Adverse reactions : תופעות לוואי

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