Natalizumab interacts in the following cases:
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human dose; natalizumab did not affect male fertility. It is considered unlikely that natalizumab will affect fertility performance in humans following the maximum recommended dose.
Studies in animals have shown reproductive toxicity.
Data from clinical trials, a prospective pregnancy registry, post-marketing cases and available literature do not suggest an effect of natalizumab exposure on pregnancy outcomes.
The completed prospective natalizumab pregnancy registry contained 355 pregnancies with available outcomes. There were 316 live births, 29 of which were reported to have birth defects. Sixteen of the 29 were classified as major defects. The rate of defects corresponds to the defect rates reported in other pregnancy registries involving MS patients. There is no evidence of a specific pattern of birth defects with natalizumab.
Cases from published literature reported transient mild to moderate thrombocytopenia and anaemia observed in infants born to women exposed to natalizumab in their third trimester of pregnancy. Therefore, it is recommended that newborns of women exposed to the medicinal product during the third trimester of pregnancy are monitored for potential haematological abnormalities.
If a woman becomes pregnant while taking natalizumab, discontinuation of the medicinal product should be considered. A benefit-risk evaluation of the use of natalizumab during pregnancy should take into account the patient’s clinical condition and the possible return of disease activity after stopping the medicinal product.
Natalizumab is excreted in human milk. The effect of natalizumab on newborn/infants is unknown. Breast-feeding should be discontinued during treatment with natalizumab.
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human dose; natalizumab did not affect male fertility. It is considered unlikely that natalizumab will affect fertility performance in humans following the maximum recommended dose.
No studies on the effects on the ability to drive and use machines have been performed with natalizumab. However, given that dizziness has been commonly reported, patients who experience this adverse reaction should be advised not to drive or use machines until it has resolved.
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%).
The highest incidence of adverse reactions identified from placebo-controlled trials in multiple sclerosis patients with natalizumab given at the recommended dose, are reported as dizziness, nausea, urticaria and rigors associated with infusions.
Adverse reactions reported with natalizumab with an incidence of 0.5% greater than reported with placebo are shown below.
The reactions are reported as MedDRA preferred terms under the MedDRA primary system organ class. Frequencies were defined as follows: Common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Common: Urinary tract infection, Nasopharyngitis
Common: Urticaria
Uncommon: Hypersensitivity
Common: Headache, Dizziness
Uncommon: Progressive Multifocal Leukoencephalopathy (PML)
Common: Vomiting, Nausea
Common: Arthralgia
Common: Rigors, Pyrexia, Fatigue
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.
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 natalizumab. Hypersensitivity reactions usually occurred during the infusion or within the 1-hour period after the completion of the infusion. 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.
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.
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.
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 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.
In postmarketing experience, rare cases of ARN have been observed in patients receiving natalizumab. 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.
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. Cases of JCV GCN have also been reported during postmarketing use of natalizumab. Symptoms of JCV GCN are similar to PML.
Spontaneous cases of serious liver injuries, increased liver enzymes, hyperbilirubinaemia have been reported during the post marketing phase.
Rare, serious cases of anaemia and haemolytic anaemia have been reported in patients treated with natalizumab in post-marketing observational studies.
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.
In 2-year controlled clinical trials in MS patients natalizumab treatment 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. During treatment with natalizumab, small reductions in haemoglobin (mean decrease 0.6 g/dl), haematocrit (mean decrease 2%) and red blood cell counts (mean decrease 0.1 × 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/mm³) without clinical symptoms. In such cases where natalizumab therapy was discontinued the elevated eosinophil levels resolved.
Serious adverse events were evaluated in 621 MS paediatric patients included in a meta-analysis. 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.
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