During a placebo-controlled study of 1617 patients with multiple sclerosis who received natalizumab for 2 years (placebo 1135), adverse events that led to early termination of participation were observed in 5.8% of patients who received natalizumab (and 4.8% of those receiving placebo). For 2 years of study, adverse events were noted in 43.5% of patients who received natalizumab, and 39.6% (undesirable events regarded as treatment-related by the attending physician) who received a placebo. The incidence of adverse events in the natalizumab group was 0.5% higher than in the placebo group, as shown below. Reactions were indicated by preferred terms taken from the medical vocabulary for regulatory activities (MedDRA), in accordance with the system-organ classes. Their frequency was the following: frequent (> 1/100, <1/10), rare (> 1/1000, <1/100).
In each group, undesirable phenomena are divided by frequency:
Infections and invasions: frequent - urinary tract infections, nasopharyngitis.
Disorders from the immune system: frequent - hives; rare - hypersensitivity.
Violations from the nervous system: frequent - headache, dizziness.
Gastrointestinal disorders: frequent - vomiting, nausea.
Musculoskeletal disorders and connective tissue lesions: frequent - joint pain.
General disorders and reactions at the injection site: frequent - chills, fever, fatigue.
Infusion reactions: According to the data of a 2-year controlled clinical trial on MS patients, the phenomena associated with infusion were considered to be side effects that occur during infusion or within 1 hour after its completion. They were observed in 23.1% of patients Multiple Sclerosiswho received natalizumab (and in 18.7% of those receiving placebo). The phenomena more often observed in the natalizumab group included dizziness, nausea, urticaria, and chills (see the section on "Hypersensitivity Reactions" below).
Hypersensitivity reactions: according to a two-year controlled clinical trial on patients Multiple Sclerosis,
the incidence of gynsensitivity has reached 4%. Anaphylactic / anaphylactoid reactions are noted in less than 1% of patients. Hypersensitivity reactions usually occur during infusion or within an hour after it.
Immunogenicity: During a biennial controlled clinical trial, antibodies to natalizumab were detected in 10% of patients with multiple sclerosis.Circulating antibodies to natalizumab (a double positive result) were found in approximately 6% of patients. A single positive result was noted in 4% of patients. Circulating antibodies decrease the effectiveness and increase the frequency of hypersensitivity reactions. Other reactions to infusion due to circulating antibodies included chills, nausea, vomiting, and "hot flashes" of blood. If there is a suspicion of circulating antibodies after about 6 months of therapy, either due to a decrease in efficacy or a response to infusion, another analysis should be made 6 weeks after the first positive result. Given the possible reduction in efficacy or increased frequency of hypersensitivity reactions in patients with circulating antibodies, treatment should be discontinued.
Infections, including progressive multifocal leukoencephalopathy and opportunistic pathogens infections: according to a two-year, controlled clinical study for MS patients, the incidence of infections was approximately 1.5 per patient year in both the natalizumab group and the placebo group.The nature of the infections in both groups was approximately similar. A case of diarrhea due to Cryptosporidium has been reported. During other clinical trials, other opportunistic infections were noted, including deaths. During clinical trials in the group receiving natalizumab, there was a slightly higher incidence of herpesvirus infection (herpes zoster virus and herpes simplex virus) than in the placebo group. During early post-marketing surveillance, one fatal case of herpesviral encephalitis was registered.
Most of the patients who developed the infection, did not stop the therapy with natalizumab and with appropriate treatment I am recovering.
During clinical trials, cases progressive multifocal leukoencephalopathy. They usually led to serious disability or death. During the basic clinical trials, two cases were recorded, including one fatal, in patients with multiple sclerosis with concomitant infection who received interferon beta treatment for more than 2 years. In another trial progressive multifocal leukoencephalopathy developed in a patient with Crohn's disease, long-term treated with immunosuppressants and suffering from lymphopenia, this patient died. Development progressive multifocal leukoencephalopathy was observed in post-marketing research in patients receiving monotherapy.
Reactions from the liver: during the postmarketing period, spontaneous reports of cases of severe liver damage, increased activity of "liver enzymes" and hyperbilirubinemnia were obtained.
Malignant neoplasms: for more than 2 years of therapy, there were no differences in the incidence of malignant neoplasms in the natalizumab and placebo groups. However, in order to completely eliminate the effect of natalizumab on the incidence of malignant neoplasms, longer studies are needed.
Influence on laboratory parameters: treatment is accompanied by an increase in the number of lymphocytes, monocytes, eosinophils, basophils and nuclear forms of erythrocytes in circulating blood. No increase in the neutrophil concentration was observed.The increase in the number of lymphocytes, monocytes, eosinophils and basophils reaches 35-140% compared to the initial value, but the total number of cells remains within normal limits. During the treatment, there was a slight decrease in hemoglobin concentration (mean decrease of 0.6 g / dl), hematocrit (mean decrease of 2%) and erythrocytes (mean decrease of 0.1 ×106/ l ). Usually, within 16 weeks after the last dose, all hematologic parameters returned to baseline, and these changes were not accompanied by clinical symptoms.