Special Warning : אזהרת שימוש

5     WARNINGS AND PRECAUTIONS

5.1    Thrombocytopenia
Thrombocytopenia has been reported with NINLARO 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 Adverse Reactions (6.1)]. Grade 3 thrombocytopenia was reported in 17% of patients in the NINLARO regimen and Grade 4 thrombocytopenia was reported in 13% in the NINLARO regimen. The rate of platelet transfusions was 10% in the NINLARO regimen and 7% in the placebo regimen.
Monitor platelet counts at least monthly during treatment with NINLARO. Consider more frequent monitoring during the first three cycles. Manage thrombocytopenia with dose modifications [see Dosage and Administration (2.2)] and platelet transfusions as per standard medical guidelines.
5.2   Gastrointestinal Toxicities
Diarrhea, constipation, nausea, and vomiting, have been reported with NINLARO, occasionally requiring use of antidiarrheal and antiemetic medications, and supportive care. Diarrhea was reported in 52% of patients in the NINLARO regimen and 43% in the placebo regimen, constipation in 35% and 28%, respectively, nausea in 32% and 23%, respectively, and vomiting in 26% and 13%, respectively. Diarrhea resulted in discontinuation of one or more of the three drugs in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen [see Adverse Reactions (6.1)]. Adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].

5.3   Peripheral Neuropathy
The majority of peripheral neuropathy adverse reactions were Grade 1 (18% in the NINLARO regimen and 16% in the placebo regimen) and Grade 2 (11% in the NINLARO regimen and 6% in the placebo regimen) [see Adverse Reactions (6.1)]. Grade 3 adverse reactions of peripheral neuropathy were reported at 2% in both regimens.
The most commonly reported reaction was peripheral sensory neuropathy (24% and 17% in the NINLARO 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 drugs in 4% of patients in the NINLARO regimen and <1% of patients in the placebo regimen. Patients should be monitored for symptoms of neuropathy. Patients experiencing new or worsening peripheral neuropathy may require dose modification [see Dosage and Administration (2.2)].
5.4   Peripheral Edema
Peripheral edema was reported in 27% and 21% of patients in the NINLARO and placebo regimens, respectively. The majority of peripheral edema adverse reactions were Grade 1 (17% in the NINLARO regimen and 14% in the placebo regimen) and Grade 2 (7% in the NINLARO regimen and 6% in the placebo regimen).
Grade 3 peripheral edema was reported in 2% and 1% of patients in the NINLARO and placebo regimens, respectively[see Adverse Reactions (6.1)]. Peripheral edema resulted in discontinuation of one or more of the three drugs in <1% of patients in both regimens. Evaluate for underlying causes and provide supportive care, as necessary. Adjust dosing of dexamethasone per its prescribing information or NINLARO for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].

5.5   Cutaneous Reactions
Rash was reported in 27% of patients in the NINLARO regimen and 16% of patients in the placebo regimen.
The majority of the rash adverse reactions were Grade 1 (15% in the NINLARO regimen and 9% in the placebo regimen) or Grade 2 (9% in the NINLARO regimen and 4% in the placebo regimen) [see Adverse Reactions (6.1)]. Grade 3 rash was reported in 3% of patients in the NINLARO regimen and 2% of patients in the placebo regimen. Serious adverse reactions of rash were reported in <1% of patients in the NINLARO regimen. The most common type of rash reported in both regimens included maculo-papular and macular rash.
Rash resulted in discontinuation of one or more of the three drugs in < 1% of patients in both regimens.
Manage rash with supportive care or with dose modification if Grade 2 or higher [see Dosage and Administration (2.2)].
Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatal cases, have been reported with NINLARO [see Adverse Reactions (6.1, 6.2)]. If Stevens-Johnson syndrome or toxic epidermal necrolysis occurs, discontinue NINLARO and manage as clinically indicated.
5.6       Thrombotic Microangiopathy
Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO [see Adverse Reactions (6.1)]. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TTP/HUS is not known.
5.7       Hepatotoxicity
Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in < 1% of patients treated with NINLARO [see Adverse Reactions (6.1)]. Hepatotoxicity has been reported (10% in the NINLARO regimen and 9% in the placebo regimen).
Monitor hepatic enzymes regularly and adjust dosing for Grade 3 or 4 symptoms [see Dosage and Administration (2.2)].

5.8       Embryo-Fetal Toxicity
NINLARO can cause fetal harm when administered to a pregnant woman based on the mechanism of action and findings in animal studies. Ixazomib caused embryo-fetal toxicity in pregnant rats and rabbits at doses resulting in exposures that were slightly higher than those observed in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with NINLARO and for 90 days following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with NINLARO and for 90 days following the last dose [see Drug Interactions (7.1) and Use in Specific Populations (8.1, 8.3)].
5.9       Increased Mortality in Patients Treated with NINLARO in the Maintenance Setting In two prospective randomized clinical trials in multiple myeloma in the maintenance setting, treatment with NINLARO resulted in increased deaths. Treatment of patients with NINLARO for multiple myeloma in the maintenance setting is not recommended outside of controlled trials [see Clinical Studies (13.2)].

6     ADVERSE REACTIONS

The following adverse reactions are described in detail in other sections of the prescribing information: •    Thrombocytopenia [see Warnings and Precautions (5.1)]
•    Gastrointestinal Toxicities [see Warnings and Precautions (5.2)] •    Peripheral Neuropathy [see Warnings and Precautions (5.3)]
•    Peripheral Edema [see Warnings and Precautions (5.4)]
•    Cutaneous Reactions [see Warnings and Precautions (5.5)]
•    Thrombotic Microangiopathy [see Warnings and Precautions (5.6)] •    Hepatotoxicity [see Warnings and Precautions (5.7)]
6.1   Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety population from the randomized, double-blind, placebo-controlled clinical study included 720 patients with relapsed and/or refractory multiple myeloma, who received NINLARO in combination with lenalidomide and dexamethasone (NINLARO regimen; N=361) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=359).
The most frequently reported adverse reactions (≥ 20% with a difference of ≥5% compared to placebo) in the NINLARO regimen were thrombocytopenia, neutropenia, diarrhea, constipation, peripheral neuropathy, nausea, peripheral edema, rash, vomiting, and bronchitis. Serious adverse reactions reported in ≥ 2% of patients in the NINLARO regimen included diarrhea (3%), thrombocytopenia (2%) and bronchitis (2%). One or more of the three drugs was permanently discontinued in 4% of patients reporting peripheral neuropathy, 3% of patients reporting diarrhea and 2% of patients reporting thrombocytopenia. Permanent discontinuation of NINLARO due to an adverse reaction occurred in 10% of patients.
Table 4 summarizes the non-hematologic adverse reactions occurring in at least 5% of patients with at least a 5% difference between the NINLARO regimen and the placebo regimen.

Table 4: Non-Hematologic Adverse Reactions Occurring in ≥ 5% of Patients with a ≥ 5% Difference Between the NINLARO Regimen and the Placebo Regimen (All Grades, Grade 3 and Grade 4) 
NINLARO +                                Placebo +
Lenalidomide and                        Lenalidomide and
Dexamethasone                           Dexamethasone
System Organ Class /
N=361                                   N=359
Preferred Term
%                                       %
All     Grade 3 Grade 4                 All      Grade 3   Grade 4
Grades                                  Grades
Gastrointestinal disorders
Diarrhea                          52         10                     0            43           3                 0 Constipation                      35        <1                      0            28           <1                0 Nausea                            32         2                      0            23           0                 0 Vomiting                          26         1                      0            13           <1                0 Nervous system disorders
Peripheral neuropathies†          32         2                      0            24            2                0 Musculoskeletal and connective tissue disorders
Back pain*                         27         <1                     0            24            3                0 Infections and infestations
Upper respiratory tract           27          1                      0            23            1                0 infection*
Bronchitis                        22          2                      0            17            2            <1 Skin and subcutaneous tissue disorders
Rash†                            27          3                      0            16            2                0 General disorders and administration site conditions
Edema peripheral                 27          2                      0            21            1                0 Note: Adverse reactions included as preferred terms are based on MedDRA version 23.0.
* At the time of the final analysis, these adverse reactions no longer met the criterion for a ≥ 5% difference †
Represents a pooling of preferred terms
Table 5 represents pooled information from adverse event and laboratory data.
Table 5: Thrombocytopenia and Neutropenia
NINLARO +                          Placebo +
Lenalidomide and                  Lenalidomide and
Dexamethasone                     Dexamethasone
N=361                             N=359
%                                   %
Any Grade         Grade 3-4       Any Grade          Grade 3-4
Thrombocytopenia              85                30              67                  14 Neutropenia                   74                34              70                 37 

Herpes Zoster
Herpes zoster was reported in 6% of patients in the NINLARO regimen and 3% of patients in the placebo regimen. Antiviral prophylaxis was allowed at the healthcare provider’s discretion.
Patients treated in the NINLARO regimen who received antiviral prophylaxis had a lower incidence (1%) of herpes zoster infection compared to patients who did not receive prophylaxis (10%).

Eye Disorders
Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 38% in patients in the NINLARO regimen. The most common adverse reactions of the eyes were cataract (15%), conjunctivitis (9%), blurred vision (7%) and dry eye (6%).

Other Clinical Trials Experience
The following serious adverse reactions have each been reported at a frequency of < 1% in patients treated with NINLARO: acute febrile neutrophilic dermatosis (Sweet’s syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.
6.2 Post marketing Experience
The following adverse reactions have been identified during post-approval use of NINLARO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.


Immune system disorders: Angioedema

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il

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