Ninlaro · 4.4 Special warnings and precautions for use · 1

HOS-097207 · has-adverse-reaction-information · PDF-Seite 9

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 NINLARO 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 9 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 reactions Grade 3 adverse Grade 4 adverse Adverse reaction (all grades) reactions reactions Infections and infestations Upper respiratory tract Very common Common infection Bronchitis Very common Common Herpes zoster Common Common Blood and lymphatic system disorders Thrombocytopenia

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HOS-097203 · has-contraindication-information · PDF-Seite 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 SmPC for these medicinal products for additional contraindications.

HOS-097202 · has-indication-information · PDF-Seite 2

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.

HOS-097205 · has-interaction-information · PDF-Seite 7

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 7 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.

HOS-097206 · has-pregnancy-information · PDF-Seite 8

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. 8 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).

HOS-097204 · has-warning-information · PDF-Seite 6

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). 6 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 cons

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