Ninlaro® 2.3 mg, 3 mg and 4 mg
CapsulesContains Ixazomib (As Citrate) 2.3 mg, 3 mg and 4 mg
FULL PRESCRIBING INFORMATION
1

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

LenalidomideDexamethasone



Days
2-7

Day 8

Days
9-14


DailyDay 15Days
16-21

Day 22

Days
23-28


DailyDaily

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 ClinicalPharmacology (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 (15.3)].
Ninlaro 2.3mg , 3mg , 4mg capsules_PI_270521_Overdosage information

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 doseshould 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 topatient’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

Dose Modification Guidelines

The NINLARO dose reduction steps are presented in Table 2 and the dose modification guidelines areprovided in Table 3.
Table 2: NINLARO Dose Reductions due to Adverse Reactions
Recommended starting dose*
4 mg

First reduction to
3 mg

Second reduction to
2.3 mg

Discontinue*Recommended starting dose of 3 mg in patients with moderate or severe hepatic impairment, severe renal impairment or endstage renal disease requiring dialysis [see Dosage and Administration (2.3, 2.4)].

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

Table 3: Dose Modifications Guidelines for NINLARO in Combination with Lenalidomide andDexamethasone
Hematological Toxicities
Recommended Actions
Thrombocytopenia (Platelet Count)Platelet count less than
• Withhold NINLARO and lenalidomide until platelet count is at least
30,000/mm330,000/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 andresume lenalidomide at its most recent dose.*Table 3: Dose Modifications Guidelines for NINLARO in Combination with Lenalidomide andDexamethasone
Neutropenia (Absolute Neutrophil Count)
Absolute neutrophil count lessthan 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.
3• If absolute neutrophil count falls to less than 500/mm again, withhold
NINLARO and lenalidomide until absolute neutrophil count is at least
500/mm3.
• Following recovery, resume NINLARO at the next lower dose andresume 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 andresume 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 orlower 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’sdiscretion, 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 NonHematological Toxicities• Withhold NINLARO. Toxicities should, at the healthcare provider’sdiscretion, 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 andtherefore 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.
3

DOSAGE FORMS AND STRENGTHSNINLARO is available in the following capsules:• 4 mg: Light orange gelatin capsule imprinted with “Takeda” on the cap and “4 mg” on the body inblack ink.
• 3 mg: Light grey gelatin capsule imprinted with “Takeda” on the cap and “3 mg” on the body inblack ink.
• 2.3 mg: Light pink gelatin capsule imprinted with “Takeda” on the cap and “2.3 mg” on the body inblack ink.
4

CONTRAINDICATIONSHypersensitivity to the active substance or to any of the excipients listed in section 14.
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. Three percent of patients in
the NINLARO regimen and 1% of patients in the placebo regimen had a platelet count ≤ 10,000/mm3 during
treatment. Less than 1% of patients in both regimens had a platelet count ≤ 5000/mm3 during treatment.
Discontinuations due to thrombocytopenia were similar in both regimens (< 1% of patients in the NINLARO
regimen and 2% of patients in the placebo regimen discontinued one or more of the three drugs). The rate ofplatelet transfusions was 6% in the NINLARO regimen and 5% in the placebo regimen.
Monitor platelet counts at least monthly during treatment with NINLARO. Consider more frequentmonitoring 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 useof antidiarrheal and antiemetic medications, and supportive care. Diarrhea was reported in 42% of patients in
the NINLARO regimen and 36% in the placebo regimen, constipation in 34% and 25%, respectively, nausea
in 26% and 21%, respectively, and vomiting in 22% and 11%, respectively. Diarrhea resulted indiscontinuation of one or more of the three drugs in 1% of patients in the NINLARO regimen and < 1% of
patients in the placebo regimen. 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
14% in the placebo regimen) and Grade 2 (8% in the NINLARO regimen and 5% in the placebo regimen).
Grade 3 adverse reactions of peripheral neuropathy were reported at 2% in both regimens; there were no
Grade 4 or serious adverse reactions.
The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% 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 1% of
patients in both regimens. 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 25% and 18% of patients in the NINLARO and placebo regimens,
respectively. The majority of peripheral edema adverse reactions were Grade 1 (16% in the NINLARO
regimen and 13% in the placebo regimen) and Grade 2 (7% in the NINLARO regimen and 4% in the placebo
regimen).
Grade 3 peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens,
respectively. There was no Grade 4 peripheral edema reported. There were no discontinuations reported due
to peripheral edema. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosingof dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms [see Dosage andAdministration (2.2)].
5.5

Cutaneous Reactions

Rash was reported in 19% of patients in the NINLARO regimen and 11% of patients in the placebo regimen.
The majority of the rash adverse reactions were Grade 1 (10% in the NINLARO regimen and 7% in theplacebo regimen) or Grade 2 (6% in the NINLARO regimen and 3% in the placebo regimen). Grade 3 rash
was reported in 3% of patients in the NINLARO regimen and 1% of patients in the placebo regimen. There
were no Grade 4 or serious adverse reactions of rash reported. The most common type of rash reported in bothregimens included maculo-papular and macular rash.
Rash resulted in discontinuation of one or more of the three drugs in < 1% of patients in both regimens.
Manage rash with supportive care or with dose modification if Grade 2 or higher [see Dosage andAdministration (2.2)].

5.6

Thrombotic Microangiopathy

Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic
purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO.
Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If thediagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy
in patients previously experiencing TTP/HUS is not known.
5.7

Hepatotoxicity

Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity haveeach been reported in < 1% of patients treated with NINLARO. Events of liver impairment have been reported(6% in the NINLARO regimen and 5% in the placebo regimen).
Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms [see Dosage andAdministration (2.2)].
5.8

Embryo-Fetal Toxicity

NINLARO can cause fetal harm when administered to a pregnant woman based on the mechanism of action
and findings in animal studies. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses
resulting in exposures that were slightly higher than those observed in patients receiving the recommended
dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use
effective non-hormonal contraception during treatment with NINLARO and for 90 days following the final
dose. Advise males with female partners of reproductive potential to use effective contraception during
treatment with NINLARO and for 90 days following the final dose [see Drug Interactions (7.1) and Use inSpecific Populations (8.1, 8.3)].
6

ADVERSE REACTIONS

The following adverse reactions are described in detail in other sections of the prescribing information:

6.1•

Thrombocytopenia [see Warnings and Precautions (5.1)]•

Gastrointestinal Toxicities [see Warnings and Precautions (5.2)]•

Peripheral Neuropathy [see Warnings and Precautions (5.3)]•

Peripheral Edema [see Warnings and Precautions (5.4)]•

Cutaneous Reactions [see Warnings and Precautions (5.5)]•

Thrombotic Microangiopathy [see Warnings and Precautions (5.6)]•

Hepatotoxicity [see Warnings and Precautions (5.7)]
Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.
The safety population from the randomized, double-blind, placebo-controlled clinical study included 720
patients with relapsed and/or refractory multiple myeloma, who received NINLARO in combination withlenalidomide and dexamethasone (NINLARO regimen; N=360) or placebo in combination with lenalidomide

and dexamethasone (placebo regimen; N=360).
The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen and greater than the placebo
regimen were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema,
vomiting, and back pain. Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia(2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of
patients in the NINLARO regimen.
Table 4 summarizes the adverse reactions occurring in at least 5% of patients with at least a 5% difference
between the NINLARO regimen and the placebo regimen.
Table 4: Non-Hematologic Adverse Reactions Occurring in ≥ 5% of Patients with a ≥ 5% Difference
Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade 3 and Grade 4)

System Organ Class /Preferred Term

NINLARO +Lenalidomide andDexamethasone
N=360
N (%)
All
Grade 3 Grade 4

Infections and infestations
Upper respiratory tract infection 69 (19)
1 (< 1)
Nervous system disorders
Peripheral neuropathies*
100 (28)
7 (2)Gastrointestinal disorders
Diarrhea
151 (42)
22 (6)
Constipation
122 (34) 1 (< 1)Nausea92 (26)6 (2)Vomiting
79 (22)4 (1)Skin and subcutaneous tissue disorders
Rash*
68 (19)9 (3)Musculoskeletal and connective tissue disorders
Back pain
74 (21)2 (< 1)
General disorders and administration site conditions
Edema peripheral
91 (25)8 (2)Placebo +Lenalidomide andDexamethasone
N=360
N (%)
All
Grade 3 Grade 40

52 (14)2 (< 1)0077 (21)

7 (2)

0

0
0
0
0

130 (36)
90 (25)74 (21)38 (11)8 (2)1 (< 1)0
2 (< 1)

0
0
0
0

0

38 (11)

5 (1)

0

0

57 (16)

9 (3)

0

0

66 (18)4 (1)0Note: Adverse reactions included as preferred terms are based on MedDRA version 16.0.
*Represents a pooling of preferred terms

Table 5 represents pooled information from adverse event and laboratory data.
Table 5: Thrombocytopenia and Neutropenia

Thrombocytopenia
Neutropenia

NINLARO +Lenalidomide andDexamethasone
N=360

Placebo +Lenalidomide andDexamethasone
N=360

N (%)

N (%)

Any Grade281 (78)240 (67)

Grade 3-4
93 (26)93 (26)

Any Grade196 (54)239 (66)

Grade 3-4
39 (11)107 (30)

Herpes Zoster
Herpes zoster was reported in 4% of patients in the NINLARO regimen and 2% of patients in theplacebo regimen. Antiviral prophylaxis was allowed at the healthcare provider’s discretion.
Patients treated in the NINLARO regimen who received antiviral prophylaxis had a lower incidence (< 1%)of herpes zoster infection compared to patients who did not receive prophylaxis (6%).
Eye Disorders
Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 26% in
patients in the NINLARO regimen and 16% of patients in the placebo regimen. The most common adverse
reactions were blurred vision (6% in the NINLARO regimen and 3% in the placebo regimen), dry eye (5% in
the NINLARO regimen and 1% in the placebo regimen), and conjunctivitis (6% in the NINLARO regimen
and 1% in the placebo regimen). Grade 3 adverse reactions were reported in 2% of patients in the NINLARO
regimen and 1% in the placebo regimen.
Adverse Reactions Reported Outside of the Randomized Controlled Trial
The following serious adverse reactions have each been reported at a frequency of < 1%: acute febrileneutrophilic dermatosis (Sweet’s syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior
reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should
be reported to the Ministry of Health according to the National Regulation by using an online form
https://sideeffects.health.gov.il
7

DRUG INTERACTIONS

7.1

Strong CYP3A Inducers

Avoid concomitant administration of NINLARO with strong CYP3A inducers (such as rifampin, phenytoin,carbamazepine, and St. John’s Wort) [see Clinical Pharmacology (11.3)].

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary
Based on its mechanism of action [see Clinical Pharmacology (11.1)] and data from animal reproduction
studies, NINLARO can cause fetal harm when administered to a pregnant woman. There are no available data
on NINLARO use in pregnant women to evaluate drug-associated risk. Ixazomib caused embryo-fetal toxicity
in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed inpatients receiving the recommended dose (see Data). Advise pregnant women of the potential risk to a fetus.
Data
Animal Data
In an embryo-fetal development study in pregnant rabbits there were increases in fetal skeletal
variations/abnormalities (fused caudal vertebrae, number of lumbar vertebrae, and full supernumerary ribs) at dosesthat were also maternally toxic (≥ 0.3 mg/kg). Exposures in the rabbit at 0.3 mg/kg were 1.9 times the clinical time
averaged exposures at the recommended dose of 4 mg. In a rat dose range-finding embryo-fetal development study,
at doses that were maternally toxic, there were decreases in fetal weights, a trend towards decreased fetal viability,
and increased post-implantation losses at 0.6 mg/kg. Exposures in rats at the dose of 0.6 mg/kg was 2.5 times theclinical time averaged exposures at the recommended dose of 4 mg.
8.2

Lactation

Risk Summary
There are no data on the presence of ixazomib or its metabolites in human milk, the effects of the drug on the breast
fed infant, or the effects of the drug on milk production. Because of the potential for serious adverse reactions fromNINLARO in a breastfed infant, advise women not to breastfeed during treatment with NINLARO and for 90 days
after the last dose.
8.3

Females and Males of Reproductive Potential

NINLARO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating NINLARO.
Contraception
Females
Advise females of reproductive potential to use effective non-hormonal contraception during treatment withNINLARO and for 90 days after the final dose. Dexamethasone is known to be a weak to moderate inducer of
CYP3A4 as well as other enzymes and transporters. Because NINLARO is administered with dexamethasone, therisk for reduced efficacy of contraceptives needs to be considered [see Drug Interactions (7.1)].
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment withNINLARO and for 90 days after the final dose.

8.4

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.
8.5

Geriatric Use

Of the total number of subjects in clinical studies of NINLARO, 55% were 65 and over, while 17% were 75 andover. No overall differences in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in responses between the elderly
and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.6

Hepatic Impairment

In patients with moderate or severe hepatic impairment, the mean AUC increased by 20% when compared topatients with normal hepatic function. Reduce the starting dose of NINLARO in patients with moderate or severe
hepatic impairment [see Dosage and Administration (2.3), Clinical Pharmacology (11.3)].
8.7

Renal Impairment

In patients with severe renal impairment or ESRD requiring dialysis, the mean AUC increased by 39% whencompared to patients with normal renal function. Reduce the starting dose of NINLARO in patients with severe
renal impairment or ESRD requiring dialysis. NINLARO is not dialyzable and therefore can be administeredwithout regard to the timing of dialysis [see Dosage and Administration (2.4), Clinical Pharmacology (11.3)].
9

OVERDOSAGE

Overdosage, including fatal overdosage, has been reported in patients taking NINLARO.
Manifestations of overdosage include adverse reactions reported at the recommended dosage [see Dosage andAdministration (2.1), Adverse Reactions (6.1)]. Serious adverse reactions reported with overdosage include severe
nausea, vomiting, diarrhea, aspiration pneumonia, multiple organ failure and death.
In the event of an overdosage, monitor for adverse reactions and provide appropriate supportive care.
NINLARO is not dialyzable.
10

DESCRIPTION

Ixazomib is a proteasome inhibitor. Ixazomib citrate, a prodrug, rapidly hydrolyzes under physiologicalconditions to its biologically active form, ixazomib. The chemical name of ixazomib citrate is 1,3,2dioxaborolane-4,4-diacetic acid, 2-[(1R)-1-[[2-[(2,5- dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]5-oxo- and the structural formula is:

The molecular formula for ixazomib citrate is C20H23BCl2N2O9 and its molecular weight is 517.12. Ixazomib
citrate has one chiral center and is the R-stereoisomer. The solubility of ixazomib citrate in 0.1N HCl (pH 1.2)
at 37°C is 0.61 mg/mL (reported as ixazomib). The solubility increases as the pH increases.
NINLARO (ixazomib) capsules for oral use contain 4, 3 or 2.3 mg of ixazomib equivalent to 5.7, 4.3 or 3.3 mgof ixazomib citrate, respectively. Inactive ingredients include microcrystalline cellulose, magnesium stearate,
and talc. Capsule shells contain gelatin and titanium dioxide. The 4 mg capsule shell contains red and yellow
iron oxide, the 3 mg capsule shell contains black iron oxide and the 2.3 mg capsule shell contains red ironoxide. The printing ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide.

11

CLINICAL PHARMACOLOGY
11.1 Mechanism of Action

Ixazomib is a reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits thechymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.
Ixazomib induced apoptosis of multiple myeloma cell lines in vitro. Ixazomib demonstrated in vitro cytotoxicity
against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib,
lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic
cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumor activity in a mouse
multiple myeloma tumor xenograft model.
11.2 Pharmacodynamics
Cardiac Electrophysiology
NINLARO did not prolong the QTc interval at clinically relevant exposures based on
pharmacokinetic-pharmacodynamic analysis of data from 245 patients.
11.3 Pharmacokinetics
Absorption
After oral administration, the median time to achieve peak ixazomib plasma concentrations was one hour. The
mean absolute oral bioavailability was 58%, based on population PK analysis. Ixazomib AUC increases in adose proportional manner over a dose range of 0.2 to 10.6 mg.
A food effect study conducted in patients with a single 4 mg dose of ixazomib showed that a high-fat meal
decreased ixazomib AUC by 28% and Cmax by 69% [see Dosage and Administration (2.1)].
Distribution
Ixazomib is 99% bound to plasma proteins and distributes into red blood cells with a blood-to-plasma ratio of
10. The steady-state volume of distribution is 543 L.
Elimination
Based on a population PK analysis, systemic clearance was approximately 1.9 L/hr with inter- individual
variability of 44%. The terminal half-life (t1/2) of ixazomib was 9.5 days. Following weekly oral dosing,
the accumulation ratio was determined to be 2-fold.
Metabolism
After oral administration of a radiolabeled dose, ixazomib represented 70% of total drug-related material inplasma. Metabolism by multiple CYP enzymes and non-CYP proteins is expected to be the major clearance
mechanism for ixazomib. At clinically relevant ixazomib concentrations, in vitro studies using human cDNAexpressed cytochrome P450 isozymes showed that no specific CYP isozyme predominantly contributes toixazomib metabolism. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP
isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%),
2C19 (5%) and 2C9 (< 1%).
Excretion
After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% of theadministered radioactivity was excreted in urine and 22% in the feces. Unchanged ixazomib accounted for <3.5% of the administered dose recovered in urine.

Specific Populations
There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area
(range 1.2-2.7 m2), or race on the clearance of ixazomib based on population PK analysis.
Patients with Hepatic Impairment
The PK of ixazomib was similar in patients with normal hepatic function and in patients with mild hepatic
impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1-1.5 x ULN and any AST) based on
population PK analysis.
The PK of ixazomib was characterized in patients with normal hepatic function at 4 mg (N=12), moderate
hepatic impairment at 2.3 mg (total bilirubin > 1.5-3 x ULN, N=13) or severe hepatic impairment at 1.5 mg(total bilirubin > 3 x ULN, N=18). Dose-normalized mean AUC was 20% higher in patients with moderate orsevere hepatic impairment as compared to patients with normal hepatic function [see Dosage andAdministration (2.3)].
Patients with Renal Impairment
The PK of ixazomib was similar in patients with normal renal function and in patients with mild or moderate
renal impairment (creatinine clearance ≥ 30 mL/min) based on population PK analysis.
The PK of ixazomib was characterized at a dose of 3 mg in patients with normal renal function (creatinine
clearance ≥ 90 mL/min, N=18), severe renal impairment (creatinine clearance< 30 mL/min, N=14), or ESRD requiring dialysis (N=6). Mean AUC was 39% higher in patients with severe
renal impairment or ESRD requiring dialysis as compared to patients with normal renal function. Pre- and postdialyzer concentrations of ixazomib measured during the hemodialysis session were similar, suggesting thatixazomib is not dialyzable [see Dosage and Administration (2.4)].
Drug Interaction Studies

Effect of Other Drugs on NINLARO
Strong CYP3A Inducers
Co-administration of NINLARO with rifampin decreased ixazomib Cmax by 54% and AUC by 74% [see Drug
Interactions (7.1)].
Strong CYP3A Inhibitors
Co-administration of NINLARO with clarithromycin did not result in a clinically meaningful change in thesystemic exposure of ixazomib.
Strong CYP1A2 Inhibitors
Co-administration of NINLARO with strong CYP1A2 inhibitors did not result in a clinically meaningful change
in the systemic exposure of ixazomib based on a population PK analysis.
Effect of NINLARO on Other Drugs
Ixazomib is neither a reversible nor a time-dependent inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or
3A4/5. Ixazomib did not induce CYP1A2, CYP2B6, and CYP3A4/5 activity or corresponding immunoreactive
protein levels. NINLARO is not expected to produce drug-drug interactions via CYP inhibition or induction.

Transporter-Based Interactions
Ixazomib is a low affinity substrate of P-gp. Ixazomib is not a substrate of BCRP, MRP2 or hepatic OATPs.
Ixazomib is not an inhibitor of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or
MATE2-K. NINLARO is not expected to cause transporter-mediated drug-drug interactions.
12

NONCLINICAL TOXICOLOGY
12.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Ixazomib was not mutagenic in a bacterial reverse mutation assay (Ames assay). Ixazomib was considered
positive in an in vitro clastogenicity test in human peripheral blood lymphocytes.
However, in vivo, ixazomib was not clastogenic in a bone marrow micronucleus assay in mice and was
negative in an in vivo comet assay in mice, as assessed in the stomach and liver. No carcinogenicity studies
have been performed with ixazomib.
Developmental toxicity studies in rats and rabbits did not show direct embryo-fetal toxicity below maternally
toxic doses of ixazomib. Studies of fertility and early embryonic development and pre- and postnatal
toxicology were not conducted with ixazomib, but evaluation of reproductive tissues was conducted in thegeneral toxicity studies. There were no effects due to ixazomib treatment on male or female reproductive
organs in studies up to 6-months duration in rats and up to 9-months duration in dogs.
13

CLINICAL STUDIESThe efficacy and safety of NINLARO in combination with lenalidomide and dexamethasone was evaluatedin a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed and/or
refractory multiple myeloma who had received at least one prior line of therapy. Patients who wererefractory to lenalidomide or proteasome inhibitors were excluded from the study.
A total of 722 patients were randomized in a 1:1 ratio to receive either the combination of NINLARO,
lenalidomide and dexamethasone (N=360; NINLARO regimen) or the combination of placebo, lenalidomide
and dexamethasone (N=362; placebo regimen) until disease progression or unacceptable toxicity.
Randomization was stratified according to number of prior lines of therapy (1 versus 2 or 3), myeloma
International Staging System (ISS) (stage I or II versus III), and previous therapy with a proteasome inhibitor(exposed or naïve). Twenty three percent (N=166) of the patients had light chain disease and 12% (N=87) ofpatients had free light chain-measurable only disease.
Thromboprophylaxis was recommended for all patients in both treatment groups according to the lenalidomide
prescribing information. Antiemetics were used in 19% of patients in the NINLARO regimen and 12% of
patients in the placebo regimen; antivirals in 64% and 60%, respectively, and antihistamines in 27% and 19%,
respectively. These medications were given to patients at the healthcare provider’s discretion as prophylaxis
and/or management of symptoms.
Patients received NINLARO 4 mg or placebo on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days 1
through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle. Patients with renal
impairment received a starting dose of lenalidomide according to its prescribing information. Treatment
continued until disease progression or unacceptable toxicities.
Table 6 summarizes the baseline patient and disease characteristics in the study. The baseline demographics
and disease characteristics were balanced and comparable between the study regimens.

Table 6: Baseline Patient and Disease Characteristics

Patient Characteristics
Median age in years (range)
Gender (%) Male/ Female
Age Group (% [< 65/ ≥ 65 years])
Race n (%)
White
Black
Asian
Other or Not Specified
ECOG performance status, n (%)
0 or 1
2
Missing
Creatinine clearance, n (%)< 30 mL/min
30-59 mL/min≥ 60 mL/min
Disease Characteristics
Myeloma ISS stage, n (%)
Stage I or II
Stage III
Prior line therapies n (%)
Median (range)
1
2 or 3
Status at Baseline n (%)
Relapsed
Refractory*
Relapsed and Refractory
Type of Prior Therapy n (%)
Bortezomib containing
Carfilzomib containing
Thalidomide containing
Lenalidomide containing
Melphalan containing
Stem cell transplantation
High risk (deletion (del) 17, t(4:14)
and/or t(14:16)
deletion del (17)NINLARO + Lenalidomide
and Dexamethasone(N = 360)

Placebo + Lenalidomide andDexamethasone(N = 362)

66 (38, 91)
58/42
41/59

66 (30, 89)
56/44
43/57

310 (86)
7 (2)30 (8)
13 (4)

301 (83)
6 (2)34 (9)
21 (6)

336 (93)
18 (5)6 (2)334 (92)
24 (7)4 (1)5 (1)
74 (21)281 (78)5 (1)
95 (26)261 (72)315 (87)
45 (13)320 (88)
42 (12)

1 (1, 3)224 (62)136 (38)

1 (1,3)217 (60)145 (40)276 (77)42 (12)41 (11)280 (77)
40 (11)42 (12)248 (69)
1 (<1)
157 (44)44 (12)293 (81)212 (59)

250 (69)4 (1)170 (47)
44 (12)291 (80)
199 (55)

75 (21)62 (17)36 (10)33 (9)*Primary refractory, defined as best response of stable disease or disease progression on all prior lines of therapy was documented
in 7% and 6% of patients in the NINLARO regimen and placebo regimens, respectively.

The efficacy of NINLARO was evaluated by progression-free survival (PFS) according to the 2011
International Myeloma Working Group (IMWG) Consensus Uniform Response Criteria as assessed by ablinded independent review committee (IRC) based on central lab results. Response was assessed every fourweeks until disease progression.
The approval of NINLARO was based upon a statistically significant improvement in PFS of the NINLARO
regimen compared to the placebo regimen. PFS results are summarized in Table 7 and shown in Figure 1.

Table 7: Progression-Free Survival and Response Rate

Progression-free SurvivalPFS Events, n (%)
Median (months)(95% CI)
Hazard Ratio*(95% CI)
p-value†
Response Rate
Overall Response Rate, n (%)
Complete Response
Very Good Partial Response

Partial Response

NINLARO + Lenalidomide andDexamethasone(N = 360)

Placebo + Lenalidomide andDexamethasone(N = 362)

129 (36)
20.6(17.0, NE)

157 (43)
14.7(12.9, 17.6)

282 (78)42 (12)131 (36)109 (30)0.74(0.59, 0.94)
0.012

259 (72)
24 (7)
117 (32)

118 (33)

NE: Not evaluable.
*
Hazard ratio is based on a stratified Cox’s proportional hazard regression model. A hazard ratio less than 1 indicates an advantage
for the NINLARO regimen.
†
P-value is based on the stratified log-rank test.

The median time to response was 1.1 months in the NINLARO regimen and 1.9 months in the placebo
regimen. The median duration of response was 20.5 months in the NINLARO regimen and 15 months in theplacebo regimen for responders in the response evaluable population.
Figure 1: Kaplan-Meier Plot of Progression-Free Survival

A non-inferential PFS analysis was conducted at a median follow up of 23 months with 372 PFS
events. Hazard ratio of PFS was 0.82 (95% confidence interval [0.67, 1.0]) for NINLARO regimen
versus placebo regimen, and estimated median PFS was 20 months in the NINLARO regimen and15.9 months in the placebo regimen. At the same time, a planned interim OS analysis was conductedwith 35% of the required number of deaths for final OS analysis; there were 81 deaths in the
NINLARO regimen and 90 deaths in the placebo regimen. An OS benefit was not demonstrated.

14 LIST OF EXCIPENTS
NINLARO 2.3 mg hard capsules
Capsule contents
Microcrystalline cellulose
Talc
Magnesium stearate
Capsule shell
GelatinTitanium dioxide
Red iron oxide
Printing ink
Shellac
Propylene glycol
Potassium hydroxide
Black iron oxide
NINLARO 3 mg hard capsules
Capsule contents
Microcrystalline cellulose
Talc
Magnesium stearate
Capsule shell
GelatinTitanium dioxide
Black iron oxide
Printing ink
Shellac
Propylene glycol
Potassium hydroxide
Black iron oxide
NINLARO 4 mg hard capsules
Capsule contents
Microcrystalline cellulose
Talc
Magnesium stearate
Capsule shell
GelatinTitanium dioxide
Yellow iron oxide
Red iron oxide
Printing ink
Shellac
Propylene glycol
Potassium hydroxide
Black iron oxide

15

HOW SUPPLIED/STORAGE AND HANDLINGHow Supplied

NINLARO is supplied as follows:
Strength per
Capsule Description
CapsuleOuter Carton

Blister Pack

4 mg

Light orange, size 3,
imprinted with “Takeda” onthe cap and “4 mg” on the
body in black ink.

Three 4 mg
single blister
packs in a
cartonEach blister has one 4 mg
capsule3 mg

Light grey, size 4, imprinted
with “Takeda” on the cap and“3 mg” on the body in blackink.

Three 3 mg
single blister
packs in a
cartonEach blister has one 3 mg
capsule2.3 mgLight pink, size 4, imprinted
with “Takeda” on the cap and“2.3 mg” on the body in blackink.

Three 2.3 mg
single blister
packs in a
cartonEach blister has one 2.3
mg capsule

Capsules are individually packaged in a PVC-Aluminum/Aluminum blister.
Storage
Do not store above 30°C. Do not freeze. Store capsules in original packaging until immediately prior to use.
The expiry date of the product is indicated on the packaging materials.
Handling and Disposal
NINLARO is a cytotoxic drug. Do not open or crush capsules. Avoid direct contact with the capsule contents. In
case of capsule breakage, avoid direct contact of capsule contents with the skin or eyes. If contact occurs with theskin, wash thoroughly with soap and water. If contact occurs with the eyes, flush thoroughly with water.
Any unused medicinal product or waste material should be disposed in accordance with local requirements.
Manufactured by:
Takeda Pharma A/S, Delta Park 45, 2665 Vallensbaek Strand, Denmark
Registration Holder:
Takeda Israel Ltd., 25 Efal St., Petach Tikva 4951125
Registration Numbers:
156-81-34609-00/01
156-82-34615-00/01
156-83-34616-00/01

Revised in May 2021 according to MoHs guidelines.