Ravulizumab

Ravulizumab therapy should be administered with caution to patients with active systemic infections. Ravulizumab blocks terminal complement activation; therefore, patients may have increased susceptibility to infections caused by Neisseria species and encapsulated bacteria. Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.

Patients should be provided with information from the Package Leaflet to increase their awareness of potential serious infections and their signs and symptoms. Physicians should advise patients about gonorrhoea prevention.

Chronic intravenous human immunoglobulin (IVIg) treatment may interfere with the endosomal neonatal Fc receptor (FcRn) recycling mechanism of monoclonal antibodies such as ravulizumab and thereby decrease serum ravulizumab concentrations.

There are no clinical data from the use of ravulizumab in pregnant women. Nonclinical reproductive toxicology studies were not conducted with ravulizumab. Reproductive toxicology studies were conducted in mice using the murine surrogate molecule BB5.1, which assessed effect of C5 blockade on the reproductive system. No specific test-article related reproductive toxicities were identified in these studies. Human IgG are known to cross the human placental barrier, and thus ravulizumab may potentially cause terminal complement inhibition in the foetal circulation.

Animal studies are insufficient with respect to reproductive toxicity.

In pregnant women the use of ravulizumab may be considered following an assessment of the risks and benefits.

It is unknown whether ravulizumab is excreted into human milk. Nonclinical reproductive toxicology studies conducted in mice with the murine surrogate molecule BB5.1 identified no adverse effect to pups resulting from consuming milk from treated dams.

A risk to infants cannot be excluded. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing infants, breast-feeding should be discontinued during treatment with ravulizumab and up to 8 months after treatment.

Women of childbearing potential

Women of childbearing potential should use effective contraception methods during treatment and up to 8 months after treatment.

Fertility

No specific non-clinical study on fertility has been conducted with ravulizumab. Nonclinical reproductive toxicology studies conducted in mice with a murine surrogate molecule (BB5.1) identified no adverse effect on fertility of the treated females or males.

Ravulizumab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse drug reactions (very common frequency) are diarrhoea, nausea, nasopharyngitis and headache. The most serious adverse reactions in patients in clinical trials are meningococcal infection and meningococcal sepsis.

Tabulated list of adverse reactions

The table below gives the adverse reactions observed from PNH and aHUS clinical trials and from postmarketing experience. Adverse reactions are listed by MedDRA System Organ Class (SOC) and frequency, using the following convention: 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); and not known (cannot be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing frequency.

Adverse reactions:

^a Meningococcal infection includes preferred terms of meningococcal infection and meningococcal sepsis
^b Estimated from post-marketing experience

Description of selected adverse reactions

Meningococcal infection/sepsis

Vaccination reduces, but does not eliminate, the risk of meningococcal infections. In clinical trials, 3 out of 261 adult PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ravulizumab; all 3 had been vaccinated. All 3 recovered while continuing treatment with ravulizumab. In the study in paediatric patients with PNH, no meningococcal infections occurred among 13 patients receiving treatment with ravulizumab. In aHUS studies, no meningococcal infections occurred among 89 patients receiving treatment with ravulizumab. In patients treated with ravulizumab, meningococcal infections presented as meningococcal sepsis. Patients should be informed of the signs and symptoms of meningococcal septicaemia and advised to seek medical care immediately.

Immunogenicity

Treatment with any therapeutic protein may induce an immune response. In adult PNH patient studies (N=261), paediatric PNH study (N=13), and aHUS studies (N=89), only 2 (0.55%) cases of development of treatment-emergent anti-drug antibody have been reported with ravulizumab (1 adult patient with PNH and 1 adult patient with aHUS). These anti-drug antibodies were transient in nature with low titre and did not correlate with clinical response or adverse events.

Paediatric population

Paroxysmal nocturnal haemoglobinuria (PNH)

In paediatric PNH patients (aged 9 to 17 years old) enrolled in the paediatric PNH Study (ALXN1210-PNH-304), the safety profile appeared similar to that observed in adult PNH patients. The most common adverse reactions reported in paediatric PNH patients were abdominal pain and nasopharyngitis, which occurred in 2 patients (15.4%).

Atypical haemolytic uremic syndrome (aHUS)

In paediatric patients with evidence of aHUS (aged 10 months to less than 18 years) included in ALXN1210-aHUS-312 study, the safety profile of ravulizumab appeared similar to that observed in adult patients with evidence of aHUS. The safety profiles in the different paediatric subsets of age appear similar. The safety data for patient below 2 years of age is limited to four patients. The most common adverse reaction reported in paediatric patients was pyrexia (32.3%).