NINLARO Hard capsule Ref.[9136] Active ingredients: Ixazomib

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).

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 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 C_max 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 C_max 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.

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).

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 undesirable effects.

Summary of the safety profile

The data presented below is the pooled safety data from the pivotal, Phase 3, global C16010 study (n=720) and the double-blind, placebo-controlled C16010 China Continuation Study (n=115). The most frequently reported adverse reactions (≥20%) across 417 patients treated within the ixazomib regimen and 418 patients within the placebo regimen were diarrhoea (39% vs. 32%), thrombocytopenia (33% vs. 21%), neutropenia (33% vs. 30%), constipation (30% vs. 22%), peripheral neuropathy (25% vs. 20%), nausea (23% vs. 18%), peripheral oedema (23% vs. 17%), vomiting (20% vs. 10%) and upper respiratory tract infection (21% vs. 16%). Serious adverse reactions reported in ≥2% of patients included thrombocytopenia (2%) and diarrhoea (2%).

Tabulated list of adverse reactions

The following convention is used for the classification of the frequency of an adverse drug reaction (ADR): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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

Note: ADRs included as preferred terms are based on MedDRA version 16.0.
* Represents a pooling of preferred terms.

Description of selected adverse reactions

Discontinuations

For each adverse reaction, one or more of the three medicinal products was discontinued in ≤1% of patients in the ixazomib regimen.

Thrombocytopenia

Three percent of patients in the ixazomib regimen and 1% of patients in the placebo regimen had a platelet count ≤10,000/mm³ during treatment. Less than 1% of patients in both regimens had a platelet count ≤5,000/mm³ during treatment. Thrombocytopenia resulted in discontinuation of one or more of the three medicinal products in <1% of patients in the ixazomib regimen and 1% of patients in the placebo regimen. Thrombocytopenia did not result in an increase in haemorrhagic events or platelet transfusions.

Gastrointestinal toxicities

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

Rash

Rash occurred in 18% of patients in the ixazomib regimen compared to 10% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Grade 3 rash was reported in 2% of patients in the ixazomib regimen compared to 1% of patients in the placebo regimen. Rash resulted in discontinuation of one or more of the three medicinal products in < 1% of patients in both regimens.

Peripheral neuropathy

Peripheral neuropathy occurred in 25% of patients in the ixazomib regimen compared to 20% of patients in the placebo regimen. Grade 3 adverse reactions of peripheral neuropathy were reported in 2% of patients in both regimens. The most commonly reported reaction was peripheral sensory neuropathy (16% and 12% in the ixazomib and placebo regimen, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (<1%). Peripheral neuropathy resulted in discontinuation of one or more of the three medicinal products in 1% of patients in the ixazomib regimen compared to <1% of patients in the placebo regimen.

Eye disorders

Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 24% in patients in the ixazomib regimen and 15% of patients in the placebo regimen. The most common adverse reactions were blurred vision (5% in the ixazomib regimen and 4% in the placebo regimen), dry eye (4% in the ixazomib regimen and 1% in the placebo regimen), conjunctivitis (5% in the ixazomib regimen and 1% in the placebo regimen) and cataract (4% in the ixazomib regimen and 5% in the placebo regimen). Grade 3 adverse reactions were reported in 2% of patients in both regimens.

Other adverse reactions

Outside of the Phase 3 study, the following serious adverse reactions were rarely reported: acute febrile neutrophilic dermatosis (Sweet’s syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumour lysis syndrome and thrombotic thrombocytopenic purpura.

In the pooled dataset from the pivotal, Phase 3, global C16010 study (n=720) and the double-blind, placebo-controlled, C16010 China Continuation Study (n=115), the following adverse reactions occurred with a similar rate between the ixazomib and placebo regimens: fatigue (26% vs. 24%), decreased appetite (12% vs. 9%), hypotension (4% each), heart failure† (3% each), arrhythmia† (12% vs. 11%), and liver impairment including enzyme changes† (8% vs. 6%).

The frequency of severe (Grade 3-4) events of hypokalaemia was higher in the ixazomib regimen (5%) than the placebo regimen (<1%).

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

^† Standardised MedDRA Queries (SMQs)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.