Adverse reactions : תופעות לוואי

4.8    Undesirable effects

The information provided in this section pertains to the use of MabThera in oncology.
For information related to the autoimmune indications, please refer to the Prescribing Information of MabThera intravenous formulation.

Summary of the safety profile

During the development programme, the safety profile of MabThera subcutaneous formulation was comparable to that of the intravenous formulation with the exception of local cutaneous reactions.
Local cutaneous reactions, including injection site reactions, were very common in patients receiving MabThera subcutaneous formulation. In the phase 3 SABRINA trial (BO22334), local cutaneous reaction were reported in up to 20% of patients receiving subcutaneous MabThera. The most common local cutaneous reactions in the MabThera subcutaneous arm were injection erythema (13%), injection pain (7%), and injection site oedema (4%). Events seen following subcutaneous administration were mild or moderate, apart from one patient who reported a local cutaneous reaction of Grade 3 intensity (injection site rash) following the first MabThera subcutaneous administration (Cycle 2). Local cutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections.

Adverse reactions reported in MabThera subcutaneous formulation usage 
The risk of acute administration-related reactions associated with the subcutaneous formulation of MabThera was assessed in two open-label trials involving patients with follicular lymphoma during induction and maintenance (SABRINA BO22334) and during maintenance only (SparkThera/BP22333). In SABRINA, severe administration-related reactions (grade≥3) were reported in two patients (2%) following administration of MabThera subcutaneous formulation.
These events were Grade 3 injection site rash and dry mouth.
In SparkThera, no severe administration-related reactions were reported.

Adverse reactions reported in MabThera intravenous formulation usage

Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia 
The overall safety profile of MabThera in non-Hodgkin’s lymphoma and CLL is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse reactions (ADRs) in patients receiving MabThera were infusion-related reactions which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1 % after eight doses of MabThera.

Infectious events (predominantly bacterial and viral) occurred in approximately 30-55 % of patients during clinical trials in patients with NHL and in 30-50 % of patients during clinical trial in patients with CLL.

The most frequent reported or observed serious adverse reactions were:
•    Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.
•    Infections, see section 4.4.
•    Cardiovascular disorders, see section 4.4.

Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.).

The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are summarised in Table 1. Frequencies are defined as very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”.

Tabulated list of adverse reactions

Table 1          ADRs reported in clinical trials or during postmarketing surveillance in patients with NHL and CLL disease treated with MabThera monotherapy/maintenance or in combination with chemotherapy
MedDRA
Very
System Organ                         Common             Uncommon           Rare         Very Rare       Not known Common
Class
Infections and     bacterial      sepsis,                               serious viral + infestations       infections,      pneumonia,                          infection2 + viral            febrile infection,
+ infections,      herpes zoster,
+              + bronchitis     respiratory tract infection, fungal infections,
infections of unknown aetiology, +acute bronchitis,
+ sinusitis,
hepatitis B1
Blood and          neutropenia,   anaemia,               coagulation                    transient     late neutropenia3 + lymphatic          leucopenia,      pancytopenia,        disorders,                     increase in +              + system               febrile        granulocytopeni      aplastic                       serum IgM disorders          neutropenia,   a                      anaemia,                       levels3 + thrombocyt                          haemolytic openia                                anaemia,
lymphadenopa thy


MedDRA
Very
System Organ                      Common               Uncommon           Rare             Very Rare          Not known Common
Class
Immune           infusion      hypersensitivity                       anaphylaxis         tumour lysis     infusion-related system           related                                                                  syndrome,        acute reversible disorders        reactions4,                                                              cytokine         thrombocytopenia 4 angioedema                                                               release syndrome4,
serum sickness
Metabolism                     hyperglycaemia,
and nutrition                  weight decrease,
disorders                      peripheral oedema, face oedema,
increased LDH,
hypocalcaemia
Psychiatric                                         depression,
disorders                                           nervousness,
Nervous                        paraesthesia,        dysgeusia                             peripheral       cranial system                         hypoaesthesia,                                             neuropathy,      neuropathy, disorders                      agitation,                                                 facial nerve     loss of other insomnia,                                                  palsy5           senses5 vasodilatation,
dizziness, anxiety
Eye disorders                  lacrimation                                                severe vision disorder,                                                  loss5 conjunctivitis
Ear and                        tinnitus, ear pain                                                          hearing loss5 labyrinth disorders
+                    +
Cardiac                          myocardial           left            severe cardiac      heart failure4 disorders                      infarction4 and 6,   ventricular       disorders 4 and 6   and 6  arrhythmia,          failure,
+                    + atrial               supraventricu fibrillation,        lar tachycardia,         tachycardia,
+                    + cardiac disorder     ventricular tachycardia,
+ angina,
+ myocardial ischaemia,
bradycardia
Vascular                       hypertension,                                              vasculitis disorders                      orthostatic                                                (predominatel hypotension,                                               y cutaneous), hypotension                                                leukocytoclast ic vasculitis
Respiratory,                   Bronchospasm4,       asthma,           interstitial        respiratory      lung infiltration, thoracic and                   respiratory          bronchiolitis     lung disease7       failure4, mediastinal                    disease, chest       obliterans,
disorders                      pain, dyspnoea,      lung disorder,
increased cough,     hypoxia rhinitis
Gastrointestin   nausea        vomiting ,           abdominal                             gastro- al disorders                   diarrhoea,           enlargement                           intestinal abdominal pain,                                            perforation7 dysphagia,
stomatitis,
constipation,
dyspepsia,
anorexia, throat irritation


MedDRA
Very
System Organ                              Common              Uncommon                Rare            Very Rare             Not known Common
Class
Skin and             pruritis, rash,   urticaria,                                                    severe bullous + subcutaneous           alopecia        sweating, night                                               skin reactions, tissue                                 sweats, +skin                                                 Stevens- disorders                              disorder                                                      Johnson Syndrome toxic epidermal necrolysis
(Lyell’s
Syndrome) 7
Musculoskelet                          hypertonia,
al, connective                         myalgia,
tissue                                 arthralgia, back disorders                              pain, neck pain,
pain
Renal and                                                                                            renal failure4 urinary disorders
General              fever , chills,   tumour pain,           infusion site disorders and        asthenia,         flushing, malaise,     pain administration       headache          cold syndrome,
+ site conditions                          fatigue,
+ shivering,
+ multi-organ failure4
Investigations       decreased
IgG levels
For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with "+" where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria) reactions. Only the highest frequency observed in the trials is reported
1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 2 see also section infection below
3 see also section haematologic adverse reactions below
4 see also section infusion-related reactions below. Rarely fatal cases reported 5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera therapy 6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions
7 includes fatal cases


The following terms have been reported as adverse events during clinical trials, however, were reported at a similar or lower incidence in the MabThera-arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50 % of patients in clinical trials involving MabThera intravenous formulation, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome.
Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12 % of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent intravenous infusions and is <1% of patients by the eighth cycle of MabThera (containing) treatment.


Description of selected adverse reactions

Infections
MabThera induces B-cell depletion in about 70-80% of patients, but was associated with decreased serum immunoglobulins only in a minority of patients.

Localized candida infections as well as Herpes zoster were reported at a higher incidence in the MabThera-containing arm of randomized studies. Severe infections were reported in about 4% of patients treated with MabThera monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when compared to observation. There was no cumulative toxicity in terms of infections reported over a 2- year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of patients had received MabThera in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (PML) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving MabThera in combination with cytotoxic chemotherapy. Progression of Kaposi’s sarcoma has been observed in MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.

Haematologic adverse reactions
In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. During MabThera maintenance treatment for up to 2 years, leucopoenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (<1 %, grade 3/4) and was not different between treatment arms. During the treatment course in studies with MabThera in combination with chemotherapy, grade 3/4 leucopoenia (R-CHOP 88% vs. CHOP 79%), neutropenia (R-CVP 24% vs.
CVP 14%; R-CHOP 97% vs. CHOP 88%), were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of MabThera were reported.

In studies of MabThera in patients with Waldenstrom’s macroglobulinaemia, transient increases in serum IgM levels have been observed following treatment initiation, which may be associated with hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline level within 4 months.

Cardiovascular adverse reactions
Cardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8% of patients with the most frequently reported events being hypotension and hypertension. Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders was comparable between patients treated with MabThera and observation. Cardiac events were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischemia) in 3% of patients treated with MabThera compared to <1% on observation. In studies evaluating MabThera in combination with chemotherapy, the incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a MabThera infusion or were associated with predisposing conditions such as fever, infection, acute myocardial 
infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease.

Respiratory system
Cases of interstitial lung disease, some with fatal outcome have been reported.

Neurologic disorders
During the treatment period (induction treatment phase comprising of R-CHOP for at most eight cycles), four patients (2 %) treated with R-CHOP, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, three patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period.

Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognized risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Gastrointestinal disorders
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of Non-Hodgkin’s lymphoma (NHL). In the majority of these cases, MabThera was administered with chemotherapy.

IgG levels
In the clinical trial evaluating MabThera maintenance treatment in relapsed/refractory follicular lymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction treatment in both the observation and the MabThera groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the MabThera group. The proportion of patients with IgG levels below the LLN was about 60% in the MabThera group throughout the 2 year treatment period, while it decreased in the observation group (36% after 2 years).

Skin and subcutaneous tissue disorders
Toxic Epidermal Necrolysis (Lyell Syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Patient subpopulations - MabThera monotherapy
Elderly ( 65 years):
The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared to younger patients (<65 years).

Bulky disease:
There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in these two groups.

Re-treatment:
The percentage of patients reporting ADRs upon re-treatment with further courses of MabThera was similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4 ADRs).

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