XPOVIO (Page 2 of 6)

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 a dose of XPOVIO is missed or delayed, instruct patients to take their next dose at the next regularly scheduled time.

If a patient vomits a dose of XPOVIO, the patient should not repeat the dose and the patient should take the next dose on the next regularly scheduled day.

3 DOSAGE FORMS AND STRENGTHS

Tablets: 20 mg, blue, round, bi-convex, film-coated tablets with “K20” debossed on one side and nothing on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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 receiving XPOVIO 80 mg twice weekly (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 receiving XPOVIO 60 mg twice weekly (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 higher 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 (n=202), neutropenia was reported as an adverse reaction in 34% of patients and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.

In patients with DLBCL (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 higher 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 3 or 4 in 13%.

Nausea/Vomiting

In patients with multiple myeloma (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% of patients treated with XPOVIO. 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 (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, diarrhea was reported as an adverse reaction in 44% of patients and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.

In patients with DLBCL, 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, anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. 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, 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

XPOVIO can cause severe or life-threatening hyponatremia [see Adverse Reactions (6.1)].

In patients with multiple myeloma (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 treated with XPOVIO. The median time to onset of the first event was 8 days.

In patients with DLBCL (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

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 (n=202), 52% of patients experienced any grade of infection after XPOVIO. Grade ≥3 infections were reported in 25% of patients, and deaths from infection 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 (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.

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