin increase 16 1.6

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