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2     DOSAGE AND ADMINISTRATION
2.1   Dosing and Administration Guidelines
NINLARO in combination with lenalidomide and dexamethasone
The recommended starting dose of NINLARO is 4 mg administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle.
The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 through 21 of a 28-day treatment cycle.
The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle.

Table 1: Dosing Schedule for NINLARO taken with Lenalidomide and Dexamethasone Take medicine
28-Day Cycle (a 4-week cycle)
Week 1           Week 2              Week 3        Week 4

Day 1     Days     Day 8     Days     Day 15     Days      Day 22      Days 2-7               9-14                16-21                 23-28
NINLARO                                                   
Lenalidomide               Daily             Daily             Daily Dexamethasone                                                                   

For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information.
NINLARO should be taken once a week on the same day and at approximately the same time for the first three weeks of a four week cycle. The importance of carefully following all dosage instructions should be discussed with patients starting treatment. Instruct patients to take the recommended dosage as directed, because overdosage has led to deaths [see Overdosage (9)].
NINLARO should be taken at least one hour before or at least two hours after food [see Clinical Pharmacology (11.3)]. The whole capsule should be swallowed with water. The capsule should not be crushed, chewed or opened [see How Supplied/Storage and Handling (14)].
If a NINLARO dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥ 72 hours away. A missed dose should not be taken within 72 hours of the next scheduled dose. A double dose should not be taken to make up for the missed dose.
If vomiting occurs after taking a dose, the patient should not repeat the dose. The patient should resume dosing at the time of the next scheduled dose.

Prior to initiating a new cycle of therapy:
•    Absolute neutrophil count should be at least 1,000/mm3
•    Platelet count should be at least 75,000/mm3
•    Non-hematologic toxicities should, at the healthcare provider’s discretion, generally be recovered to patient’s baseline condition or Grade 1 or lower
Treatment should be continued until disease progression or unacceptable toxicity.

Concomitant Medications

Consider antiviral prophylaxis in patients being treated with NINLARO to decrease the risk of herpes zoster reactivation [see Adverse Reactions (6.1)].


2.2       Dosage Modification Guidelines
The NINLARO dose reduction steps are presented in Table 2 and the dose modification guidelines are provided in Table 3.
Table 2: NINLARO Dose Reductions due to Adverse Reactions
Recommended starting dose*              First reduction to       Second reduction to Discontinue
4 mg                                    3 mg                     2.3 mg
*Recommended starting dose of 3 mg in patients with moderate or severe hepatic impairment, severe renal impairment or end- stage renal disease requiring dialysis [see Dosage and Administration (2.3, 2.4)].

An alternating dose modification approach is recommended for NINLARO and lenalidomide for thrombocytopenia, neutropenia, and rash as described in Table 3. Refer to the lenalidomide prescribing information if dose reduction is needed for lenalidomide.

Table 3: Dosage Modifications Guidelines for NINLARO in Combination with Lenalidomide and Dexamethasone
Hematological Toxicities      Recommended Actions
Thrombocytopenia (Platelet Count)
Platelet count less than      • Withhold NINLARO and lenalidomide until platelet count is at least 30,000/mm3                        30,000/mm3.
• Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose.
• If platelet count falls to less than 30,000/mm3 again, withhold
NINLARO and lenalidomide until platelet count is at least 30,000/mm3.
• Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.*
Table 3: Dose Modifications Guidelines for NINLARO in Combination with Lenalidomide and Dexamethasone

Neutropenia (Absolute Neutrophil Count)
Absolute neutrophil count less    • Withhold NINLARO and lenalidomide until absolute neutrophil count is than 500/mm3                        at least 500/mm3. Consider adding G-CSF as per clinical guidelines.
• Following recovery, resume lenalidomide at the next lower dose according to its prescribing information and resume NINLARO at its most recent dose.
• If absolute neutrophil count falls to less than 500/mm again, withhold 3

NINLARO and lenalidomide until absolute neutrophil count is at least
500/mm3.
• Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.*
Non-Hematological Toxicities      Recommended Actions
Rash
Grade† 2 or 3                     • Withhold lenalidomide until rash recovers to Grade 1 or lower.
• Following recovery, resume lenalidomide at the next lower dose according to its prescribing information.
• If Grade 2 or 3 rash occurs again, withhold NINLARO and lenalidomide until rash recovers to Grade 1 or lower.
• Following recovery, resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose.*
Grade 4                           Discontinue treatment regimen.
Peripheral Neuropathy
Grade 1 Peripheral Neuropathy     • Withhold NINLARO until peripheral neuropathy recovers to Grade 1 or with Pain or Grade 2                lower without pain or patient's baseline.
Peripheral Neuropathy             • Following recovery, resume NINLARO at its most recent dose.
Grade 2 Peripheral Neuropathy     • Withhold NINLARO. Toxicities should, at the healthcare provider’s with Pain or Grade 3                discretion, generally recover to patient’s baseline condition or Grade Peripheral Neuropathy               1 or lower prior to resuming NINLARO.
• Following recovery, resume NINLARO at the next lower dose.
Grade 4 Peripheral Neuropathy     Discontinue treatment regimen.
Other Non-Hematological Toxicities
Other Grade 3 or 4 Non-           • Withhold NINLARO. Toxicities should, at the healthcare provider’s Hematological Toxicities            discretion, generally recover to patient’s baseline condition or Grade 1 or lower prior to resuming NINLARO.
• If attributable to NINLARO, resume NINLARO at the next lower dose following recovery.
*For additional occurrences, alternate dose modification of lenalidomide and NINLARO †
Grading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4.03 2.3    Dosage in Patients with Hepatic Impairment
Reduce the starting dose of NINLARO to 3 mg in patients with moderate (total bilirubin greater than 1.5-3 x ULN) or severe (total bilirubin greater than 3 x ULN) hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (11.3)].
2.4    Dosage in Patients with Renal Impairment
Reduce the starting dose of NINLARO to 3 mg in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis [see Use in Specific Populations (8.7) and Clinical Pharmacology (11.3)].
Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.