Adverse reactions : תופעות לוואי

4.8       Undesirable effects
Summary of the safety profile

In placebo-controlled trials in 1,617 MS patients treated with natalizumab for up to 2 years (placebo: 1,135), adverse events leading to discontinuation of therapy occurred in 5.8% of patients treated with natalizumab (placebo: 4.8%). Over the 2-year duration of the studies, 43.5% of patients treated with natalizumab reported adverse reactions (placebo: 39.6%).

In clinical trials in 6786 patients treated with natalizumab (intravenous infusion and subcutaneous injection), the most frequently occurring adverse reactions were headache (32%), nasopharyngitis (27%), fatigue (23%), urinary tract infection (16%), nausea (15%), arthralgia (14%), and dizziness (11%) associated with natalizumab administration.

Tabulated list of adverse reactions

Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneous reports are presented in Table 1, below. Within the system organ classes they are listed under the following headings: 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions

MedDRA System                             Frequency of Adverse Reactions Organ Class             Very Common        Common            Uncommon            Rare               Not known 

Infections and          Nasopharyngitis    Herpes            Progressive       Herpes               Meningoencephalitis infestations            Urinary tract      infection         multifocal        ophthalmic           herpetic infection                            leukoencephalopat                      JC virus granule hy                                     cell neuropathy
Necrotising herpetic retinopathy


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Immune system                            Hypersensitivity   Anaphylactic disorders                                                   reaction
Immune reconstitution inflammatory syndrome
Blood and                                Anaemia            Thrombocytopenia,   Haemolytic lymphatic                                                   Immune              anaemia system disorders                                            thrombocytopenic    Nucleated purpura (ITP)       red cells
Eosinophilia
Hepatobiliary                                                                   Hyperbilirubinae Liver injury disorders                                                                       mia Investigations                           Hepatic enzyme increased Drug specific antibody present
Injury,               Infusion related poisoning and         reaction procedural complications
Respiratory,                             Dyspnoea thoracic and mediastinal disorders
Gastrointestinal      Nausea             Vomiting disorders
General               Fatigue            Pyrexia            Face oedema disorders and                            Chills administration                           Infusion site site conditions                          reaction
Injection site reaction
Skin and                                 Pruritus Rash                          Angioedema subcutaneous tissue                      Urticaria disorders

Vascular disorders                       Flushing

Nervous system        Dizziness disorders             Headache
Musculoskeletal       Arthralgia and connective tissue disorders


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Description of selected adverse reactions

Infusion-related reactions (IRR)

In 2-year controlled clinical trials in MS patients, an infusion-related event was defined as an adverse event occurring during the infusion or within 1 hour of the completion of the infusion. These occurred in 23.1% of MS patients treated with natalizumab (placebo: 18.7%). Events reported more commonly with natalizumab than with placebo included dizziness, nausea, urticaria and rigors.

Hypersensitivity reactions

In 2-year controlled clinical trials in MS patients, hypersensitivity reactions occurred in up to 4% of patients. Anaphylactic/anaphylactoid reactions occurred in less than 1% of patients receiving this medicinal product. Hypersensitivity reactions usually occurred during the infusion or within the
1-hour period after the completion of the infusion (see section 4.4). In post- marketing experience, there have been reports of hypersensitivity reactions which have occurred with one or more of the following associated symptoms: hypotension, hypertension, chest pain, chest discomfort, dyspnoea, angioedema, in addition to more usual symptoms such as rash and urticaria.

Immunogenicity

In 10% of patients antibodies against natalizumab were detected in 2-year controlled clinical trials in MS patients. Persistent anti-natalizumab antibodies (one positive test reproducible on retesting at least 6 weeks later) developed in approximately 6% of patients. Antibodies were detected on only one occasion in an additional 4% of patients. Persistent antibodies were associated with a substantial decrease in the effectiveness of natalizumab and an increased incidence of hypersensitivity reactions. Additional infusion-related reactions associated with persistent antibodies included rigors, nausea, vomiting and flushing (see section 4.4).

If, after approximately 6 months of therapy, persistent antibodies are suspected, either due to reduced efficacy or due to occurrence of infusion-related events, they may be detected and confirmed with a subsequent test 6 weeks after the first positive test. Given that efficacy may be reduced or the incidence of hypersensitivity or infusion-related reactions may be increased in a patient with persistent antibodies, treatment should be discontinued in patients who develop persistent antibodies.

Infections, including PML and opportunistic infections

In 2-year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per patient-year in both natalizumab- and placebo-treated patients. The nature of the infections was generally similar in natalizumab- and placebo-treated patients. A case of cryptosporidium diarrhoea was reported in MS clinical trials. In other clinical trials, cases of additional opportunistic infections have been reported, some of which were fatal. The majority of 12
patients did not interrupt natalizumab therapy during infections and recovery occurred with appropriate treatment.

In clinical trials, herpes infections (Varicella-Zoster virus, Herpes-simplex virus) occurred slightly more frequently in natalizumab-treated patients than in placebo-treated patients. In post-marketing experience, serious, life-threatening, and sometimes fatal cases of encephalitis and meningitis caused by herpes simplex or varicella zoster have been reported in multiple sclerosis patients receiving
 natalizumab. The duration of treatment with natalizumab prior to onset ranged from a few months to several years (see section 4.4).

In postmarketing experience, rare cases of ARN have been observed in patients receiving this medicinal product. Some cases have occurred in patients with central nervous system (CNS) herpes infections (e.g. herpes meningitis and encephalitis). Serious cases of ARN, either affecting one or both eyes, led to blindness in some patients. The treatment reported in these cases included anti-viral therapy and in some cases, surgery (see section 4.4).

Cases of PML have been reported from clinical trials, post-marketing observational studies and post- marketing passive surveillance. PML usually leads to severe disability or death (see section 4.4).
Cases of JCV GCN have also been reported during postmarketing use of Tysabri. Symptoms of JCV GCN are similar to PML.

Hepatic events

Spontaneous cases of serious liver injuries, increased liver enzymes, hyperbilirubinaemia have been reported during the post-marketing phase (see section 4.4).

Anaemia and haemolytic anaemia

Rare, serious cases of anaemia and haemolytic anaemia have been reported in patients treated with this medicinal product in post-marketing observational studies.

Malignancies

No differences in incidence rates or the nature of malignancies between natalizumab- and placebo-treated patients were observed over 2 years of treatment. However, observation over longer treatment periods is required before any effect of natalizumab on malignancies can be excluded (see section 4.3).

Effects on laboratory tests

In 2-year controlled clinical trials in MS patients treatment with natalizumab was associated with increases in circulating lymphocytes, monocytes, eosinophils, basophils and nucleated red blood cells. Elevations in neutrophils were not seen. Increases from baseline for lymphocytes, monocytes, eosinophils and basophils ranged from 35% to 140% for individual cell types but mean cell counts remained within normal ranges with IV administration. During treatment with IV form of this medicinal product, small reductions in haemoglobin (mean decrease 0.6 g/dL), haematocrit (mean decrease 2%) and red blood 
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cell counts (mean decrease 0.1 x 106/L) were seen. All changes in haematological variables returned to pre-treatment values, usually within 16 weeks of last dose of the medicinal product and the changes were not associated with clinical symptoms. In post-marketing experience, there have also been reports of eosinophilia (eosinophil count >1,500/mm 3) without clinical symptoms. In such cases where therapy was discontinued the elevated eosinophil levels resolved.

Thrombocytopenia
In post-marketing experience, thrombocytopenia and immune thrombocytopenic purpura (ITP) have been reported with uncommon frequency.


Paediatric population
Serious adverse events were evaluated in 621 MS paediatric patients included in a meta- analysis (see also section 5.1). Within the limitations of these data, there were no new safety signals identified in this patient population. 1 case of herpes meningitis was reported in the meta-analysis. No cases of PML were identified in the meta-analysis, however, PML has been reported in natalizumab-treated paediatric patients in the post- marketing setting.

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