Ninlaro

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 2.3 mg hard capsules 
NINLARO 3 mg hard capsules 
NINLARO 4 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
NINLARO 2.3 mg hard capsules 
 
Each capsule contains 2.3 mg of ixazomib (as 3.3 mg of ixazomib citrate) 
 
NINLARO 3 mg hard capsules 
 
Each capsule contains 3 mg of ixazomib (as 4.3 mg of ixazomib citrate)  
 
NINLARO 4 mg hard capsules 
 
Each capsule contains 4 mg of ixazomib (as 5.7 mg of ixazomib citrate) 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule. 
 
NINLARO 2.3 mg hard capsules 
 
Light pink, size 4 gelatin hard capsule, marked “Takeda” on the cap and “2.3 mg” on the body with 
black ink. 
 
NINLARO 3 mg hard capsules 
 
Light grey, size 4 gelatin hard capsule, marked “Takeda” on the cap and “3 mg” on the body with 
black ink. 
 
NINLARO 4 mg hard capsules 
 
Light orange, size 3 gelatin hard capsule, marked “Takeda” on the cap and “4 mg” on the body with 
black ink. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
NINLARO in combination with lenalidomide and dexamethasone is indicated for the treatment of 
adult patients with multiple myeloma who have received at least one prior therapy. 
 



3 

4.2 Posology and method of administration 
 
Treatment must be initiated and monitored under the supervision of a physician experienced in the 
management of multiple myeloma.  
 
Posology 
 
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. 

For additional information regarding lenalidomide and dexamethasone, refer to the Summary of 
Product Characteristics (SmPC) for these medicinal products. 
 
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 
 
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 section 5.1). 
 
Delayed or missed doses  
 
In the event that a 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. 
 
Dose modifications 
 
The ixazomib dose reduction steps are presented in Table 1 and the dose modification guidelines are 
provided in Table 2.  
 

Dosing schedule: Ixazomib taken with lenalidomide and dexamethasone 
28-day cycle (a 4-week cycle) 
 Week 1 Week 2 Week 3 Week 4 
 Day 1 Days  

2 to 7 
Day 8 Days  

9 to 14 
Day 
15 

Days  
16 to 21 

Day 
22 

Days 23 
to 28 

Ixazomib         
Lenalidomide  Daily  Daily  Daily   
Dexamethasone         
= intake of medicinal product 
 



4 

Table 1: Ixazomib dose reduction steps 
Recommended starting dose*  First reduction to Second reduction to Discontinue 4 mg 3 mg 2.3 mg 
*Recommended reduced dose of 3 mg in the presence of moderate or severe hepatic impairment, severe renal 

impairment or end-stage renal disease (ESRD) requiring dialysis. 
 
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, section 4.2 for 
the dose reduction steps for these toxicities. 
 

Table 2: Dose modifications guidelines for ixazomib in combination with lenalidomide and 
dexamethasone  
Haematological toxicities Recommended actions 
Thrombocytopenia (platelet count) 
Platelet count < 30,000/mm3 • Withhold ixazomib and lenalidomide until platelet count 

≥ 30,000/mm3. 
• Following recovery, resume lenalidomide at the next lower 

dose according to its SmPC and resume ixazomib at its most 
recent dose.  

• If platelet count falls to < 30,000/mm3 again, withhold 
ixazomib and lenalidomide until platelet count 
≥ 30,000/mm3. 

• Following recovery, resume ixazomib at the next lower dose 
and resume lenalidomide at its most recent dose.* 

Neutropenia (absolute neutrophil count) 
Absolute neutrophil count 
< 500/mm3 

• Withhold ixazomib and lenalidomide until absolute 
neutrophil count is ≥ 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 
ixazomib at its most recent dose.  

• If absolute neutrophil count falls to < 500/mm3 again, 
withhold ixazomib and lenalidomide until absolute 
neutrophil count is ≥ 500/mm3. 

• Following recovery, resume ixazomib at the next lower dose 
and resume lenalidomide at its most recent dose.* 

Non-haematological toxicities Recommended actions 
Rash 
Grade† 2 or 3 
 

• Withhold lenalidomide until rash recovers to ≤ Grade 1. 
• Following recovery, resume lenalidomide at the next lower 

dose according to its SmPC.  
• If Grade 2 or 3 rash occurs again, withhold ixazomib and 

lenalidomide until rash recovers to ≤ Grade 1. 
• Following recovery, resume ixazomib at the next lower dose 

and resume lenalidomide at its most recent dose.* 
Grade 4 Discontinue treatment regimen. 



5 

Table 2: Dose modifications guidelines for ixazomib in combination with lenalidomide and 
dexamethasone  
Peripheral neuropathy 
Grade 1 peripheral neuropathy with 
pain or Grade 2 peripheral 
neuropathy 

• Withhold ixazomib until peripheral neuropathy recovers to 
≤ Grade 1 without pain or patient's baseline. 

• Following recovery, resume ixazomib at its most recent 
dose. 

Grade 2 peripheral neuropathy with 
pain or Grade 3 peripheral 
neuropathy 
 
 

• Withhold ixazomib. Toxicities should, at the physician’s 
discretion, generally recover to patient’s baseline condition 
or ≤ Grade 1 prior to resuming ixazomib. 

• Following recovery, resume ixazomib at the next lower 
dose. 

Grade 4 peripheral neuropathy Discontinue treatment regimen. 
Other non-haematological toxicities 
Other Grade 3 or 4 
non-haematological toxicities 

• Withhold ixazomib. Toxicities should, at the physician’s 
discretion, generally recover to patient’s baseline condition 
or at most Grade 1 prior to resuming ixazomib. 

• If attributable to ixazomib, resume ixazomib at the next 
lower dose following recovery. 

*For additional occurrences, alternate dose modification of lenalidomide and ixazomib 
†Grading based on National Cancer Institute Common Terminology Criteria (CTCAE) Version 4.03 
 

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 
 
No dose adjustment of ixazomib is required for patients with mild hepatic impairment (total bilirubin 
≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin 
> 1-1.5 x ULN and any AST). The reduced dose of 3 mg is recommended in patients with moderate 
(total bilirubin > 1.5-3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic impairment (see 
section 5.2). 
 



6 

Renal impairment 
 
No dose adjustment of ixazomib is required for patients with mild or moderate renal impairment 
(creatinine clearance ≥ 30 mL/min). The reduced dose of 3 mg is recommended in patients with severe 
renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease (ESRD) requiring 
dialysis. Ixazomib is not dialyzable and, therefore, can be administered without regard to the timing of 
dialysis (see section 5.2). 
 
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 section 5.2). The capsule should be swallowed 
whole with water. It should not be crushed, chewed, or opened (see section 6.6).  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPC 
for these medicinal products for additional contraindications. 
 
4.4 Special warnings and precautions for use 
 
As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPC 
for these medicinal products for additional special warnings and precautions for use. 
 
Thrombocytopenia 
 
Thrombocytopenia has been reported with ixazomib (see section 4.8) 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 section 4.8).  
 
Platelet counts should be monitored at least monthly during ixazomib treatment. More frequent 
monitoring should be considered during the first three cycles as per the lenalidomide SmPC. 
Thrombocytopenia can be managed with dose modifications (see section 4.2) and platelet transfusions 
as per standard medical guidelines.  
 
Gastrointestinal toxicities 
 
Diarrhoea, constipation, nausea and vomiting have been reported with ixazomib, occasionally 
requiring use of antiemetic and antidiarrhoeal medicinal products and supportive care (see 
section 4.8). The dose should be adjusted for severe (Grade 3-4) symptoms (see section 4.2). In case of 
severe gastrointestinal events, monitoring of serum potassium level is recommended. 
 



7 

Peripheral neuropathy 
 
Peripheral neuropathy has been reported with ixazomib (see section 4.8). The patient should be 
monitored for symptoms of peripheral neuropathy. Patients experiencing new or worsening peripheral 
neuropathy may require dose modification (see section 4.2). 
 
Peripheral oedema 
 
Peripheral oedema has been reported with ixazomib (see section 4.8). The patient should be evaluated 
for underlying causes and provide supportive care, as necessary. The dose of dexamethasone should be 
adjusted per its prescribing information or ixazomib for Grade 3 or 4 symptoms (see section 4.2). 
 
Cutaneous reactions 
 
Rash has been reported with ixazomib (see section 4.8). Rash should be managed with supportive care 
or with dose modification if Grade 2 or higher (see section 4.2). 
 
Hepatotoxicity 
 
Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and 
hepatotoxicity have been uncommonly reported with ixazomib (see section 4.8). Hepatic enzymes 
should be monitored regularly and the dose should be adjusted for Grade 3 or 4 symptoms (see 
section 4.2). 
 
Pregnancy 
 
Women should avoid becoming pregnant while being treated with ixazomib. If ixazomib is used 
during pregnancy or if the patient becomes pregnant while taking ixazomib, the patient should be 
apprised of the potential hazard to the foetus.  
 
Women of childbearing potential must use highly effective contraception while taking ixazomib and 
for 90 days after stopping treatment (see sections 4.5 and 4.6). Women using hormonal contraceptives 
should additionally use a barrier method of contraception. 
 
Posterior reversible encephalopathy syndrome  
 
Posterior reversible encephalopathy syndrome (PRES) has occurred in patients receiving ixazomib. 
PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, 
headache, altered consciousness, and visual disturbances. Brain imaging, preferably Magnetic 
Resonance Imaging, is used to confirm the diagnosis. In patients developing PRES, discontinue 
ixazomib.  
 
Strong CYP3A inducers 
 
Strong inducers may reduce the efficacy of ixazomib, therefore the concomitant use of strong CYP3A 
inducers such as carbamazepine, phenytoin, rifampicin and St. John’s Wort (Hypericum perforatum), 
should be avoided (see sections 4.5 and 5.2). Closely monitor patients for disease control if co-
administration with a strong CYP3A inducer cannot be avoided. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Pharmacokinetic interactions 
 
CYP inhibitors 
 
Co-administration of ixazomib with clarithromycin, a strong CYP3A inhibitor, did not result in a 
clinically meaningful change in the systemic exposure of ixazomib. Ixazomib Cmax was decreased by 



8 

4% and AUC was increased by 11%. Therefore, no dose modification is required for ixazomib with 
co-administration of strong CYP3A inhibitors. 
 
Co-administration of ixazomib with strong CYP1A2 inhibitors did not result in a clinically meaningful 
change in the systemic exposure of ixazomib based on the results of a population pharmacokinetic 
(PK) analysis. Therefore, no dose modification is required for ixazomib with co-administration of 
strong CYP1A2 inhibitors. 
 
CYP inducers 
 
Co-administration of ixazomib with rifampicin decreased ixazomib Cmax by 54% and AUC by 74%. 
Therefore, co-administration of strong CYP3A inducers with ixazomib is not recommended (see 
section 4.4). 
 
Effect of ixazomib on other medicinal products 
 
Ixazomib is not a reversible or 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. Ixazomib 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. Ixazomib is not expected to cause transporter-mediated drug-drug 
interactions.  
 
Oral contraceptives 
 
When ixazomib is administered together with dexamethasone, which is known to be a weak to 
moderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacy 
of oral contraceptives needs to be considered. Women using hormonal contraceptives should 
additionally use a barrier method of contraception. 
 
4.6 Fertility, pregnancy and lactation 
 
As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPC 
for these medicinal products for additional information on fertility, pregnancy and lactation. 
 
Women of childbearing potential/Contraception in males and females 
 
Male and female patients who are able to have children must use effective contraceptive measures 
during and for 90 days following treatment. Ixazomib is not recommended in women of childbearing 
potential not using contraception. 
 
When ixazomib is administered together with dexamethasone, which is known to be a weak to 
moderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacy 
of oral contraceptives needs to be considered. Therefore, women using oral hormonal contraceptives 
should additionally use a barrier method of contraception. 
 
Pregnancy 
 
Ixazomib is not recommended during pregnancy as it can cause foetal harm when administered to a 
pregnant woman. Therefore, women should avoid becoming pregnant while being treated with 
ixazomib.  
 



9 

There are no data for the use of ixazomib in pregnant women. Studies in animals have shown 
reproductive toxicity (see section 5.3). 
Ixazomib is given in combination with lenalidomide. Lenalidomide is structurally related to 
thalidomide. Thalidomide is a known human teratogenic active substance that causes severe 
life-threatening birth defects. If lenalidomide is taken during pregnancy, a teratogenic effect in humans 
is expected. The conditions of the Pregnancy Prevention Programme for lenalidomide must be fulfilled 
for all patients unless there is reliable evidence that the patient does not have childbearing potential. 
Please refer to the current lenalidomide SmPC. 
 
Breast-feeding 
 
It is unknown whether ixazomib or its metabolites are excreted in human milk. No animal data are 
available. A risk to newborns/infants cannot be excluded and therefore breast-feeding should be 
discontinued.  
 
Ixazomib will be given in combination with lenalidomide and breast-feeding should be stopped 
because of the use of lenalidomide. 
 
Fertility 
 
Fertility studies have not been conducted with ixazomib (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Ixazomib has minor influence on the ability to drive or use machines. Fatigue and dizziness have been 
observed in clinical trials. Patients should be advised not to drive or operate machines if they 
experience any of these symptoms. 
 
4.8 Undesirable effects 
 
As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPC 
for these medicinal products for additional undesirable effects. 
 
Summary of the safety profile 
 
The data presented below is the pooled safety data from the pivotal, Phase 3, global C16010 study 
(n=720) and the double-blind, placebo-controlled C16010 China Continuation Study (n=115). The 
most frequently reported adverse reactions (≥ 20%) across 417 patients treated within the ixazomib 
regimen and 418 patients within the placebo regimen were diarrhoea (39% vs. 32%), 
thrombocytopenia (33% vs. 21%), neutropenia (33% vs. 30%), constipation (30% vs. 22%), peripheral 
neuropathy (25% vs. 20%), nausea (23% vs. 18%), peripheral oedema (23% vs. 17%), vomiting (20% 
vs. 10%) and upper respiratory tract infection (21% vs. 16%). Serious adverse reactions reported in 
≥ 2% of patients included thrombocytopenia (2%) and diarrhoea (2%).  
 
Tabulated list of adverse reactions 
 
The following convention is used for the classification of the frequency of an adverse drug reaction 
(ADR): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available 
data). Within each system organ class, the ADRs are ranked by frequency, with the most frequent 
reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing 
seriousness. 
 



10 

Table 3: Adverse reactions in patients treated with ixazomib in combination with lenalidomide 
and dexamethasone (all grades, grade 3 and grade 4)  
System organ class / 
Adverse reaction 

 Adverse reactions 
(all grades) 

Grade 3 adverse 
reactions 

Grade 4 adverse 
reactions 

Infections and infestations 
Upper respiratory tract 
infection 

Very common Uncommon  

Herpes zoster Common Common  
Blood and lymphatic system disorders 
Thrombocytopenia* Very common Very common Common 
Neutropenia* Very common Very common Common 
Nervous system disorders 
Peripheral neuropathies* Very common Common  
Gastrointestinal disorders 
Diarrhoea Very common Common  
Nausea Very common Common  
Vomiting Very common Uncommon  
Constipation Very common Uncommon  
Skin and subcutaneous tissue disorders 
Rash* Very common Common  
Musculoskeletal and connective tissue disorders 
Back pain Very common  Uncommon  
General disorders and administration site conditions 
Oedema peripheral Very common Common  
Note: ADRs included as preferred terms are based on MedDRA version 16.0. 
*Represents a pooling of preferred terms 
 
Description of selected adverse reactions 
 
Discontinuations 
 
For each adverse reaction, one or more of the three medicinal products was discontinued in ≤ 1% of 
patients in the ixazomib regimen. 
 
Thrombocytopenia 
 
Three percent of patients in the ixazomib 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 ≤ 5,000/mm3 during treatment. Thrombocytopenia resulted in discontinuation of one or more of 
the three medicinal products in < 1% of patients in the ixazomib regimen and 1% of patients in the 
placebo regimen. Thrombocytopenia did not result in an increase in haemorrhagic events or platelet 
transfusions. 
 
Gastrointestinal toxicities 
 
Diarrhoea resulted in discontinuation of one or more of the three medicinal products in 1% of patients 
in the ixazomib regimen and < 1% of patients in the placebo regimen. 
 
Rash 
 
Rash occurred in 18% of patients in the ixazomib regimen compared to 10% of patients in the placebo 
regimen. The most common type of rash reported in both regimens was maculo-papular and macular 
rash. Grade 3 rash was reported in 2% of patients in the ixazomib regimen compared to 1% of patients 
in the placebo regimen. Rash resulted in discontinuation of one or more of the three medicinal 
products in < 1% of patients in both regimens. 
 



11 

Peripheral neuropathy 
 
Peripheral neuropathy occurred in 25% of patients in the ixazomib regimen compared to 20% of 
patients in the placebo regimen. Grade 3 adverse reactions of peripheral neuropathy were reported in 
2% of patients in both regimens. The most commonly reported reaction was peripheral sensory 
neuropathy (16% and 12% in the ixazomib 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 medicinal products in 1% of patients in the ixazomib 
regimen compared to <1% of patients in the placebo regimen. 
 
Eye disorders  
 
Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 
24% in patients in the ixazomib regimen and 15% of patients in the placebo regimen. The most 
common adverse reactions were blurred vision (5% in the ixazomib regimen and 4% in the placebo 
regimen), dry eye (4% in the ixazomib regimen and 1% in the placebo regimen), conjunctivitis (5% in 
the ixazomib regimen and 1% in the placebo regimen) and cataract (4% in the ixazomib regimen and 
5% in the placebo regimen). Grade 3 adverse reactions were reported in 2% of patients in both 
regimens. 
 
Other adverse reactions 
 
Outside of the Phase 3 study, the following serious adverse reactions were rarely reported: acute 
febrile neutrophilic dermatosis (Sweet’s syndrome), Stevens-Johnson syndrome, transverse myelitis, 
posterior reversible encephalopathy syndrome, tumour lysis syndrome and thrombotic 
thrombocytopenic purpura. 
In the pooled dataset from the pivotal, Phase 3, global C16010 study (n=720) and the double-blind, 
placebo-controlled, C16010 China Continuation Study (n=115), the following adverse reactions 
occurred with a similar rate between the ixazomib and placebo regimens: fatigue (26% vs. 24%), 
decreased appetite (12% vs. 9%), hypotension (4% each), heart failure† (3% each), arrhythmia† (12% 
vs. 11%), and liver impairment including enzyme changes† (8% vs. 6%). 
 
The frequency of severe (Grade 3-4) events of hypokalaemia was higher in the ixazomib regimen 
(5%) than the placebo regimen (<1%).  
 
Fungal and viral pneumonia resulting in fatal outcome were rarely reported in patients given the 
ixazomib, lenalidomide and dexamethasone combination. 
 
† Standardised MedDRA Queries (SMQs) 
 
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. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no known specific antidote for ixazomib overdose. Clinical data is limited but doses up to 
12 mg have been reported in the randomised controlled trial. In the event of an overdose, monitor the 
patient for adverse reactions (section 4.8) and provide appropriate supportive care. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


12 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX50 
 
Mechanism of action 
 
Ixazomib citrate, a prodrug, is a substance that rapidly hydrolyses under physiological conditions to its 
biologically active form, ixazomib.  
 
Ixazomib is an oral, highly selective and reversible proteasome inhibitor. Ixazomib preferentially 
binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.  
 
Ixazomib induced apoptosis of several tumour cell types 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 antitumour activity in various tumour xenograft models, including models of 
multiple myeloma. In vitro, ixazomib affected cell types found in the bone marrow microenvironment 
including vascular endothelial cells, osteoclasts and osteoblasts. 
 
Cardiac electrophysiology 
 
Ixazomib did not prolong the QTc interval at clinically relevant exposures based on the results of a 
pharmacokinetic-pharmacodynamic analysis of data from 245 patients. At the 4 mg dose, 
mean change from baseline in QTcF was estimated to be 0.07 msec (90% CI; -0.22, 0.36) from the 
model based analysis. There was no discernible relationship between ixazomib concentration and the 
RR interval suggesting no clinically meaningful effect of ixazomib on heart rate. 
 
Clinical efficacy and safety 
 
The efficacy and safety of ixazomib in combination with lenalidomide and dexamethasone was 
evaluated in an international randomised, double-blind, placebo-controlled, multicenter Phase 3 
superiority study (C16010) in patients with relapsed and/or refractory multiple myeloma who had 
received at least one prior therapy. A total of 722 patients (intent-to-treat [ITT] population) were 
randomised in a 1:1 ratio to receive either the combination of ixazomib, lenalidomide, and 
dexamethasone (N=360; ixazomib regimen) or placebo, lenalidomide and dexamethasone 
(N=362; placebo regimen) until disease progression or unacceptable toxicity. Patients enrolled in the 
trial had multiple myeloma that was refractory, including primary refractory, had relapsed after prior 
therapy, or had relapsed and was refractory to any prior therapy. Patients that changed therapies prior 
to disease progression were eligible for enrolment, as well as those with controlled cardiovascular 
conditions. The Phase 3 study excluded patients who were refractory to lenalidomide or proteasome 
inhibitors and patients who received more than three prior therapies. For the purposes of this study, 
refractory disease was defined as disease progression on treatment or progression within 60 days after 
the last dose of lenalidomide or a proteasome inhibitor. As data are limited in these patients, a careful 
risk-benefit assessment is recommended before initiating the ixazomib regimen. 
 
Thromboprophylaxis was recommended for all patients in both treatment groups according to the 
lenalidomide SmPC. Concomitant medicinal products, such as antiemetic, antiviral, and antihistamine 
medicinal products were given to patients at the physician's discretion as prophylaxis and/or 
management of symptoms.   
 
Patients received ixazomib 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 SmPC. Treatment continued until 
disease progression or unacceptable toxicities. 



13 

 
The baseline demographics and disease characteristics were balanced and comparable between the 
study regimens. The median age was 66 years, range 38-91 years; 58% of patients were older than 
65 years. Fifty seven percent of patients were male. Eighty five percent of the population was White, 
9% Asian and 2% Black. Ninety three percent of patients had an ECOG performance status of 0-1 and 
12% had baseline ISS stage III disease (N=90). Twenty five percent of patients had a creatinine 
clearance of < 60 mL/min. Twenty three percent of patients had light chain disease and 12% of 
patients had measurable disease by free light chain assay only. Nineteen percent had high-risk 
cytogenetic abnormalities (del[17], t[4;14], t[14;16]) (N=137), 10% had del(17) (N=69) and 34% had 
1q amplification (1q21) (N=247). Patients received one to three prior therapies (median of 1) 
including prior treatment with bortezomib (69%), carfilzomib (<1%), thalidomide (45%), 
lenalidomide (12%), melphalan (81%). Fifty seven percent of patients had undergone prior stem cell 
transplantation. Seventy seven percent of patients relapsed after prior therapies and 11% were 
refractory to prior therapies. Primary refractory, defined as best response of stable disease or disease 
progression on all prior therapies, was documented in 6% of patients. 
 
The primary endpoint was progression-free survival (PFS) according to the 2011 International 
Myeloma Working Group (IMWG) Consensus Uniform Response Criteria as assessed by a blinded 
independent review committee (IRC) based on central laboratory results. Response was assessed every 
4 weeks until disease progression. At the primary analysis (median follow up of 14.7 months and a 
median of 13 cycles), PFS was statistically significantly different between the treatment arms. PFS 
results are summarised in Table 4 and Figure 1. The improvement in PFS in the ixazomib regimen was 
supported by improvements in overall response rate. 
 
Table 4: Progression free survival and response Results in multiple myeloma patients treated 
with ixazomib or placebo in combination with lenalidomide and dexamethasone (intent-to-treat 
population) 
 Ixazomib + Lenalidomide and 

Dexamethasone 
(N = 360) 

Placebo + Lenalidomide and 
Dexamethasone 
(N = 362) 

Progression-Free Survival 
Events, n (%) 129 (36) 157 (43) 
Median (months) 20.6 14.7 
p-value* 0.012 
Hazard Ratio† 
(95% CI) 

0.74 
(0.59, 0.94) 

Overall Response Rate‡, n (%)  282 (78.3) 259 (71.5) 
Response Category, n (%) 
Complete Response  42 (11.7) 24 (6.6) 
Very Good Partial Response  131 (36.4) 117 (32.3) 
Partial Response  109 (30.3) 118 (32.6) 
Time to Response, months 
Median 1.1 1.9 
Duration of Response§, months 
Median 20.5 15.0 
*P-value is based on the stratified log-rank test. 
†Hazard ratio is based on a stratified Cox’s proportional hazard regression model. A hazard ratio less than 1 

indicates an advantage for the ixazomib regimen. 
‡ORR = CR+VGPR+PR 
§Based on responders in the response-evaluable population 
 



14 

Figure 1: Kaplan-Meier plot of progression-free survival in the intent-to-treat population 

 
 
A planned interim analysis for overall survival (OS) at a median follow up of 23 months was 
conducted with 35% of the required number of deaths for final OS analysis in the ITT population; 
there were 81 deaths in the ixazomib regimen and 90 deaths in the placebo regimen. Median overall 
survival was not reached in either regimen. At this analysis, estimated median PFS was 20 months in 
the ixazomib regimen and 15.9 months in the placebo regimen (HR=0.82 [95% CI (0.67, 1.0)]) in the 
ITT population. 
 
A randomised, double-blind, placebo-controlled Phase 3 study was conducted in China (N=115) with 
a similar study design and eligibility criteria. Many of the patients enrolled in the study had advanced 
disease with Durie-Salmon Stage III (69%) at initial diagnosis and a treatment history of receiving at 
least 2 prior therapies (60%) and being thalidomide refractory (63%). At the primary analysis (median 
follow up of 8 months and a median of 6 cycles), the median PFS was 6.7 months in the ixazomib 
regimen compared to 4 months in the placebo regimen (p-value=0.035, HR=0.60). At the final 
analysis for OS at a median follow up of 19.8 months, OS was improved for patients treated in the 
ixazomib regimen compared with placebo [p-value=0.0014, HR=0.42, 95% CI: 0.242, 0.726 ]). 

Probability of Progression Free Survival 

0.0 

0.2 

0.4 

0.6 

0.8 

1.0 

Time (months) from Randomization 
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 

Number of Patients at Risk 
Placebo Regimen 362 340 325 308 288 274 254 237 218 208 188 157 130 101 85 71 58 46 31 22 15 5 3 0 0 
Number of Patients at Risk 

NINLARO Regimen 360 345 332 315 298 283 270 248 233 224 206 182 145 119 111 95 72 58 44 34 26 14 9 1 0 

Log-rank test P-value: 0.012 

Censored 
Censored 

Hazard ratio (95% CI): 0.742 (0.587, 0.939) 

Censored 
Censored 

Median: Placebo Regimen: 14.7, NINLARO Regimen: 20.6 
Censored 
Censored 

Num of events: Placebo Regimen:157, NINLARO Regimen:129 
Censored 
Censored Placebo Regimen NINLARO Regimen 



15 

As multiple myeloma is a heterogeneous disease, benefit may vary across subgroups in the Phase 3 
study (C16010) (see Figure 2).  
 
Figure 2: Forest plot of progression-free survival in subgroups 

 
 
In the Phase 3 study (C16010), 10 patients (5 in each treatment regimen) had severe renal impairment 
at baseline. Of the 5 patients in the ixazomib regimen, one patient had a confirmed partial response 
and 3 confirmed stable disease (however 2 were unconfirmed partial response and 1 was an 
unconfirmed very good partial response). Of the 5 patients in the placebo regimen, 2 had a confirmed 
very good partial response. 
 
Quality of life as assessed by global health scores (EORTC QLQ-C30 and MY-20) was maintained 
during treatment and was similar in both treatment regimens in the Phase 3 study (C16010). 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ixazomib in all subsets of the paediatric population in multiple myeloma (see section 4.2 for 
information on paediatric use). 
 



16 

5.2 Pharmacokinetic properties 
 
Absorption 
 
After oral administration, peak plasma concentrations of ixazomib were achieved at approximately 
one hour after dosing. The mean absolute oral bioavailability is 58%. Ixazomib AUC increases in a 
dose proportional manner over a dose range of 0.2-10.6 mg.  
 
Administration with a high-fat meal decreased ixazomib AUC by 28% compared with administration 
after an overnight fast (see section 4.2).  
 
Distribution 
 
Ixazomib is 99% bound to plasma proteins and distributes into red blood cells with a blood-to-plasma 
AUC ratio of 10. The steady-state volume of distribution is 543 L.  
 
Biotransformation 
 
After oral administration of a radiolabeled dose, 70% of total drug-related material in plasma was 
accounted for by ixazomib. 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 cDNA-expressed cytochrome P450 isozymes indicate that no specific 
CYP isozyme predominantly contributes to ixazomib metabolism and non-CYP proteins contribute to 
overall metabolism. At concentrations exceeding those observed clinically, ixazomib was metabolized 
by multiple CYP isoforms with estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 
2B6 (16.0%), 2C8 (6.0%), 2D6 (4.8%), 2C19 (4.8%) and 2C9 (< 1%). 
 
Elimination 
 
Ixazomib exhibits a multi-exponential disposition profile. Based on a population PK analysis, systemic 
clearance (CL) was approximately 1.86 L/hr with inter-individual variability of 44%. The terminal 
half-life (t1/2) of ixazomib was 9.5 days. Approximately 2-fold accumulation in AUC was observed 
with weekly oral dosing on Day 15. 
 
Excretion 
 
After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% of 
the administered radioactivity was excreted in urine and 22% in the faeces. Unchanged ixazomib 
accounted for < 3.5% of the administered dose recovered in urine. 
 
Special populations 
 
Hepatic impairment 
 
The PK of ixazomib is 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 the results of a 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). Unbound dose-normalized AUC was 
27% higher in patients with moderate or severe hepatic impairment as compared to patients with 
normal hepatic function (see section 4.2). 
 



17 

Renal impairment 
 
The PK of ixazomib is similar in patients with normal renal function and in patients with mild or 
moderate renal impairment (creatinine clearance ≥ 30 mL/min) based on the results of a 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). Unbound AUC was 38% higher in patients 
with severe renal impairment or ESRD requiring dialysis as compared to patients with normal renal 
function. Pre- and post-dialyzer concentrations of ixazomib measured during the haemodialysis 
session were similar, suggesting that ixazomib is not dialyzable (see section 4.2).  
 
Age, gender, race 
 
There was no clinically meaningful effect of age (23-91 years), sex, body surface area (1.2-2.7 m2), or 
race on the clearance of ixazomib based on the results of a population PK analysis. The mean AUC 
was 35% higher in Asian patients; however, there was overlap in the AUC of ixazomib across White 
and Asian patients. 
 
5.3 Preclinical safety data 
 
Mutagenicity 
 
Ixazomib was not mutagenic in a bacterial reverse mutation assay (Ames assay) or clastogenic in a 
bone marrow micronucleus assay in mice. Ixazomib was positive in an in vitro clastogenicity test in 
human peripheral blood lymphocytes. However, ixazomib was negative in an in vivo comet assay in 
mice, in which percent tail DNA was assessed in the stomach and liver. Therefore, the weight of 
evidence indicates that ixazomib is not considered to present a genotoxic risk.  
 
Reproductive and embryo-foetal development 
 
Ixazomib caused embryo-foetal toxicity in pregnant rats and rabbits only at maternally toxic doses and 
at exposures that were slightly higher than those observed in patients receiving the recommended 
dose. Studies of fertility and early embryonic development and pre- and post-natal toxicology were not 
conducted with ixazomib, but evaluation of reproductive tissues was conducted in the general 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.  
 
Animal toxicology and/or pharmacology 
 
In multi-cycle repeated-dose toxicity studies conducted in rats and dogs, the principal target organs 
included the gastrointestinal tract, lymphoid tissues, and the nervous system. In the 9-month study 
(10 cycles) in dogs orally administered with a dosing schedule mimicking the clinical regimen 
(28-day cycle), microscopic neuronal effects were generally minimal in nature and only observed at 
0.2 mg/kg (4 mg/m2). The majority of target organ findings demonstrated partial to full recovery 
following discontinuation of treatment, with the exception of neuronal findings in the lumbar dorsal 
root ganglion and dorsal column.  
 
Following oral administration, a tissue distribution study in rats revealed that the brain and spinal cord 
were amongst the tissues with the lowest levels, suggesting that the penetration of ixazomib through 
the blood-brain barrier appears to be limited. However, the relevance to humans is unknown. 
 
Non-clinical safety pharmacology studies both in vitro (on hERG channels) and in vivo (in telemetered 
dogs following single oral administration) demonstrated no effects of ixazomib on cardiovascular or 
respiratory functions at AUC more than 8-fold higher than the clinical value. 



18 

 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
NINLARO 2.3 mg hard capsules 
 
Capsule contents 
Microcrystalline cellulose 
Magnesium stearate 
Talc 
 
Capsule shell 
Gelatin 
Titanium dioxide (E171) 
Red iron oxide (E172) 
 
Printing ink 
Shellac 
Propylene glycol 
Potassium hydroxide 
Black iron oxide (E172) 
 
NINLARO 3 mg hard capsules 
 
Capsule contents 
Microcrystalline cellulose 
Magnesium stearate 
Talc 
 
Capsule shell 
Gelatin 
Titanium dioxide (E171) 
Black iron oxide (E172) 
 
Printing ink 
Shellac 
Propylene glycol 
Potassium hydroxide 
Black iron oxide (E172) 
 
NINLARO 4 mg hard capsules 
 
Capsule contents 
Microcrystalline cellulose  
Magnesium stearate 
Talc 
 
Capsule shell 
Gelatin 
Titanium dioxide (E171) 
Yellow iron oxide (E172) 
Red iron oxide (E172)  
 



19 

Printing ink 
Shellac 
Propylene glycol 
Potassium hydroxide 
Black iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. Do not freeze.   
 
Store in the original package in order to protect from moisture.  
 
6.5 Nature and contents of container  
 
PVC-Aluminium /Aluminium blister sealed inside a wallet pack containing one capsule. 
Three single blister wallet packs are packaged in one carton. 
 
6.6 Special precautions for disposal and other handling 
 
Ixazomib is cytotoxic. The capsule should not be removed until just prior to dosing. The capsules 
should not be opened or crushed. Direct contact with the capsule contents should be avoided. In case 
of capsule breakage, avoid raising dust during clean-up. If contact occurs, wash thoroughly with soap 
and water.  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10  
2630 Taastrup 
Denmark 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1094/001 
EU/1/16/1094/002 
EU/1/16/1094/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21 November 2016 
Date of Last Renewal: 16 September 2019 
 
 



20 

10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE CONDITIONAL 
MARKETING AUTHORISATION 



22 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Takeda Ireland Limited 
Grange Castle Business Park 
Dublin 22 
D22 XR57 
Ireland 
 
Takeda GmbH 
Production Site Singen 
Robert Bosch Strasse 8 
78224 Singen 
Germany 
 
Takeda Pharma A/S 
Dybendal Alle 10 
2630 Taastrup 
Denmark 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached.  
 



23 

• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measure: 
 

Description Due date 
Post-authorisation efficacy study (PAES) C16010: To provide an interim report of overall 
survival at the time of the 3rd interim analysis and to provide a final report for the final 
analysis of OS from the phase 3, randomized, double-blind study C16010 in adult patients 
with relapsed and/or refractory multiple myeloma. 

June 2021 

 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE CONDITIONAL MARKETING AUTHORISATION  
 
This being a conditional marketing authorisation and pursuant to Article 14a(4) of Regulation (EC) 
No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: 
 

Description Due date 
C16014: In order to further investigate the efficacy the MAH should conduct a phase 3, 
randomized, double-blind, multicenter study comparing ixazomib plus lenalidomide and 
dexamethasone versus placebo plus lenalidomide and dexamethasone in adult patients with 
newly diagnosed multiple myeloma not eligible for stem cell transplantation (SCT) and 
provide the final report for primary endpoint PFS. 

December 
2020 

C16019: In order to further investigate the efficacy the MAH should provide additional 
OS/PFS2 data when approximately 200 death events have occurred from the Phase 3, 
randomized, placebo-controlled, double-blind study of ixazomib in maintenance therapy in 
patients with multiple myeloma following SCT.  

December 
2021  

NSMM-5001: The MAH should conduct a global, prospective, non-interventional, 
observational study in multiple myeloma patients and provide a report with the final analysis 
when at least 110 PFS events are expected to have occurred in subjects prospectively 
exposed to ixazomib. 

July 2022 

 
 
 
 
 
 



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 



26 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING WALLET UNIT PACKS 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 2.3 mg hard capsules 
ixazomib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 2.3 mg of ixazomib (as 3.3 mg of ixazomib citrate) 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
3 packs of 1 hard capsule. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30ºC. Do not freeze.  
Store in the original package in order to protect from moisture. 
 
 



27 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S  
Dybendal Alle 10  
2630 Taastrup  
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1094/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
NINLARO 2.3 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



28 

 
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
CARTON CONTAINING WALLET UNIT 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 2.3 mg hard capsules  
ixazomib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 2.3 mg of ixazomib (as 3.3 mg of ixazomib citrate) 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
1 hard capsule. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30ºC. Do not freeze.  
Store in the original package in order to protect from moisture. 
 
 



29 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S  
Dybendal Alle 10  
2630 Taastrup  
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1094/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
NINLARO 2.3 mg  
 
 
 
 
 
 
 
 
 



30 

 
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
WALLET 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 2.3 mg hard capsules  
ixazomib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule  
 
1 hard capsule 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Do not crush, open or chew the capsules. Take each NINLARO capsule whole with water at the same 
time each week, at least one hour before or no sooner than two hours after any food. 
The capsule should not be removed until just prior to dosing. 
Oral use  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



31 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 



32 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOR WALLET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 2.3 mg 
ixazomib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



33 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING WALLET UNIT PACKS  
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 3 mg hard capsules 
ixazomib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 3 mg of ixazomib (as 4.3 mg of ixazomib citrate)  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule  
 
3 packs of 1 hard capsule. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30ºC. Do not freeze.  
Store in the original package in order to protect from moisture. 
 



34 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S  
Dybendal Alle 10  
2630 Taastrup  
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1094/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
NINLARO 3 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



35 

 
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
CARTON CONTAINING WALLET UNIT  
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 3 mg hard capsules  
ixazomib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 3 mg of ixazomib (as 4.3 mg of ixazomib citrate)  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
1 hard capsule.  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30ºC. Do not freeze.  
Store in the original package in order to protect from moisture. 
 



36 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S  
Dybendal Alle 10  
2630 Taastrup  
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1094/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
NINLARO 3 mg  
 
 



37 

 
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
WALLET   
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 3 mg hard capsules  
ixazomib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule  
 
1 hard capsule 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Do not crush, open or chew the capsules. Take each NINLARO capsule whole with water at the same 
time each week, at least one hour before or no sooner than two hours after any food. 
The capsule should not be removed until just prior to dosing. 
Oral use  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 



38 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
 



39 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOR WALLET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 3 mg 
ixazomib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER  
 
Lot 
 
 
5. OTHER 
 



40 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON CONTAINING WALLET UNIT PACKS  
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 4 mg hard capsules 
ixazomib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 4 mg of ixazomib (as 5.7 mg of ixazomib citrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
3 packs of 1 hard capsule. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use  
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30ºC. Do not freeze.  
Store in the original package in order to protect from moisture. 
 
 



41 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S  
Dybendal Alle 10  
2630 Taastrup  
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1094/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
NINLARO 4 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



42 

 
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
CARTON CONTAINING WALLET UNIT  
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 4 mg hard capsules  
ixazomib  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 4 mg of ixazomib (as 5.7 mg of ixazomib citrate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
 
1 hard capsule.  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30ºC. Do not freeze.  
 
Store in the original package in order to protect from moisture. 
 



43 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S  
Dybendal Alle 10  
2630 Taastrup  
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1094/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
NINLARO 4 mg  
 
 
 



44 

 
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
WALLET   
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 4 mg hard capsules  
ixazomib  
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule  
 
1 hard capsule 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Do not crush, open or chew the capsules. Take each NINLARO capsule whole with water at the same 
time each week, at least one hour before or no sooner than two hours after any food. 
The capsule should not be removed until just prior to dosing. 
Oral use  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 



45 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 



46 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOR WALLET 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NINLARO 4 mg 
ixazomib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



47 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



48 

 
 

Package leaflet: Information for the patient 
 

NINLARO 2.3 mg hard capsules 
NINLARO 3 mg hard capsules 
NINLARO 4 mg hard capsules 

ixazomib 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.   
 
Read all of this leaflet carefully before you start taking this medicine because it contains  
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What NINLARO is and what it is used for 
2. What you need to know before you take NINLARO 
3. How to take NINLARO 
4. Possible side effects 
5. How to store NINLARO 
6. Contents of the pack and other information 
 
 
1. What NINLARO is and what it is used for 
 
What NINLARO is 
NINLARO is a cancer medicine that contains ixazomib, a ‘proteasome inhibitor’. 
 
NINLARO is used to treat a cancer of the bone marrow called multiple myeloma. Its active substance 
ixazomib works by blocking the action of proteasomes. These are structures inside the cell that digest 
proteins and are important for cell survival. Because myeloma cells produce a lot of proteins, blocking 
the action of proteasomes can kill the cancerous cells. 
 
What NINLARO is used for 
NINLARO is used to treat adults with multiple myeloma. NINLARO will be given to you together 
with lenalidomide and dexamethasone, which are other medicines used to treat multiple myeloma. 
 
What multiple myeloma is  
Multiple myeloma is a cancer of the blood which affects a type of cell, called the plasma cell. A 
plasma cell is a blood cell that normally produces proteins to fight infections. People with multiple 
myeloma have cancerous plasma cells, also called myeloma cells, which can damage the bones. 
Protein produced by myeloma cells can damage the kidneys. Treatment for multiple myeloma involves 
killing myeloma cells and reducing the symptoms of the disease.  
 
 

javascript:void(0);


49 

2. What you need to know before you take NINLARO 
 
Do not take NINLARO 
- if you are allergic to ixazomib or to any of the other any of the other ingredients of this 

medicine (listed in section 6). 
 
If you are uncertain whether the condition above applies to you, talk to your doctor, pharmacist or 
nurse before taking NINLARO. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before taking NINLARO if: 
• you have a history of bleeding 
• you have persistent nausea, vomiting or diarrhoea 
• you have a history of nerve problems, to include tingling and numbness 
• you have a history of swelling 
• you have a persistent rash 
• you have or have had liver or kidney problems as your dose may have to be adjusted. 
 
Your doctor will examine you and you will be monitored closely during treatment. Before starting 
NINLARO and during treatment, you will have blood tests to check that you have enough blood cells. 
 
Children and adolescents 
NINLARO is not recommended for use in children and adolescents aged under 18 years. 
 
Other medicines and NINLARO 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. This includes any medicines obtained without a prescription, such as vitamins or herbal 
remedies. This is because other medicines can affect the way NINLARO works. In particular, tell your 
doctor, pharmacist or nurse if you are taking any of the following medicines: carbamazepine, 
phenytoin, rifampicin and St. John’s wort (Hypericum perforatum). These medicines should be 
avoided as they may reduce the effectiveness of NINLARO. 
 
Pregnancy and breast-feeding 
NINLARO is not recommended during pregnancy as it may harm your unborn baby. Breast-feeding 
should be stopped when taking NINLARO. 
 
Avoid becoming pregnant or breast-feeding while being treated with NINLARO. If you are pregnant 
or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or 
pharmacist for advice before taking this medicine.  
 
If you are a woman of childbearing potential or a man who can father a child, you must use effective 
contraception during and for 90 days after treatment. Women using hormonal contraceptives should 
additionally use a barrier method of contraception. Tell doctor right away if you or your partner 
becomes pregnant while receiving NINLARO. 
As NINLARO is given in combination with lenalidomide, you should adhere to the pregnancy 
prevention programme of lenalidomide because lenalidomide can be harmful to the unborn child. 
 
See the package leaflets for lenalidomide and dexamethasone for additional information on pregnancy 
and breast-feeding 
 
Driving and using machines 
NINLARO may affect your ability to drive or use machines. You may feel tired and dizzy while 
taking NINLARO. Do not drive or operate machines if you have these side effects. 
 
 



50 

3. How to take NINLARO 
 
NINLARO must be prescribed to you by a doctor with experience of treating multiple myeloma. 
Always take this medicine exactly as your doctor or pharmacist has told you.  
 
NINLARO is used with lenalidomide (a medicine which affects how your immune system works) and 
dexamethasone (an anti-inflammatory medicine). 
 
NINLARO, lenalidomide and dexamethasone are taken in 4-week treatment cycles. NINLARO is 
taken once a week (on the same day of the week) for the first 3 weeks of this cycle. The recommended 
dose is one 4 mg capsule taken by mouth. 
 
The recommended dose of lenalidomide is 25 mg taken every day for the first 3 weeks of the cycle. 
The recommended dose of dexamethasone is 40 mg taken once a week on the same day for all 
4 weeks of the cycle.  
 

 
You should read the Package Leaflets of these other medicines for further information on their use and 
effects.  
 
If you have liver or kidney problems, your doctor may prescribe NINLARO capsules containing 3 mg. 
If you have side effects, your doctor may prescribe NINLARO capsules containing 3 mg or 2.3 mg. 
The doctor may also adjust the doses of the other medicines. 
 
How and when to take NINLARO  
• Take NINLARO at least one hour before or at least two hours after food.  
• Swallow the capsule whole with water. Do not crush, chew or open the capsule.  
• Do not let the contents of the capsule come into contact with your skin. If the powder 

accidentally comes into contact with your skin, wash it off thoroughly with soap and water. If 
the capsule breaks, clean up the powder, taking care that it does not cause dust in the air.  

 
If you take more NINLARO than you should  
If you take more NINLARO than you should, talk to a doctor or go to a hospital straight away. Take 
the medicine pack with you. 
 
Duration of the treatment with NINLARO  
You should continue treatment until your doctor tells you to stop.  
 
If you forget to take NINLARO  
If a dose is missed or delayed, you should take the dose as long as the next scheduled dose is more 
than 3 days or 72 hours away. Do not take a missed dose if it is within 3 days or 72 hours of your next 
scheduled dose. 
 
If you vomit after taking a dose, do not take an extra dose. Take the next dose, as normal, when it is 
due.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

Dosing schedule: 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 to 7 
Day 8 Days  

9 to 14 
Day 
15 

Days  
16 to 21 

Day 
22 

Days 23 
to 28 

NINLARO         
Lenalidomide  Daily  Daily  Daily   
Dexamethasone         



51 

 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor or pharmacist straight away if you notice any of these following very common 
serious side effects which may affect more than 1 in 10 people: 
• low platelet counts (thrombocytopenia) which may increase the risk of nose bleeds and you may 

easily bruise  
• nausea, vomiting and diarrhoea 
• numbness, tingling or burning of the hands or feet (peripheral neuropathy) 
• swelling of the legs or feet (peripheral oedema) 
• skin rash that may be itchy and in a few areas or all over the body  
 
Additionally, tell a doctor immediately if you notice any of these following rare side effects which 
may affect up to 1 in 1,000 people:  
• severe skin rashes such as red to purple bumps (Sweet’s syndrome) or rash with skin peeling 

and mouth sores (Stevens-Johnson syndrome) 
• muscle weakness, loss of feelings of the toes and feet or loss of leg movement (transverse 

myelitis) 
• changes in vision, changes in mental status, or seizures (posterior reversible encephalopathy 

syndrome) 
• rapid death of cancer cells that may cause dizziness, decreased urination, confusion, vomiting, 

nausea, swelling, shortness of breath, or heart rhythm disturbances (tumour lysis syndrome) 
• rare blood condition resulting from blood clots that may cause fatigue, fever, bruising, nose 

bleeds, decreased urination (thrombotic thrombocytopenic purpura) 
 
Other possible side effects  
Tell your doctor or pharmacist if any of the side effects below become severe.  
 
Very common side effects may affect more than 1 in 10 people: 
• constipation 
• back pain 
• cold-like symptoms (upper respiratory tract infection) 
• feeling tired or weak (fatigue) 
• lowered white blood cells called neutrophils (neutropenia) that may increase the risk of 

infection  
• not feeling like eating (decreased appetite) 
• irregular heart rate (arrhythmia) 
• vision conditions including blurred vision, dry eye and pink eye (conjunctivitis) 
 
Common side effects may affect up to 1 in 10 people: 
• reactivation of the chicken pox virus (shingles) that can cause a skin rash and pain (herpes 

zoster) 
• lowered blood pressure (hypotension) 
• shortness of breath or persistent coughing or wheezing (heart failure) 
• yellow discoloration of eyes and skin (jaundice which could be a symptom of liver  impairment) 
• low levels of potassium in the blood (hypokalaemia) 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


52 

 
5. How to store NINLARO 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the blister, wallet and carton after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. Do not freeze.  
 
Store in the original package in order to protect from moisture. 
 
Do not remove the capsule until you need to take a dose. 
 
Do not use this medicine if you notice any damage or signs of tampering to medicine packaging. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What NINLARO contains  
NINLARO 2.3 mg hard capsule:  
- The active substance is ixazomib. Each capsule contains 2.3 mg of ixazomib (as 3.3 mg of 

ixazomib citrate). 
- The other ingredients are: 
• In the capsule: microcrystalline cellulose, magnesium stearate and talc. 
• The capsule shell contains: gelatin, titanium dioxide (E171) and red iron oxide (E172)  
• The printing ink contains: shellac, propylene glycol, potassium hydroxide, and black iron 
 oxide (E172). 
 
NINLARO 3 mg hard capsule:  
- The active substance is ixazomib. Each capsule contains 3 mg of ixazomib (as 4.3 mg of 

ixazomib citrate).  
- The other ingredients are: 

• In the capsule: microcrystalline cellulose, magnesium stearate and talc. 
• The capsule shell contains: gelatin, titanium dioxide (E171) and black iron oxide (E172)  
• The printing ink contains: shellac, propylene glycol, potassium hydroxide, and black iron 

oxide (E172). 
 
NINLARO 4 mg hard capsule:  
- The active substance is ixazomib. Each capsule contains 4 mg of ixazomib (as 5.7 mg of 

ixazomib citrate).  
- The other ingredients are 

• In the capsule: microcrystalline cellulose, magnesium stearate and talc. 
• The capsule shell contains: gelatin, titanium dioxide (E171), yellow iron oxide (E172) 

and red iron oxide (E172)  
• The printing ink contains: shellac, propylene glycol, potassium hydroxide, and black iron 

oxide (E172). 
 
 
What NINLARO looks like and contents of the pack 
NINLARO 2.3 mg hard capsule: Light pink, size 4, marked “Takeda” on the cap and “2.3 mg” on the 
body with black ink. 
 



53 

NINLARO 3 mg hard capsule: Light grey, size 4, marked “Takeda” on the cap and “3 mg” on the 
body with black ink. 
 
NINLARO 4 mg hard capsule: Light orange, size 3, marked “Takeda” on the cap and “4 mg” on the 
body with black ink. 
 
Each pack contains 3 hard capsules (three single cartons, each containing a blister sealed inside a 
wallet. Each blister contains one capsule). 
 
Marketing Authorisation Holder  
Takeda Pharma A/S 
Dybendal Alle 10  
2630 Taastrup 
Denmark 
 
Manufacturer 
Takeda Ireland Limited 
Grange Castle Business Park 
Dublin 22 
D22 XR57 
Ireland 
 
Takeda Pharma A/S 
Dybendal Alle 10  
2630 Taastrup 
Denmark 
 
Takeda GmbH 
Takeda (Werk Singen) 
Robert Bosch Straße 8 
78224 Singen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Takeda Belgium  
Tel/Tél: +32 2 464 06 11  
takeda-belgium@takeda.com  
 

Lietuva 
Takeda, UAB  
Tel: +370 521 09 070  
lt-info@takeda.com  
 

България 
Такеда България  
Тел.: + 359 2 958 27 36;  
 
 

Luxembourg/Luxemburg 
Takeda Belgium  
Tel/Tél: +32 2 464 06 11  
takeda-belgium@takeda.com  

Česká republika 
Takeda Pharmaceuticals  
Czech Republic s.r.o.  
Tel: + 420 234722722  

Magyarország 
Takeda Pharma Kft.  
Tel: +361 2707030  

Danmark 
Takeda Pharma A/S  
Tlf: +45 46 77 11 11  
 

Malta 
Takeda Italia S.p.A.  
Tel: +39 06 502601  



54 

Deutschland 
Takeda GmbH  
Tel: 0800 825 3325  
medinfo@takeda.de  
 

Nederland 
Takeda Nederland bv  
Tel: +31 23 56 68 777  
nl.medical.info@takeda.com  

Eesti 
Takeda Pharma AS  
Tel: +372 6177 669  
 

Norge 
Takeda AS  
Tlf: +47 6676 3030  
infonorge@takeda.com  
 

Ελλάδα 
TAKEDA ΕΛΛΑΣ Α.Ε  
Tηλ: +30 210 6387800 
gr.info@takeda.com  
 

Österreich 
Takeda Pharma Ges.m.b.H.  
Tel: +43 (0) 800-20 80 50  

España 
Takeda Farmacéutica España S.A  
Tel: +34 917 14 99 00  
spain@takeda.com  
 

Polska 
Takeda Pharma sp. z o.o 
Tel.: + 48 22 608 13 00  

France 
Takeda France  
Tél: +33 1 46 25 16 16  

Portugal 
Takeda Farmacêuticos Portugal, Lda.  
Tel: + 351 21 120 1457  

 
Hrvatska 
Takeda Pharmaceuticals Croatia d.o.o.  
Tel: +385 1 377 88 96  
 
Ireland 
Takeda Products Ireland Limited  
Tel: +353 (0) 1 6420021  
 

 
România 
Takeda Pharmaceuticals SRL  
Tel: +40 21 335 03 91  
 
Slovenija 
Takeda GmbH Podružnica Slovenija  
Tel.+ 386 (0) 59 082 480  

Ísland 
Vistor hf.  
Sími: +354 535 7000  
vistor@vistor.is  
 

Slovenská republika 
Takeda Pharmaceuticals Slovakia s.r.o.  
Tel: +421 (2) 20 602 600  

Italia 
Takeda Italia S.p.A.  
Tel: +39 06 502601  

Suomi/Finland 
Takeda Oy   
Puh/Tel: +358 20 746 5000  
 

Κύπρος 
A. POTAMITIS MEDICARE LTD  
Tηλ: +357 22583333 
info@potamitismedicare.com  
 

Sverige 
Takeda Pharma AB  
Tel: +46 8 731 28 00  
infosweden@takeda.com  

 
Latvija 
Takeda Latvia SIA  
Tel: +371 67840082  
 

 
United Kingdom 
Takeda UK Ltd  
Tel: +44 (0)1628 537 900  
 

 



55 

This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION 
	A. LABELLING
	B. PACKAGE LEAFLET