Posology : מינונים

2.   DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage for Multiple Myeloma
In Combination with Bortezomib and Dexamethasone (SVd)
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(Sd)
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 orally taken 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

Multiple Myeloma
Multiple Myeloma In
In Combination with                                                  Diffuse Large B-Cell Combination with
Recommended                   Bortezomib and                                                         Lymphoma Dexamethasone (Sd)
Starting Dosage           Dexamethasone (SVd)
100mg once weekly              80 mg Days 1 and 3 of each          60 mg Days 1 and 3 of week (160 mg total per          each week (120 mg total week)                          per week)
First Reduction             80 mg once weekly                                                  40 mg Days 1 and 3 of 100 mg once weekly             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 non- hematologic 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     Any       • Reduce Xpovio by 1 dose level (see Table 1).
than 75,000/mcL
Platelet count 25,000 to less     Any       • Interrupt Xpovio.
than 75,000/mcL with                        • Restart Xpovio at 1 dose level lower (see Table 1) after bleeding has resolved.
concurrent bleeding                         • Administer platelet transfusions per clinical guidelines Platelet count less than             Any        • Interrupt Xpovio.
25,000/mcL                                      • Monitor until platelet count returns to at least 50,000/mcL.
• Restart Xpovio at 1 dose level lower (see Table 1).
Neutropenia [see Warning and Precautions (5.2)]
Absolute neutrophil count of      Any         • Reduce Xpovio by 1 dose level (see Table 1).
0.5 to 1 x 109/L without fever
Absolute neutrophil count         Any         • Interrupt Xpovio.
less than 0.5 x 109/L OR febrile              • Monitor until neutrophil counts return to 1 x 109/L or higher.
neutropenia                                   • 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                  Any         • Interrupt Xpovio.
consequences                                  • 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  Any              • Interrupt one dose of Xpovio.
less than 75,000/mcL                       • Restart Xpovio at the same dose level.
Platelet count 25,000 to  1st              • Interrupt Xpovio.
less than 50,000/mcL                       • Monitor until platelet count returns to at least 50,000/mcL.
without bleeding                           • Reduce Xpovio by 1 dose level (see Table 1).

Platelet count 25,000 to        Any              • Interrupt Xpovio.
less than 50,000/mcL with                        • Monitor until platelet count returns to at least 50,000/mcL.
concurrent bleeding                              • Restart Xpovio at 1 dose level lower (see Table 1), after bleeding has resolved.
• Administer platelet transfusions per clinical guidelines.
Platelet count less than        Any              • Interrupt Xpovio.
25,000/mcL                                       • 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       1st occurrence   • Interrupt Xpovio.
of 0.5 to less than 1 x 109/L                    • Monitor until neutrophil counts return to 1 x 109/L or higher.
without fever                                    • 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       Any              • Interrupt Xpovio.
less than 0.5 x 109/L OR                         • Monitor until neutrophil counts return to 1 x 109/L or higher.
Febrile neutropenia                              • Administer growth factors per clinical guidelines.
• Restart Xpovio at 1 dose level lower (see Table 1).
Anemia
Hemoglobin less than 8          Any              • Reduce Xpovio by 1 dose level (see Table 1).
g/dL                                             • Administer blood transfusions per clinical guidelines.
Any              • Interrupt Xpovio.
Life-threatening                                 • Monitor hemoglobin until levels return to 8 g/dL or higher.
consequences                                     • 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     Any       • Maintain Xpovio and initiate additional anti-nausea medications.
decreased without significant weight loss, dehydration or malnutrition) OR Grade 1 or 2 vomiting (5 or fewer episodes per day)
Grade 3 nausea (inadequate           Any       • Interrupt Xpovio.
oral caloric or fluid intake) OR               • Monitor until nausea or vomiting has resolved to Grade 2 or lower or baseline.
Grade 3 or higher vomiting (6 or               • Initiate additional anti-nausea medications.
more episodes per day)                         • Restart Xpovio at 1 dose level lower (see Table 1).
Diarrhea [see Warning and Precautions (5.3)]
Grade 2 (increase of 4 to 6           1st      • Maintain Xpovio and institute supportive care.
stools per day over baseline)        nd
2 and       • Reduce Xpovio by 1 dose level (see Table 1).
subsequent • Institute supportive care.
Grade 3 or higher (increase of 7     Any       • Interrupt Xpovio and institute supportive care.
stools or more per day over                    • Monitor until diarrhea resolves to Grade 2 or lower.
baseline; hospitalization                      • Restart Xpovio at 1 dose level lower (see Table 1).
indicated)
Weight Loss and Anorexia [see Warning and Precautions (5.3)]
Weight loss of 10% to less than      Any       • Interrupt Xpovio and institute supportive care.
20% OR anorexia associated                     • Monitor until weight returns to more than 90% of baseline weight.
with significant weight loss or                • Restart Xpovio at 1 dose level lower (see Table 1).
malnutrition
Hyponatremia [see Warning and Precautions (5.4)]
Sodium level 130 mmol/L or           Any       • Interrupt Xpovio, evaluate, and provide supportive care.
less                                           • 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       Any       • Interrupt Xpovio.
days                                           • Monitor until fatigue resolves to Grade 1 or baseline.
OR                                             • Restart Xpovio at 1 dose level lower (see Table 1).
Grade 3
Ocular Toxicity
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).



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 film, coated bi-convex round tablet debossed with “K20” on one side and nothing on the other.