4.1. Therapeutic indications

Ixazomib 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.

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.

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

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.

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.

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).

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.

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). Severe cutaneous adverse reactions (SCARs) including Toxic epidermal necrolysis (TEN) and Stevens‑Johnson syndrome (SJS), which can 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 monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, ixazomib should 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, treatment with 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. Signs and symptoms of TMA should be monitored for. If the diagnosis is suspected, stop ixazomib and evaluate 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.

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 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.

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 safety profile of Ixazomib is based on available clinical trial data and post‑marketing experience to date. Frequencies of adverse reactions described below and in Table 3 have been determined based on 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 treated within 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 patients included diarrhoea (3%), thrombocytopenia (2%) and bronchitis (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.

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

Common

Bronchitis

Very common

Common

Herpes zoster

Common

Common

Blood and lymphatic system disorders

Thrombocytopenia*

Very common

Very common

Common

Neutropenia*

Very common

Very common

Common

Thrombotic microangiopathy

Rare

Rare

Thrombotic thrombocytopenic purpura†

Rare

Rare

Rare

Immune system disorders

Anaphylactic reaction†

Rare

Very rare

Very rare

Angioedema†

Rare

Rare

Metabolism and nutrition disorders

Tumour lysis syndrome†

Rare

Rare

Rare

Nervous system disorders

Peripheral neuropathies*

Very common

Common

Posterior reversible encephalopathy disorders*†

Rare

Rare

Rare

Transverse myelitis†

Rare

Rare

Gastrointestinal disorders

Diarrhoea

Very common

Common

Constipation

Very common

Uncommon

Nausea

Very common

Common

Vomiting

Very common

Uncommon

Skin and subcutaneous tissue disorders

Rash*

Very common

Common

Stevens‑Johnson syndrome†

Rare

Rare

Acute febrile neutrophilic dermatosis

Rare

Rare

Toxic epidermal necrolysis†

Rare

Rare

Musculoskeletal and connective tissue disorders

Back pain

Very common

Uncommon

Arthralgia

Very common

Common

General disorders and administration site conditions

Oedema peripheral

Very common

Common

Pyrexia

Very common

Uncommon

*Represents a pooling of preferred terms

†Reported outside of the Phase 3 studies

Description of selected adverse reactions

Discontinuations

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

Thrombocytopenia

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 the three medicinal products in 2% of patients in the ixazomib regimen and 3% 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 2% of patients in the ixazomib regimen and 1% of patients in the placebo regimen.

Rash

Rash occurred in 25% of patients in the ixazomib regimen compared to 15% 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 3% of patients in the ixazomib regimen compared to 2% 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.

Peripheral neuropathy

Peripheral neuropathy occurred in 28% of patients in the ixazomib regimen compared to 22% of patients in the placebo regimen. Grade 3 adverse reactions of peripheral neuropathy were reported in 2% of patients in the ixazomib regimen compared to 1% in the placebo regimen. The most commonly reported reaction was peripheral sensory neuropathy (21% and 15% 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 3% 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 34% in patients in the ixazomib regimen and 28% of patients in the placebo regimen. The most common adverse reactions were blurred vision (6% in the ixazomib regimen and 5% in the placebo regimen), dry eye (6% in the ixazomib regimen and 1% in the placebo regimen), conjunctivitis (8% in the ixazomib regimen and 2% in the placebo regimen) and cataract (13% in the ixazomib regimen and 17% in the placebo regimen). Grade 3 adverse reactions were reported in 6% of patients in the ixazomib 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 reactions occurred 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 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose has been reported in patients taking Ixazomib. Symptoms of overdose are generally consistent with the known risks of Ixazomib (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 organ failure and death.

There is no known specific antidote for ixazomib overdose. In the event of an overdose, monitor the patient 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 Ixazomib. The importance of carefully following all dosage instructions should be discussed with patients starting treatment. Instruct patients to take the recommended dosage as directed because overdose has led to deaths.