XPOVIO

XPOVIO- selinexor tablet, film coated
Karyopharm Therapeutics Inc.

1 INDICATIONS AND USAGE

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.

1.2 Diffuse Large B-Cell Lymphoma

XPOVIO is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy.

This indication is approved under accelerated approval based on response rate [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for Multiple Myeloma

In Combination with Bortezomib and Dexamethasone (XVd)

The recommended dosage of XPOVIO is 100 mg taken orally once weekly on Day 1 of each week until disease progression or unacceptable toxicity in combination with:

• Bortezomib 1.3 mg/m² administered subcutaneously once weekly on Day 1 of each week for 4 weeks followed by 1 week off.
• Dexamethasone 20 mg taken orally twice weekly on Days 1 and 2 of each week.

Refer to Clinical Studies (14.1) and the prescribing information of bortezomib and dexamethasone for additional dosing information.

In Combination with Dexamethasone (Xd)

The recommended dosage of XPOVIO is 80 mg taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity in combination with dexamethasone 20 mg taken orally with each dose of XPOVIO on Days 1 and 3 of each week.

For additional information regarding the administration of dexamethasone, refer to its prescribing information.

2.2 Recommended Dosage for Diffuse Large B-Cell Lymphoma

The recommended dosage of XPOVIO is 60 mg taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity.

2.3 Recommended Monitoring for Safety

Monitor complete blood count (CBC) with differential, standard blood chemistries, body weight, nutritional status, and volume status at baseline and during treatment as clinically indicated. Monitor more frequently during the first three months of treatment [see Warning and Precautions (5.1, 5.2, 5.3, and 5.4)]. Assess the need for dosage modifications of XPOVIO for adverse reactions [see Dosage and Administration (2.5)].

2.4 Recommended Concomitant Treatments

Advise patients to maintain adequate fluid and caloric intake throughout treatment. Consider intravenous hydration for patients at risk of dehydration [see Warnings and Precautions (5.3, 5.4)].

Provide prophylactic antiemetics. Administer a 5-HT3 receptor antagonist and other anti-nausea agents prior to and during treatment with XPOVIO [see Warnings and Precautions (5.3)].

2.5 Dosage Modification for Adverse Reactions

Recommended XPOVIO dosage reduction steps are presented in Table 1.

Table 1: XPOVIO Dosage Reduction Steps for Adverse Reactions

Recommended Starting Dosage	Multiple Myeloma In Combination with Bortezomib and Dexamethasone (XVd)	Multiple Myeloma In Combination with Dexamethasone (Xd)	Diffuse Large B-Cell Lymphoma
	100 mg once weekly	80 mg Days 1 and 3 of each week(160 mg total per week)	60 mg Days 1 and 3 of each week(120 mg total per week)
First Reduction	80 mg once weekly	100 mg once weekly	40 mg Days 1 and 3 of each week(80 mg total per week)
Second Reduction	60 mg once weekly	80 mg once weekly	60 mg once weekly
Third Reduction	40 mg once weekly	60 mg once weekly	40 mg once weekly
Fourth Reduction	Permanently discontinue	Permanently discontinue	Permanently discontinue

Recommended dosage modifications for hematologic adverse reactions in patients with multiple myeloma and DLBCL are presented in Table 2 and Table 3, respectively. Recommended dosage modifications for nonhematologic adverse reactions are presented in Table 4.

Table 2: XPOVIO Dosage Modification Guidelines for Hematologic Adverse Reactions in Patients with Multiple Myeloma

Adverse Reaction	Occurrence	Action
Thrombocytopenia [see Warning and Precautions (5.1)]
Platelet count 25,000 to less than 75,000/mcL	Any	Reduce XPOVIO by 1 dose level (see Table 1).
Platelet count 25,000 to less than 75,000/mcL with concurrent bleeding	Any	Interrupt XPOVIO. Restart XPOVIO at 1 dose level lower (see Table 1) after bleeding has resolved. Administer platelet transfusions per clinical guidelines.
Platelet count less than 25,000/mcL	Any	Interrupt XPOVIO. Monitor until platelet count returns to at least 50,000/mcL. Restart XPOVIO at 1 dose level lower (see Table 1).
Adverse Reaction	Occurrence	Action
Neutropenia [see Warning and Precautions (5.2)]
Absolute neutrophil count of 0.5 to 1 x 109 /L without fever	Any	Reduce XPOVIO by 1 dose level (see Table 1).
Absolute neutrophil count less than 0.5 x 109 /L OR febrile neutropenia	Any	Interrupt XPOVIO. Monitor until neutrophil counts return to 1 x 109 /L or higher. Restart XPOVIO at 1 dose level lower (see Table 1).
Anemia
Hemoglobin less than 8 g/dL	Any	Reduce XPOVIO by 1 dose level (see Table 1). Administer blood transfusions per clinical guidelines.
Life-threatening consequences	Any	Interrupt XPOVIO. Monitor hemoglobin until levels return to 8 g/dL or higher. Restart XPOVIO at 1 dose level lower (see Table 1). Administer blood transfusions per clinical guidelines.

Table 3: XPOVIO Dosage Modification Guidelines for Hematologic Adverse Reactions in Patients with Diffuse Large B-Cell Lymphoma

Adverse Reaction	Occurrence	Action
Thrombocytopenia [see Warning and Precautions (5.1)]
Platelet count 50,000 to less than 75,000/mcL	Any	Interrupt one dose of XPOVIO. Restart XPOVIO at the same dose level.
Platelet count 25,000 to less than 50,000/mcL without bleeding	1st	Interrupt XPOVIO. Monitor until platelet count returns to at least 50,000/mcL. Reduce XPOVIO by 1 dose level (see Table 1).
Platelet count 25,000 to less than 50,000/mcL with concurrent bleeding	Any	Interrupt XPOVIO. Monitor until platelet count returns to at least 50,000/mcL. Restart XPOVIO at 1 dose level lower (see Table 1), after bleeding has resolved. Administer platelet transfusions per clinical guidelines.
Platelet count less than 25,000/mcL	Any	Interrupt XPOVIO. Monitor until platelet count returns to at least 50,000/mcL. Restart XPOVIO at 1 dose level lower (see Table 1). Administer platelet transfusions per clinical guidelines.
Neutropenia [see Warning and Precautions (5.2)]
Absolute neutrophil count of 0.5 to less than 1 x 109 /L without fever	1st occurrence	Interrupt XPOVIO. Monitor until neutrophil counts return to 1 x 109 /L or higher. Restart XPOVIO at the same dose level.
	Recurrence	Interrupt XPOVIO. Monitor until neutrophil counts return to 1 x 109 /L or higher. Administer growth factors per clinical guidelines. Restart XPOVIO at 1 dose level lower (see Table 1).
Absolute neutrophil count less than 0.5 x 109 /LOR Febrile neutropenia	Any	Interrupt XPOVIO. Monitor until neutrophil counts return to 1 x 109 /L or higher. Administer growth factors per clinical guidelines. Restart XPOVIO at 1 dose level lower (see Table 1).
Anemia
Hemoglobin less than 8 g/dL	Any	Reduce XPOVIO by 1 dose level (see Table 1). Administer blood transfusions per clinical guidelines.
Life-threatening consequences	Any	Interrupt XPOVIO. Monitor hemoglobin until levels return to 8 g/dL or higher. Restart XPOVIO at 1 dose level lower (see Table 1). Administer blood transfusions per clinical guidelines.

Table 4: XPOVIO Dosage Modification Guidelines for Non-Hematologic Adverse Reactions

Adverse Reaction	Occurrence	Action
Nausea and Vomiting [see Warning and Precautions (5.3)]
Grade 1 or 2 nausea (oral intake decreased without significant weight loss,dehydration or malnutrition)OR Grade 1 or 2 vomiting (5 or fewer episodes per day)	Any	Maintain XPOVIO and initiate additional anti-nausea medications.
Grade 3 nausea (inadequate oral caloric or fluid intake)OR Grade 3 or higher vomiting (6 or more episodes per day)	Any	Interrupt XPOVIO. Monitor until nausea or vomiting has resolved to Grade 2 or lower or baseline. Initiate additional anti-nausea medications. Restart XPOVIO at 1 dose level lower (see Table 1).
Diarrhea [see Warning and Precautions (5.3)]
Grade 2 (increase of 4 to 6 stools per day over baseline)	1st	Maintain XPOVIO and institute supportive care.
	2nd and subsequent	Reduce XPOVIO by 1 dose level (see Table 1). Institute supportive care.
Grade 3 or higher (increase of 7 stools or more per day over baseline; hospitalization indicated)	Any	Interrupt XPOVIO and institute supportive care. Monitor until diarrhea resolves to Grade 2 or lower. Restart XPOVIO at 1 dose level lower (see Table 1).
Weight Loss and Anorexia [see Warning and Precautions (5.3)]
Weight loss of 10% to less than 20%OR Anorexia associated with significant weight loss or malnutrition	Any	Interrupt XPOVIO and institute supportive care. Monitor until weight returns to more than 90% of baseline weight. Restart XPOVIO at 1 dose level lower (see Table 1).
Hyponatremia [see Warning and Precautions (5.4)]
Sodium level 130 mmol/L or less	Any	Interrupt XPOVIO, evaluate, and provide supportive care. Monitor until sodium levels return to greater than 130 mmol/L. Restart XPOVIO at 1 dose level lower (see Table 1).
Fatigue
Grade 2 lasting greater than 7 daysOR Grade 3	Any	Interrupt XPOVIO. Monitor until fatigue resolves to Grade 1 or baseline. Restart XPOVIO at 1 dose level lower (see Table 1).
Ocular Toxicity [see Warning and Precautions (5.8)]
Grade 2, excluding cataract	Any	Perform ophthalmologic evaluation. Interrupt XPOVIO and provide supportive care. Monitor until ocular symptoms resolve to Grade 1 or baseline. Restart XPOVIO at 1 dose level lower (see Table 1).
Grade ≥3, excluding cataract	Any	Permanently discontinue XPOVIO. Perform ophthalmologic evaluation.
Other Non-Hematologic Adverse Reactions [see Warning and Precautions (5.6)]
Grade 3 or 4	Any	Interrupt XPOVIO. Monitor until resolved to Grade 2 or lower; restart XPOVIO at 1 dose level lower (see Table 1).