Ninlaro Adverse Reactions

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 as follows and in Table 13 have been determined based on data generated from clinical studies.
(1) Treatment of patients with multiple myeloma who have received at least one prior therapy in combination with lenalidomide and dexamethasone (TOURMALINE MM1 - Study C16010 - NCT01564537): Unless otherwise noted, the data presented as follows 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 adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 13.)

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(2) Maintenance therapy with multiple myeloma following autologous stem cell transplantation (TOURMALINE-MM3 - Study C16019 - NCT02181413): Frequencies of adverse reactions described as follows have been determined based on the safety data from several Phase 3 randomized, double-blind, placebo-controlled studies. Safety data on maintenance therapy is from TOURMALINE-MM3 which included 653 patients with multiple myeloma following ASCT, who received NINLARO (N=394) or placebo (N=259).
For maintenance therapy with multiple myeloma following autologous stem cell transplantation (TOURMALINE-MM3), the most frequently reported adverse reactions (≥ 20%) in patients receiving were nausea (ixazomib 39% vs. placebo 15%), diarrhea (ixazomib 35% vs. placebo 24%), vomiting (ixazomib 27% vs. placebo 11%), upper respiratory tract infection (ixazomib 26% vs. placebo 21%), arthralgia (ixazomib 22% vs. placebo 12%), and rash (ixazomib 21% vs. placebo 14%). Serious adverse reactions reported in ≥ 2% of patients included pneumonia (6%). For each adverse reaction, ixazomib was discontinued in < 1% of patients.
The following convention is used for the classification of the frequency of an adverse drug reaction (ADR) and is based on the Council for International Organizations of Medical Sciences (CIOMS) guidelines: 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). (See Table 14.)

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(3) Maintenance therapy with multiple myeloma not treated with stem cell transplantation (TOURMALINE-MM4 - Study C16021 - NCT02312258): Safety data on maintenance therapy in patients with multiple myeloma not treated with stem cell transplantation is from TOURMALINE-MM4, which included 702 patients who received NINLARO (N=426) or placebo (N=276).
For maintenance therapy with multiple myeloma not treated with stem cell transplantation (TOURMALINE MM4, the most frequently reported adverse reactions (≥ 20%) in patients receiving were nausea (ixazomib 27% vs. placebo 8%), vomiting (ixazomib 24% vs. placebo 4%), and diarrhea (ixazomib 23% vs. placebo 12%). Serious adverse reactions reported in ≥ 2% of patients included pneumonia (4%). For each adverse reaction, ixazomib was discontinued in < 1% of patients. (See Table 15.)

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Description of selected adverse reactions: Discontinuations: Combination Therapy with Lenalidomide and Dexamethasone (TOURMALINE MM1): For each adverse reaction, one or more of the three medicinal products was discontinued in ≤ 1% of patients in the IXAZOMIB regimen.
Maintenance Therapy following autologous stem cell transplantation (TOURMALINE MM3): For each adverse reaction, ixazomib was discontinued in <1% of patients.
Maintenance Therapy not treated with stem cell transplantation (TOURMALINE MM4): For each adverse reaction, ixazomib was discontinued in <1% of patients.
Thrombocytopenia: Combination Therapy with Lenalidomide and Dexamethasone (TOURMALINE MM1): 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.
Maintenance Therapy following autologous stem cell transplantation (TOURMALINE MM3): Grade 3 thrombocytopenia was reported in 4% of patients receiving ixazomib. There were no reports of Grade 3 thrombocytopenia in patients receiving placebo. Grade 4 thrombocytopenia was reported in 1% of patients receiving ixazomib and < 1% of patients receiving placebo. Serious adverse reactions of thrombocytopenia were reported in < 1% of patients receiving either ixazomib or placebo.
Maintenance Therapy not treated with stem cell transplantation (TOURMALINE MM4): Grade 3 thrombocytopenia was reported in 2% of patients receiving ixazomib. There were no reports of Grade 3 thrombocytopenia in patients receiving placebo. No serious adverse reactions of thrombocytopenia were reported in patients receiving ixazomib or placebo.
Gastrointestinal toxicities: Combination Therapy with Lenalidomide and Dexamethasone (TOURMALINE MM1): 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.
Maintenance Therapy following autologous stem cell transplantation (TOURMALINE MM3): Diarrhoea resulted in discontinuation of ixazomib in <1% of patients; no patients in the placebo arm discontinued due to diarrhoea.
Maintenance Therapy not treated with stem cell transplantation (TOURMALINE MM4): Nausea and vomiting resulted in discontinuation of ixazomib in <1% of patients; no patients in the placebo arm discontinued due to nausea or vomiting.
Rash: Combination Therapy with Lenalidomide and Dexamethasone (TOURMALINE MM1): 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.
Maintenance Therapy following autologous stem cell transplantation (TOURMALINE MM3): The most common types of rash reported in patients receiving ixazomib or placebo included maculo-papular and macular rash. Grade 3 rash was reported in 1% of patients receiving ixazomib; no patients receiving placebo reported Grade 3 rash. Serious adverse reactions of rash were reported in < 1% of patients receiving ixazomib; no patients receiving placebo reported a serious adverse reaction of rash.
Maintenance Therapy not treated with stem cell transplantation (TOURMALINE MM4): The most common types of rash reported in patients receiving ixazomib or placebo included maculo-papular and macular rash. Grade 3 rash was reported in 2% of patients receiving ixazomib; no patients receiving placebo reported Grade 3 rash. Serious adverse reactions of rash were reported in < 1% of patients receiving ixazomib; no patients receiving placebo reported a serious adverse reaction of rash.
Peripheral neuropathy: Combination Therapy with Lenalidomide and Dexamethasone (TOURMALINE MM1): 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.
Maintenance Therapy following autologous stem cell transplantation (TOURMALINE MM3): Grade 3 adverse reactions of peripheral neuropathy were reported in < 1% of patients receiving ixazomib; no patients receiving placebo reported Grade 3 adverse reaction of peripheral neuropathy. No serious adverse reactions of peripheral neuropathy were reported in patients receiving ixazomib or placebo. The most commonly reported reaction was peripheral neuropathy unspecified (10% and 8% in patients receiving ixazomib and placebo, respectively). No patients receiving ixazomib reported peripheral motor neuropathy; < 1% of patients receiving placebo reported peripheral motor neuropathy.
Maintenance Therapy not treated with stem cell transplantation (TOURMALINE MM4): Grade 3 adverse reactions of peripheral neuropathy were reported in 2% of patients receiving ixazomib; no patients receiving placebo reported Grade 3 adverse reaction of peripheral neuropathy. No serious adverse reactions of peripheral neuropathy were reported in patients receiving ixazomib or placebo. The most commonly reported reaction was peripheral sensory neuropathy (15% and 9% in patients receiving ixazomib and placebo, respectively). Peripheral motor neuropathy was reported in <1% of patients receiving ixazomib; no patients receiving placebo reported peripheral motor neuropathy.
Peripheral Edema: Combination Therapy with Lenalidomide and Dexamethasone (TOURMALINE MM1): Peripheral edema was reported in 25% and 18% of patients in ixazomib and placebo regimens, respectively. The majority of peripheral edema adverse reactions were Grade 1 (16% in ixazomib regimen and 13% in the placebo regimen) and Grade 2 (7% in ixazomib regimen and 4% in the placebo regimen).
Grade 3 peripheral edema was reported in 2% and 1% of patients in ixazomib and placebo regimens, respectively. There was no Grade 4 peripheral edema reported. There were no discontinuations reported due to peripheral edema.
Maintenance Therapy following autologous stem cell transplantation (TOURMALINE MM3): Grade 3 peripheral edema was reported in < 1% of patients receiving ixazomib; no patients receiving placebo reported Grade 3 peripheral edema. There were no serious adverse reactions of peripheral edema reported in patients receiving ixazomib or placebo.
Maintenance Therapy not treated with stem cell transplantation (TOURMALINE MM4): There were no serious adverse reactions of peripheral edema reported in patients receiving ixazomib or placebo.
Pneumonia: Maintenance Therapy following autologous stem cell transplantation (TOURMALINE MM3): Grade 3 pneumonia was reported in 6% of patients receiving ixazomib and 4% of patients receiving placebo. Grade 4 pneumonia was reported in < 1% of patients receiving ixazomib, and in no patients receiving placebo. Serious adverse reactions of pneumonia were reported in 6% of patients receiving ixazomib and 4% of patients receiving placebo. There was one case of fatal pneumonia in a patient receiving ixazomib. Pyrexia, which commonly occurred in association with infections, including pneumonia, was reported in 21% and 15% of patients receiving ixazomib and placebo, respectively.
Maintenance Therapy not treated with stem cell transplantation (TOURMALINE MM4): Grade 3 pneumonia was reported in 4% of patients receiving ixazomib and 1% of patients receiving placebo. Serious adverse reactions of pneumonia were reported in 4% of patients receiving ixazomib and <1% of patients receiving placebo. Pyrexia, which commonly occurred in association with infections, including pneumonia, was reported in 11% and 5% of patients receiving ixazomib and placebo, respectively.
Eye Disorders: Combination Therapy with Lenalidomide and Dexamethasone (TOURMALINE MM1): 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: 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.