PLGB 15475/0059-0061/OD1

Multiple myeloma

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.

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 .

As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPC for these medicinal products for additional . 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 and Stevens-Johnson syndrome, 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.

Pharmacokinetic

As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPC for these medicinal products for additional information on . 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).

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.

As ixazomib is administered in combination with lenalidomide and dexamethasone, refer to the SmPC for these medicinal products for additional . 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 System organ class / Adverse reaction Adverse reactions (all grades) Grade 3 adverse reactions Grade 4 adverse reactions 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.

has been reported in patients taking Ixazomib. Symptoms of are generally consistent with the known risks of Ixazomib (see section 4.8). 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 . In the event of an , monitor the patient closely for adverse reactions (see section 4.8) and provide appropriate supportive care. Ixazomib is not dialyzable (see section 5.2). s 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 has led to deaths.

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 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.

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