NINLARO 4mg capsules medication leaflet

NINLARO 2.3 mg hard capsules

NINLARO 3 mg hard capsules

NINLARO 4 mg hard capsules

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.

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 withblack ink.

NINLARO 3 mg hard capsules

Light grey, size 4 gelatin hard capsule, marked “Takeda” on the cap and “3 mg” on the body withblack ink.

NINLARO 4 mg hard capsules

Light orange, size 3 gelatin hard capsule, marked “Takeda” on the cap and “4 mg” on the body withblack ink.

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

Treatment must be initiated and monitored under the supervision of a physician experienced in themanagement of multiple myeloma.

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 a28-day treatment cycle.

The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a28-day treatment cycle.

Dosing schedule: Ixazomib taken with lenalidomide and dexamethasone28-day cycle (a 4-week cycle)

Week 1 Week 2 Week 3 Week 4

Day 1 Days Day 8 Days Day Days Day Days 232 to 7 9 to 14 15 16 to 21 22 to 28

Ixazomib   

Lenalidomide  Daily  Daily  Daily

Dexamethasone    = intake of medicinal product

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 topatient’s baseline condition or ≤ Grade 1

Treatment should be continued until disease progression or unacceptable toxicity. Treatment withixazomib in combination with lenalidomide and dexamethasone for longer than 24 cycles should bebased on an individual benefit risk assessment, as the data on the tolerability and toxicity beyond24 cycles are limited (see section 5.1).

In the event that a ixazomib dose is delayed or missed, the dose should be taken only if the nextscheduled dose is ≥ 72 hours away. A missed dose should not be taken within 72 hours of the nextscheduled 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 dosingat the time of the next scheduled dose.

The ixazomib dose reduction steps are presented in Table 1 and the dose modification guidelines areprovided in Table 2.

Table 1: Ixazomib dose reduction steps

Recommended starting dose* First reduction to Second reduction to

Discontinue4 mg 3 mg 2.3 mg

*Recommended reduced dose of 3 mg in the presence of moderate or severe hepatic impairment, severe renalimpairment or end-stage renal disease (ESRD) requiring dialysis.

An alternating dose modification approach is recommended for ixazomib and lenalidomide foroverlapping toxicities of thrombocytopenia, neutropenia and rash. For these toxicities, the first dosemodification step is to withhold/reduce lenalidomide. Refer to the lenalidomide SmPC, section 4.2 forthe dose reduction steps for these toxicities.

Table 2: Dose modifications guidelines for ixazomib in combination with lenalidomide anddexamethasone

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 lowerdose according to its SmPC and resume ixazomib at its mostrecent dose.

* If platelet count falls to < 30 000/mm3 again, withholdixazomib and lenalidomide until platelet count≥ 30 000/mm3.

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

Neutropenia (absolute neutrophil count)

Absolute neutrophil count * Withhold ixazomib and lenalidomide until absolute< 500/mm3 neutrophil count is ≥ 500/mm3. Consider adding G-CSF asper clinical guidelines.

* Following recovery, resume lenalidomide at the next lowerdose according to its prescribing information and resumeixazomib at its most recent dose.

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

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

Non-haematological toxicities Recommended actions

Grade† 2 or 3 * Withhold lenalidomide until rash recovers to ≤ Grade 1.

* Following recovery, resume lenalidomide at the next lowerdose according to its SmPC.

* If Grade 2 or 3 rash occurs again, withhold ixazomib andlenalidomide until rash recovers to ≤ Grade 1.

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

Grade 4 Discontinue treatment regimen.

Grade 1 peripheral neuropathy with * Withhold ixazomib until peripheral neuropathy recovers topain or Grade 2 peripheral ≤ Grade 1 without pain or patient's baseline.neuropathy * Following recovery, resume ixazomib at its most recentdose.

Grade 2 peripheral neuropathy with * Withhold ixazomib. Toxicities should, at the physician’spain or Grade 3 peripheral discretion, generally recover to patient’s baseline conditionneuropathy or ≤ Grade 1 prior to resuming ixazomib.

* Following recovery, resume ixazomib at the next lowerdose.

Grade 4 peripheral neuropathy Discontinue treatment regimen.

Table 2: Dose modifications guidelines for ixazomib in combination with lenalidomide anddexamethasone

Other non-haematological toxicities

Other Grade 3 or 4 * Withhold ixazomib. Toxicities should, at the physician’snon-haematological toxicities discretion, generally recover to patient’s baseline conditionor at most Grade 1 prior to resuming ixazomib.

* If attributable to ixazomib, resume ixazomib at the nextlower 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

Antiviral prophylaxis should be considered in patients being treated with ixazomib to decrease the riskof herpes zoster reactivation. Patients included in studies with ixazomib who received antiviralprophylaxis had a lower incidence of herpes zoster infection compared to patients who did not receiveprophylaxis.

Thromboprophylaxis is recommended in patients being treated with ixazomib in combination withlenalidomide and dexamethasone, and should be based on an assessment of the patient’s underlyingrisks and clinical status.

For other concomitant medicinal products that may be required, refer to the current lenalidomide anddexamethasone SmPC.

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 ixazomibregimen and 10 patients (16%) in the placebo regimen. Cardiac arrhythmias in patients > 75 years ofage were observed in 10 patients (21%) in the ixazomib regimen and 9 patients (15%) in the placeboregimen.

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 (seesection 5.2).

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 severerenal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease (ESRD) requiringdialysis. Ixazomib is not dialyzable and, therefore, can be administered without regard to the timing ofdialysis (see section 5.2).

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

The safety and efficacy of ixazomib in children below 18 years of age have not been established. Nodata are available.

Ixazomib is for oral use.

Ixazomib should be taken at approximately the same time on Days 1, 8, and 15 of each treatment cycleat least 1 hour before or at least 2 hours after food (see section 5.2). The capsule should be swallowedwhole with water. It should not be crushed, chewed, or opened (see section 6.6).

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 SmPCfor these medicinal products for additional contraindications.

As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPCfor these medicinal products for additional special warnings and precautions for use.

Thrombocytopenia has been reported with ixazomib (see section 4.8) with platelet nadirs typicallyoccurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the nextcycle (see section 4.8).

Platelet counts should be monitored at least monthly during ixazomib treatment. More frequentmonitoring 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 transfusionsas per standard medical guidelines.

Gastrointestinal toxicities

Diarrhoea, constipation, nausea and vomiting have been reported with ixazomib, occasionallyrequiring use of antiemetic and antidiarrhoeal medicinal products and supportive care (seesection 4.8). The dose should be adjusted for severe (Grade 3-4) symptoms (see section 4.2). In case ofsevere gastrointestinal events, monitoring of serum potassium level is recommended.

Peripheral neuropathy has been reported with ixazomib (see section 4.8). The patient should bemonitored for symptoms of peripheral neuropathy. Patients experiencing new or worsening peripheralneuropathy 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 evaluatedfor underlying causes and provide supportive care, as necessary. The dose of dexamethasone should beadjusted per its prescribing information or ixazomib for Grade 3 or 4 symptoms (see section 4.2).

Rash has been reported with ixazomib (see section 4.8). Rash should be managed with supportive careor with dose modification if Grade 2 or higher (see section 4.2). Severe cutaneous adverse reactions(SCARs) including Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), whichcan be life-threatening or fatal, have also been rarely reported in association with ixazomib treatment(see section 4.8).

At the time of prescription patients should be advised of the signs and symptoms and monitoredclosely for skin reactions. If signs and symptoms suggestive of these reactions appear, ixazomibshould be withdrawn immediately and an alternative treatment considered (as appropriate).

If the patient has developed a serious reaction such as SJS or TEN with the use of ixazomib, treatmentwith ixazomib must not be restarted in this patient at any time.

Thrombotic microangiopathy

Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP),have been reported in patients who received ixazomib. Some of these events have been fatal. Signsand symptoms of TMA should be monitored for. If the diagnosis is suspected, stop ixazomib andevaluate patients for possible TMA. If the diagnosis of TMA is excluded, ixazomib can be restarted.

The safety of reinitiating ixazomib therapy in patients previously experiencing TMA is not known.

Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic andhepatotoxicity have been uncommonly reported with ixazomib (see section 4.8). Hepatic enzymesshould be monitored regularly and the dose should be adjusted for Grade 3 or 4 symptoms (seesection 4.2).

Women should avoid becoming pregnant while being treated with ixazomib. If ixazomib is usedduring pregnancy or if the patient becomes pregnant while taking ixazomib, the patient should beapprised of the potential hazard to the foetus.

Women of childbearing potential must use highly effective contraception while taking ixazomib andfor 90 days after stopping treatment (see sections 4.5 and 4.6). Women using hormonal contraceptivesshould additionally use a barrier method of contraception.

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, discontinueixazomib.

Strong CYP3A inducers

Strong inducers may reduce the efficacy of ixazomib, therefore the concomitant use of strong CYP3Ainducers 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 ifco-administration with a strong CYP3A inducer cannot be avoided.

CYP inhibitors

Co-administration of ixazomib with clarithromycin, a strong CYP3A inhibitor, did not result in aclinically meaningful change in the systemic exposure of ixazomib. Ixazomib Cmax was decreased by4% and AUC was increased by 11%. Therefore, no dose modification is required for ixazomib withco-administration of strong CYP3A inhibitors.

Co-administration of ixazomib with strong CYP1A2 inhibitors did not result in a clinically meaningfulchange 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 ofstrong 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 (seesection 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 correspondingimmunoreactive 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-druginteractions.

When ixazomib is administered together with dexamethasone, which is known to be a weak tomoderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacyof oral contraceptives needs to be considered. Women using hormonal contraceptives shouldadditionally use a barrier method of contraception.

As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPCfor these medicinal products for additional information on fertility, pregnancy and lactation.

Male and female patients who are able to have children must use effective contraceptive measuresduring and for 90 days following treatment. Ixazomib is not recommended in women of childbearingpotential not using contraception.

When ixazomib is administered together with dexamethasone, which is known to be a weak tomoderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacyof oral contraceptives needs to be considered. Therefore, women using oral hormonal contraceptivesshould additionally use a barrier method of contraception.

Ixazomib is not recommended during pregnancy as it can cause foetal harm when administered to apregnant woman. Therefore, women should avoid becoming pregnant while being treated withixazomib.

There are no data for the use of ixazomib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Ixazomib is given in combination with lenalidomide. Lenalidomide is structurally related tothalidomide. Thalidomide is a known human teratogenic active substance that causes severelife-threatening birth defects. If lenalidomide is taken during pregnancy, a teratogenic effect in humansis expected. The conditions of the Pregnancy Prevention Programme for lenalidomide must be fulfilledfor all patients unless there is reliable evidence that the patient does not have childbearing potential.

Please refer to the current lenalidomide SmPC.

It is unknown whether ixazomib or its metabolites are excreted in human milk. No animal data areavailable. A risk to newborns/infants cannot be excluded and therefore breast-feeding should bediscontinued.

Ixazomib will be given in combination with lenalidomide and breast-feeding should be stoppedbecause of the use of lenalidomide.

Fertility studies have not been conducted with ixazomib (see section 5.3).

Ixazomib has minor influence on the ability to drive or use machines. Fatigue and dizziness have beenobserved in clinical trials. Patients should be advised not to drive or operate machines if theyexperience any of these symptoms.

As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPCfor these medicinal products for additional undesirable effects.

The safety profile of NINLARO is based on available clinical trial data and post-marketing experienceto date. Frequencies of adverse reactions described below and in Table 3 have been determined basedon data generated from clinical studies.

Unless otherwise noted, 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 418 patients treatedwithin the ixazomib regimen and 417 patients within the placebo regimen were diarrhoea (47% vs.

38%), thrombocytopenia (41% vs. 24%), neutropenia (37% vs. 36%), constipation (31% vs. 24%),upper respiratory tract infection (28% vs. 24%), peripheral neuropathy (28% vs. 22%), nausea (28%vs. 20%), back pain (25% vs. 21%), rash (25% vs. 15%), peripheral oedema (24% vs. 19%), vomiting(23% vs. 12%) and bronchitis (20% vs. 15%). Serious adverse reactions reported in ≥ 2% of patientsincluded diarrhoea (3%), thrombocytopenia (2%) and bronchitis (2%).

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 availabledata). Within each system organ class, the ADRs are ranked by frequency, with the most frequentreactions first. Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

Table 3: Adverse reactions in patients treated with ixazomib in combination with lenalidomideand dexamethasone (all grades, grade 3 and grade 4)

System organ class/Adverse reactions Grade 3 adverse Grade 4 adverse

Adverse reaction (all grades) reactions reactions

Upper respiratory tract Very common Commoninfection

Bronchitis Very common Common

Herpes zoster Common Common

Thrombocytopenia* Very common Very common Common

Neutropenia* Very common Very common Common

Thrombotic Rare Raremicroangiopathy

Thrombotic Rare Rare Rarethrombocytopenicpurpura†

Anaphylactic reaction† Rare Very rare Very rare

Angioedema† Rare Rare

Tumour lysis syndrome† Rare Rare Rare

Peripheral neuropathies* Very common Common

Posterior reversible Rare Rare Rareencephalopathydisorders*†

Transverse myelitis† Rare Rare

Diarrhoea Very common Common

Constipation Very common Uncommon

Nausea Very common Common

Vomiting Very common Uncommon

Rash* Very common Common

Stevens-Johnson Rare Raresyndrome†

Acute febrile neutrophilic Rare Raredermatosis

Toxic epidermal Rare Rarenecrolysis†

Back pain Very common Uncommon

Arthralgia Very common Common

System organ class/Adverse reactions Grade 3 adverse Grade 4 adverse

Adverse reaction (all grades) reactions reactions

Oedema peripheral Very common Common

Pyrexia Very common Uncommon

*Represents a pooling of preferred terms†Reported outside of the Phase 3 studies

Discontinuations

For each adverse reaction, one or more of the three medicinal products was discontinued in ≤ 3% ofpatients in the ixazomib regimen.

Two percent of patients in both the ixazomib regimen and 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 thethree medicinal products in 2% of patients in the ixazomib regimen and 3% of patients in the placeboregimen. Thrombocytopenia did not result in an increase in haemorrhagic events or platelettransfusions.

Gastrointestinal toxicities

Diarrhoea resulted in discontinuation of one or more of the three medicinal products in 2% of patientsin the ixazomib regimen and 1% of patients in the placebo regimen.

Rash occurred in 25% of patients in the ixazomib regimen compared to 15% of patients in the placeboregimen. The most common type of rash reported in both regimens was maculo-papular and macularrash. Grade 3 rash was reported in 3% of patients in the ixazomib regimen compared to 2% of patientsin the placebo regimen. Rash resulted in discontinuation of one or more of the three medicinalproducts in < 1% of patients in both regimens.

Peripheral neuropathy occurred in 28% of patients in the ixazomib regimen compared to 22% ofpatients in the placebo regimen. Grade 3 adverse reactions of peripheral neuropathy were reported in2% of patients in the ixazomib regimen compared to 1% in the placebo regimen. The most commonlyreported reaction was peripheral sensory neuropathy (21% and 15% in the ixazomib and placeboregimen, respectively). Peripheral motor neuropathy was not commonly reported in either regimen(< 1%). Peripheral neuropathy resulted in discontinuation of one or more of the three medicinalproducts in 3% of patients in the ixazomib regimen compared to < 1% of patients in the placeboregimen.

Eye disorders were reported with many different preferred terms but in aggregate, the frequency was34% in patients in the ixazomib regimen and 28% of patients in the placebo regimen. The mostcommon adverse reactions were blurred vision (6% in the ixazomib regimen and 5% in the placeboregimen), dry eye (6% in the ixazomib regimen and 1% in the placebo regimen), conjunctivitis (8% inthe ixazomib regimen and 2% in the placebo regimen) and cataract (13% in the ixazomib regimen and17% in the placebo regimen). Grade 3 adverse reactions were reported in 6% of patients in theixazomib regimen and 8% of patients in the placebo regimen.

Other adverse reactions

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 reactionsoccurred with a similar rate between the ixazomib and placebo regimens: fatigue (28% vs. 26%),decreased appetite (13% vs. 11%), hypotension (5% vs. 4%), heart failure† (5% each), arrhythmia†(17% vs. 16%), and liver impairment including enzyme changes† (11% vs. 9%).

The frequency of severe (Grade 3-4) events of hypokalaemia was higher in the ixazomib regimen(7%) than the placebo regimen (2%).

Fungal and viral pneumonia resulting in fatal outcome were rarely reported in patients given theixazomib, lenalidomide and dexamethasone combination.

† Standardised MedDRA Queries (SMQs)

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose has been reported in patients taking NINLARO. Symptoms of overdose are generallyconsistent with the known risks of NINLARO (see section 4.8). Overdose of 12 mg (taken at one time)has resulted in serious adverse events, such as severe nausea, aspiration pneumonia, multiple organfailure and death.

There is no known specific antidote for ixazomib overdose. In the event of an overdose, monitor thepatient closely for adverse reactions (see section 4.8) and provide appropriate supportive care.

Ixazomib is not dialyzable (see section 5.2).

Overdoses were most common in patients starting treatment with NINLARO. The importance ofcarefully following all dosage instructions should be discussed with patients starting treatment.

Instruct patients to take the recommended dosage as directed because overdose has led to deaths.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XG03.

Ixazomib citrate, a prodrug, is a substance that rapidly hydrolyses under physiological conditions to itsbiologically active form, ixazomib.

Ixazomib is an oral, highly selective and reversible proteasome inhibitor. Ixazomib preferentiallybinds 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 vitrocytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies,including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib andlenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo,ixazomib demonstrated antitumour activity in various tumour xenograft models, including models ofmultiple myeloma. In vitro, ixazomib affected cell types found in the bone marrow microenvironmentincluding vascular endothelial cells, osteoclasts and osteoblasts.

Ixazomib did not prolong the QTc interval at clinically relevant exposures based on the results of apharmacokinetic-pharmacodynamic analysis of data from 245 patients. At the 4 mg dose, meanchange from baseline in QTcF was estimated to be 0.07 msec (90% CI; -0.22, 0.36) from the modelbased analysis. There was no discernible relationship between ixazomib concentration and the RRinterval suggesting no clinically meaningful effect of ixazomib on heart rate.

The efficacy and safety of ixazomib in combination with lenalidomide and dexamethasone wasevaluated in an international randomised, double-blind, placebo-controlled, multicenter Phase 3superiority study (C16010) in patients with relapsed and/or refractory multiple myeloma who hadreceived at least one prior therapy. A total of 722 patients (intent-to-treat [ITT] population) wererandomised in a 1:1 ratio to receive either the combination of ixazomib, lenalidomide, anddexamethasone (N = 360; ixazomib regimen) or placebo, lenalidomide and dexamethasone(N = 362; placebo regimen) until disease progression or unacceptable toxicity. Patients enrolled in thetrial had multiple myeloma that was refractory, including primary refractory, had relapsed after priortherapy, or had relapsed and was refractory to any prior therapy. Patients that changed therapies priorto disease progression were eligible for enrolment, as well as those with controlled cardiovascularconditions. The Phase 3 study excluded patients who were refractory to lenalidomide or proteasomeinhibitors 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 afterthe last dose of lenalidomide or a proteasome inhibitor. As data are limited in these patients, a carefulrisk-benefit assessment is recommended before initiating the ixazomib regimen.

Thromboprophylaxis was recommended for all patients in both treatment groups according to thelenalidomide SmPC. Concomitant medicinal products, such as antiemetic, antiviral, and antihistaminemedicinal products were given to patients at the physician's discretion as prophylaxis and/ormanagement of symptoms.

Patients received ixazomib 4 mg or placebo on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days 1through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle. Patients with renalimpairment received a starting dose of lenalidomide according to its SmPC. Treatment continued untildisease progression or unacceptable toxicities.

The baseline demographics and disease characteristics were balanced and comparable between thestudy regimens. The median age was 66 years, range 38-91 years; 58% of patients were older than65 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 and12% had baseline ISS stage III disease (N = 90). Twenty five percent of patients had a creatinineclearance of < 60 mL/min. Twenty three percent of patients had light chain disease and 12% ofpatients had measurable disease by free light chain assay only. Nineteen percent had high-riskcytogenetic 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 celltransplantation. Seventy seven percent of patients relapsed after prior therapies and 11% wererefractory to prior therapies. Primary refractory, defined as best response of stable disease or diseaseprogression 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 blindedindependent review committee (IRC) based on central laboratory results. Response was assessed every4 weeks until disease progression. At the primary analysis (median follow up of 14.7 months and amedian of 13 cycles), PFS was statistically significantly different between the treatment arms. PFSresults are summarised in Table 4 and Figure 1. The improvement in PFS in the ixazomib regimen wassupported by improvements in overall response rate.

Table 4: Progression free survival and response Results in multiple myeloma patients treatedwith ixazomib or placebo in combination with lenalidomide and dexamethasone (intent-to-treatpopulation, primary analysis)

Ixazomib + Lenalidomide and Placebo + Lenalidomide and

Dexamethasone Dexamethasone(N = 360) (N = 362)

Progression-Free Survival

Events, n (%) 129 (36) 157 (43)

Median (months) 20.6 14.7p-value* 0.012

Hazard Ratio† 0.74(95% CI) (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 1indicates an advantage for the ixazomib regimen.‡ORR = CR+VGPR+PR§Based on responders in the response-evaluable population

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

A second, non-inferential, PFS analysis was conducted with a median follow up of 23 months. At thisanalysis, estimated median PFS was 20 months in the ixazomib regimen and 15.9 months in theplacebo regimen (HR = 0.82 [95% CI (0.67, 1.0)]) in the ITT population. For patients with one priortherapy, the median PFS was 18.7 months in the ixazomib regimen and 17.6 months in the placeboregimen (HR = 0.99). For patients with 2 or 3 prior therapies, PFS was 22.0 months in the ixazomibregimen and 13.0 months in the placebo regimen (HR = 0.62).

At the final analysis for OS at a median duration of follow up of approximately 85 months, median OSin the ITT population was 53.6 months for patients in the ixazomib regimen and 51.6 months forpatients in the placebo regimen (HR = 0.94 [95% CI: 0.78, 1.13; p = 0.495]). For patients with oneprior therapy, the median OS was 54.3 months in the ixazomib regimen and 58.3 months in theplacebo regimen (HR = 1.02 [95% CI: 0.80, 1.29]). For patients with 2 or 3 prior therapies, the median

OS was 53.0 months in the ixazomib regimen and 43.0 months in the placebo regimen (HR = 0.85[95% CI: 0.64, 1.11]).

A randomised, double-blind, placebo-controlled Phase 3 study was conducted in China (N = 115) witha similar study design and eligibility criteria. Many of the patients enrolled in the study had advanceddisease with Durie-Salmon Stage III (69%) at initial diagnosis and a treatment history of receiving atleast 2 prior therapies (60%) and being thalidomide refractory (63%). At the primary analysis (medianfollow up of 8 months and a median of 6 cycles), the median PFS was 6.7 months in the ixazomibregimen compared to 4 months in the placebo regimen (p-value = 0.035, HR = 0.60). At the finalanalysis for OS at a median follow up of 19.8 months, OS was improved for patients treated in theixazomib regimen compared with placebo [p-value = 0.0014, HR = 0.42, 95% CI: 0.242, 0.726 ]).

As multiple myeloma is a heterogeneous disease, benefit may vary across subgroups in the Phase 3study (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 impairmentat baseline. Of the 5 patients in the ixazomib regimen, one patient had a confirmed partial responseand 3 confirmed stable disease (however 2 were unconfirmed partial response and 1 was anunconfirmed very good partial response). Of the 5 patients in the placebo regimen, 2 had a confirmedvery good partial response.

Quality of life as assessed by global health scores (EORTC QLQ-C30 and MY-20) was maintainedduring treatment and was similar in both treatment regimens in the Phase 3 study (C16010).

The European Medicines Agency has waived the obligation to submit the results of studies withixazomib in all subsets of the paediatric population in multiple myeloma (see section 4.2 forinformation on paediatric use).

After oral administration, peak plasma concentrations of ixazomib were achieved at approximatelyone hour after dosing. The mean absolute oral bioavailability is 58%. Ixazomib AUC increases in adose 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 administrationafter an overnight fast (see section 4.2).

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.

After oral administration of a radiolabeled dose, 70% of total drug-related material in plasma wasaccounted for by ixazomib. Metabolism by multiple CYP enzymes and non-CYP proteins is expectedto 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 tooverall metabolism. At concentrations exceeding those observed clinically, ixazomib was metabolizedby 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%).

Ixazomib exhibits a multi-exponential disposition profile. Based on a population PK analysis, systemicclearance (CL) was approximately 1.86 L/hr with inter-individual variability of 44%. The terminalhalf-life (t1/2) of ixazomib was 9.5 days. Approximately 2-fold accumulation in AUC was observedwith weekly oral dosing on Day 15.

Excretion

After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% ofthe administered radioactivity was excreted in urine and 22% in the faeces. Unchanged ixazomibaccounted for < 3.5% of the administered dose recovered in urine.

The PK of ixazomib is similar in patients with normal hepatic function and in patients with mildhepatic 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 hepaticimpairment at 1.5 mg (total bilirubin > 3 x ULN, N = 18). Unbound dose-normalized AUC was27% higher in patients with moderate or severe hepatic impairment as compared to patients withnormal hepatic function (see section 4.2).

The PK of ixazomib is similar in patients with normal renal function and in patients with mild ormoderate renal impairment (creatinine clearance ≥ 30 mL/min) based on the results of a population PKanalysis.

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 patientswith severe renal impairment or ESRD requiring dialysis as compared to patients with normal renalfunction. Pre- and post-dialyzer concentrations of ixazomib measured during the haemodialysissession were similar, suggesting that ixazomib is not dialyzable (see section 4.2).

There was no clinically meaningful effect of age (23-91 years), sex, body surface area (1.2-2.7 m2), orrace on the clearance of ixazomib based on the results of a population PK analysis. The mean AUCwas 35% higher in Asian patients; however, there was overlap in the AUC of ixazomib across Whiteand Asian patients.

Ixazomib was not mutagenic in a bacterial reverse mutation assay (Ames assay) or clastogenic in abone marrow micronucleus assay in mice. Ixazomib was positive in an in vitro clastogenicity test inhuman peripheral blood lymphocytes. However, ixazomib was negative in an in vivo comet assay inmice, in which percent tail DNA was assessed in the stomach and liver. Therefore, the weight ofevidence 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 andat exposures that were slightly higher than those observed in patients receiving the recommendeddose. Studies of fertility and early embryonic development and pre- and post-natal toxicology were notconducted with ixazomib, but evaluation of reproductive tissues was conducted in the general toxicitystudies. There were no effects due to ixazomib treatment on male or female reproductive organs instudies up to 6-months duration in rats and up to 9-months duration in dogs.

In multi-cycle repeated-dose toxicity studies conducted in rats and dogs, the principal target organsincluded 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 at0.2 mg/kg (4 mg/m2). The majority of target organ findings demonstrated partial to full recoveryfollowing discontinuation of treatment, with the exception of neuronal findings in the lumbar dorsalroot ganglion and dorsal column.

Following oral administration, a tissue distribution study in rats revealed that the brain and spinal cordwere amongst the tissues with the lowest levels, suggesting that the penetration of ixazomib throughthe 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 telemetereddogs following single oral administration) demonstrated no effects of ixazomib on cardiovascular orrespiratory functions at AUC more than 8-fold higher than the clinical value.

NINLARO 2.3 mg hard capsules

Microcrystalline cellulose

Magnesium stearate

Talc

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

Shellac

Potassium hydroxide

Black iron oxide (E172)

NINLARO 3 mg hard capsules

Microcrystalline cellulose

Magnesium stearate

Talc

Gelatin

Titanium dioxide (E171)

Black iron oxide (E172)

Shellac

Potassium hydroxide

Black iron oxide (E172)

NINLARO 4 mg hard capsules

Microcrystalline cellulose

Magnesium stearate

Talc

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Shellac

Potassium hydroxide

Black iron oxide (E172)

Not applicable.

3 years.

Do not store above 30 °C. Do not freeze.

Store in the original package in order to protect from moisture.

PVC-Aluminium /Aluminium blister strip containing three capsules, sealed inside a wallet pack.

One wallet pack is packaged in one carton.

Ixazomib is cytotoxic. The capsule should not be removed until just prior to dosing. The capsulesshould not be opened or crushed. Direct contact with the capsule contents should be avoided. In caseof capsule breakage, avoid raising dust during clean-up. If contact occurs, wash thoroughly with soapand water.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Takeda Pharma A/S

Delta Park 452665 Vallensbaek Strand

DenmarkmedinfoEMEA@takeda.com

EU/1/16/1094/001

EU/1/16/1094/002

EU/1/16/1094/003

Date of first authorisation: 21 November 2016

Date of latest renewal: 01 September 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.