NINLARO: Package Insert and Label Information

NINLARO- ixazomib citrate capsule
Takeda Pharmaceuticals America, Inc.

1 INDICATIONS AND USAGE

NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Limitations of Use: NINLARO is not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone outside of controlled clinical trials [see Warnings and Precautions (5.9) and Clinical Studies (14.2, 14.3)].

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 2-7 Day 8 Days 9-14 Day 15 Days 16-21 Day 22 Days 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 (10)].

NINLARO should be taken at least one hour before or at least two hours after food [see Clinical Pharmacology (12.3)]. The whole capsule should be swallowed with water. The capsule should not be crushed, chewed or opened [see How Supplied/Storage and Handling (16)].

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 dosage modification guidelines are provided in Table 3.

Table 2: NINLARO Dose Reductions due to Adverse Reactions
*
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)].
Recommended starting dose * First reduction to Second reduction to Discontinue
4 mg 3 mg 2.3 mg

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
*
For additional occurrences, alternate dose modification of lenalidomide and NINLARO
Grading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4.03
Hematological Toxicities Recommended Actions
Thrombocytopenia (Platelet Count)
Platelet count less than 30,000/mm3
  • Withhold NINLARO and lenalidomide until platelet count is at least 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.*
Neutropenia (Absolute Neutrophil Count)
Absolute neutrophil count less than 500/mm3
  • Withhold NINLARO and lenalidomide until absolute neutrophil count is 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/mm3 again, withhold 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 with Pain or Grade 2 Peripheral Neuropathy
  • Withhold NINLARO until peripheral neuropathy recovers to Grade 1 or lower without pain or patient’s baseline.
  • Following recovery, resume NINLARO at its most recent dose.
Grade 2 Peripheral Neuropathy with Pain or Grade 3 Peripheral Neuropathy
  • Withhold NINLARO. Toxicities should, at the healthcare provider’s discretion, generally recover to patient’s baseline condition or Grade 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-Hematological Toxicities
  • Withhold NINLARO. Toxicities should, at the healthcare provider’s 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.

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 × ULN) or severe (total bilirubin greater than 3 × ULN) hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

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 (12.3)].

Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.

3 DOSAGE FORMS AND STRENGTHS

NINLARO is available in the following capsules:

  • 4 mg: Light orange gelatin capsule imprinted with “Takeda” on the cap and “4 mg” on the body in black ink.
  • 3 mg: Light grey gelatin capsule imprinted with “Takeda” on the cap and “3 mg” on the body in black ink.
  • 2.3 mg: Light pink gelatin capsule imprinted with “Takeda” on the cap and “2.3 mg” on the body in black ink.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Thrombocytopenia

Thrombocytopenia has been reported with NINLARO with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle [see Adverse Reactions (6.1)]. Grade 3 thrombocytopenia was reported in 17% of patients in the NINLARO regimen and Grade 4 thrombocytopenia was reported in 13% in the NINLARO regimen. The rate of platelet transfusions was 10% in the NINLARO regimen and 7% in the placebo regimen.

Monitor platelet counts at least monthly during treatment with NINLARO. Consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications [see Dosage and Administration (2.2)] and platelet transfusions as per standard medical guidelines.

5.2 Gastrointestinal Toxicities

Diarrhea, constipation, nausea, and vomiting have been reported with NINLARO, occasionally requiring use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea was reported in 52% of patients in the NINLARO regimen and 43% in the placebo regimen, constipation in 35% and 28%, respectively, nausea in 32% and 23%, respectively, and vomiting in 26% and 13%, respectively. Diarrhea resulted in discontinuation of one or more of the three drugs in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen [see Adverse Reactions (6.1)]. Adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].

5.3 Peripheral Neuropathy

The majority of peripheral neuropathy adverse reactions were Grade 1 (18% in the NINLARO regimen and 16% in the placebo regimen) and Grade 2 (11% in the NINLARO regimen and 6% in the placebo regimen) [see Adverse Reactions (6.1)]. Grade 3 adverse reactions of peripheral neuropathy were reported at 2% in both regimens.

The most commonly reported reaction was peripheral sensory neuropathy (24% and 17% in the NINLARO and placebo regimen, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Peripheral neuropathy resulted in discontinuation of one or more of the three drugs in 4% of patients in the NINLARO regimen and <1% of patients in the placebo regimen. Patients should be monitored for symptoms of neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification [see Dosage and Administration (2.2)].

5.4 Peripheral Edema

Peripheral edema was reported in 27% and 21% of patients in the NINLARO and placebo regimens, respectively. The majority of peripheral edema adverse reactions were Grade 1 (17% in the NINLARO regimen and 14% in the placebo regimen) and Grade 2 (7% in the NINLARO regimen and 6% in the placebo regimen).

Grade 3 peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens, respectively [see Adverse Reactions (6.1)]. Peripheral edema resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].

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