Ravulizumab interacts in the following cases:
No interaction studies have been performed. Based on the potential inhibitory effect of ravulizumab on complement-dependent cytotoxicity of rituximab, ravulizumab may reduce the expected pharmacodynamic effects of rituximab.
Prior to initiating ravulizumab therapy, it is recommended that patients initiate immunisations according to current immunisation guidelines.
Vaccination may further activate complement. As a result, patients with complement-mediated diseases may experience increased signs and symptoms of their underlying disease. Therefore, patients should be closely monitored for disease symptoms after recommended vaccination.
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 Information 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 should use effective contraception methods during treatment and up to 8 months after treatment.
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.
The most common adverse reactions with ravulizumab are headache (28.2%), upper respiratory tract infection (19.9%), nasopharyngitis (19.5%), diarrhoea (16.9%), pyrexia (16.4%), nausea (13.7%), arthralgia (13.2%), fatigue (13.1%), back pain (12.6%), abdominal pain (11.8%), and dizziness (10.1%). The most serious adverse reactions are meningococcal infection (0.7%) including meningococcal sepsis, encephalitis meningococcal, meningococcal infection and disseminated gonococcal infection (0.1%).
The table below gives the adverse reactions observed from clinical trials and from post-marketing 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 seriousness.
Adverse reactions from clinical trials and postmarketing experience:
| MedDRA System Organ Class | Very common (≥1/10) | Common (≥1/100 to <1/10) | Uncommon (≥1/1,000 to <1/100) |
|---|---|---|---|
| Infections and infestations | Upper respiratory tract infection, Nasopharyngitis | Urinary tract infection | Meningococcal infectiona, Disseminated Gonococcal infectionb |
| Immune system disorders | Hypersensitivityd | Anaphylactic reactionc | |
| Nervous system disorders | Headache, Dizziness | ||
| Gastrointestinal disorders | Diarrhoea, Nausea, Abdominal pain | Vomiting, Dyspepsia | |
| Skin and subcutaneous tissue disorders | Urticaria, Pruritus, Rash | ||
| Musculoskeletal and connective tissue disorders | Arthralgia, Back pain | Myalgia, Muscle spasms | |
| General disorders and administration site conditions | Pyrexia, Fatigue | Influenza like illness, Chills, Asthenia | |
| Injury, poisoning and procedural complications | Infusion-related reaction |
a Meningococcal infection includes preferred terms of meningococcal infection, meningococcal sepsis, and encephalitis meningococcal
b Disseminated gonococcal infection includes preferred terms of disseminated gonococcal infection and gonococcal infection
c Estimated from postmarketing experience
d Hypersensitivity is a group term for Preferred Term drug hypersensitivity with related causality and Preferred Term hypersensitivity
Vaccination reduces, but does not eliminate, the risk of meningococcal infections. In clinical trials, <1% of patients developed serious meningococcal infections while receiving treatment with ravulizumab; all were adult patients with PNH or NMOSD who had been vaccinated. In patients treated with ravulizumab, meningococcal infections have presented as meningococcal sepsis and encephalitis meningococcal. Patients should be informed of the signs and symptoms of meningococcal infection and advised to seek medical care immediately.
In clinical trials, infusion-related reactions were common (≥1%). These events, which were mild to moderate in severity and transient, included back pain, abdominal pain, muscle spasms, drop in blood pressure, elevation in blood pressure, rigors, limb discomfort, hypersensitivity (allergic reaction), dysgeusia (bad taste), and drowsiness. These reactions did not require discontinuation of ravulizumab.
In adult PNH patient studies (N=475), a paediatric PNH study (N=13), aHUS studies (N=89), a gMG study (N=86), and an NMOSD study (N=58), 2 (0.3%) 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.
In paediatric PNH patients (N=13, 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, nausea, nasopharyngitis and headache which occurred in 3 patients (23.1%).
In paediatric patients with evidence of aHUS (N=34, 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%).
Ravulizumab has not been studied in paediatric patients with gMG.
Ravulizumab has not been studied in paediatric patients with NMOSD.
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