Ninlaro Dosage/Direction for Use

Treatment must be initiated and monitored under the supervision of a physician experienced in the management of multiple myeloma.
Posology: Recommended Dose: 1) Treatment of patients with multiple myeloma who have received at least one prior therapy in combination with lenalidomide and dexamethasone: The recommended starting dose of IXAZOMIB 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 to 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. (See Table 6.)

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For additional information regarding lenalidomide and dexamethasone, refer to the Summary of Product Characteristics (SmPC) for these medicinal products.
Treatment should be continued until disease progression or unacceptable toxicity. Treatment with IXAZOMIB in combination with lenalidomide and dexamethasone for longer than 24 cycles should be based on an individual benefit risk assessment, as the data on the tolerability and toxicity beyond 24 cycles are limited (see PHARMACOLOGY: Pharmacodynamics under Actions).
2) Maintenance therapy in patients with multiple myeloma following autologous stem cell transplantation and in patients with multiple myeloma not treated with stem cell transplantation: The recommended dose of ixazomib maintenance therapy is one 4 mg capsule administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle. Treatment should be initiated at 3 mg and should be escalated to 4 mg on Day 1 of cycle 5, if tolerated during the first 4 cycles. Treatment should be continued for 24 months, or until disease progression, or unacceptable toxicity, whichever comes first.
Dose modifications: 1) Treatment of patients with multiple myeloma who have received at least one prior therapy in combination with lenalidomide and dexamethasone: The IXAZOMIB dose reduction steps in combination with lenalidomide and dexamethasone are presented in Table 7 and the dose modification guidelines are provided in Table 8. (See Table 7.)

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An alternating dose modification approach is recommended for IXAZOMIB and lenalidomide for overlapping toxicities of thrombocytopenia, neutropenia and rash. For these toxicities, the first dose modification step is to withhold/reduce lenalidomide. Refer to the lenalidomide SmPC, as follows for the dose reduction steps for these toxicities. (See Table 8.)

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2) Maintenance therapy in patients with multiple myeloma following autologous stem cell transplantation and in patients with multiple myeloma not treated with stem cell transplantation: The dose reduction steps are presented in Table 9 and the dose modification guidelines are provided in Table 10. (See Tables 9 and 10.)

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Concomitant medicinal products: Antiviral prophylaxis should be considered in patients being treated with IXAZOMIB to decrease the risk of herpes zoster reactivation. Patients included in studies with IXAZOMIB who received antiviral prophylaxis had a lower incidence of herpes zoster infection compared to patients who did not receive prophylaxis.
Thromboprophylaxis is recommended in patients being treated with IXAZOMIB in combination with lenalidomide and dexamethasone, and should be based on an assessment of the patient's underlying risks and clinical status.
For other concomitant medicinal products that may be required, refer to the current lenalidomide and dexamethasone SmPC.
Special patient populations: Elderly: No dose adjustment of IXAZOMIB is required for patients over 65 years of age.
Discontinuations in patients > 75 years of age were reported in 13 patients (28%) in the IXAZOMIB regimen and 10 patients (16%) in the placebo regimen. Cardiac arrhythmias in patients > 75 years of age were observed in 10 patients (21%) in the IXAZOMIB regimen and 9 patients (15%) in the placebo regimen.
Hepatic impairment: The ixazomib starting dose adjustments for patients with impaired hepatic function (see Specific Populations as follows) are provided in Table 11. (See Table 11.)

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Renal impairment: The ixazomib starting dose adjustments for patients with impaired renal function are provided in Table 12. (See Table 12.)

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IXAZOMIB is not dialyzable and, therefore, can be administered without regard to the timing of dialysis (see PHARMACOLOGY: Pharmacokinetics under Actions).
Refer to the lenalidomide SmPC for dosing recommendations in patients with renal impairment.
Paediatric population: The safety and efficacy of IXAZOMIB in children below 18 years of age have not been established. No data are available.
Method of administration: IXAZOMIB is for oral use.
IXAZOMIB should be taken at approximately the same time on days 1, 8, and 15 of each treatment cycle at least 1 hour before or at least 2 hours after food (see PHARMACOLOGY: Pharmacokinetics under Actions). The capsule should be swallowed whole with water. It should not be crushed, chewed, or opened (see Special precautions for disposal and other handling under Cautions for Usage).
Prior to initiating a new cycle of therapy: Absolute neutrophil count should be ≥ 1,000/mm³; Platelet count should be ≥ 75,000/mm³; Non-haematologic toxicities should, at the physician's discretion, generally be recovered to patient's baseline condition or ≤ Grade 1.
Delayed or missed doses: In the event that an ixazomib 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 a missed dose.
If a patient vomits after taking a dose, the patient should not repeat the dose but should resume dosing at the time of the next scheduled dose.