Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Thrombocytopenia
(Additions and/or
revisions underlined)
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
3 or 4 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
3 or 4 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
(Additions and/or
revisions underlined)
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 3 neutropenia developed in 21%
of patients and Grade 4 neutropenia developed in 9% of patients. The median
time to first onset of Grade 3 or 4 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
(Additions and/or
revisions underlined)
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 3 or 4 in 13%.
Nausea/Vomiting
In
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 3 nausea was reported in 8% of patients. The median
time to onset of the first event was 6 days. Vomiting was reported in 21% of
patients and Grade 3 vomiting was reported in 4.1% of patients. The median time
to onset of the first event was 8
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 3 nausea occurred in 9%. The median time to
first onset of nausea was 3 days. Vomiting was reported in 41% of patients and
Grade 3 vomiting occurred in 4% of patients. The median time to first onset of
vomiting was 5 days.
In
patients with DLBCL (SADAL, n=134) with use of antiemetic prophylaxis,
nausea occurred in 57% of patients and Grade 3 nausea occurred in 6% of
patients. Vomiting occurred in 28% of patients and Grade 3 vomiting occurred in
1.5% of patients. The median time to first onset was 3 days for nausea and 7
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.
Diarrhea
In
patients with multiple myeloma who received XPOVIO once weekly (BOSTON, n=195),
diarrhea was reported in 32% of patients and Grade 3 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 3
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 3 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
Loss
In
patients with multiple myeloma who received XPOVIO 100 mg once weekly
(BOSTON, n=195), anorexia was reported in 35% of patients and Grade 3 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 3 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 3 anorexia
occurred in 5% of patients. The median time to onset of anorexia was 8 days.
Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3
weight loss occurred in 1% of patients treated with XPOVIO. The median time to
onset of weight loss was 15 days.
In
patients with DLBCL (SADAL, n=134), anorexia was reported as an adverse reaction
in 37% of patients and Grade 3 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
(Additions and/or
revisions underlined)
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 3 or 4
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 3
or 4 hyponatremia was reported in 22% of patients. The median time to onset of
the first event was 8 days.
In
patients with DLBCL (SADAL, n=134), hyponatremia developed in 62% of
patients and Grade 3 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
(Additions and/or
revisions underlined)
XPOVIO
can cause serious and fatal infections. Most of these infections were not
associated with Grade 3 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 3
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 herpesvirus infection.
Monitor
for signs and symptoms of infection, evaluate and treat promptly.
5.6 Neurological Toxicity
(Additions and/or
revisions underlined)
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 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.
5.8 Cataract
(Newly added
subsection)
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.
6
Adverse Reactions
(Additions and/or
revisions underlined)
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
(Extensive
changes; please refer to label)
8
Use in Specific Populations
8.5 Geriatric Use
(Additions and/or
revisions underlined)
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 a higher incidence of discontinuation
due to an adverse reaction (28% vs 13%) and a 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 a higher
incidence of discontinuation due to an adverse reaction (44% vs 27%), higher incidence
of serious adverse reactions (70% vs 58%), and higher incidence of fatal adverse
reactions (17% vs 9%).
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Extensive
changes; please refer to label)
PATIENT COUNSELING INFORMATION
(Addition of new information)
Cataract
Advise
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)].
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