ULTOMIRIS Concentrate for solution for infusion Ref.[50087] Active ingredients: Ravulizumab

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Serious meningococcal infection

Due to its mechanism of action, the use of ravulizumab increases the patient’s susceptibility to meningococcal infection/sepsis (Neisseria meningitidis). Meningococcal disease due to any serogroup may occur. To reduce this risk of infection, all patients must be vaccinated against meningococcal infections at least two weeks prior to initiating ravulizumab unless the risk of delaying ravulizumab therapy outweighs the risk of developing a meningococcal infection. Patients who initiate ravulizumab treatment less than 2 weeks after receiving a meningococcal vaccine, must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Vaccines against serogroups A, C, Y, W135 and B where available, are recommended in preventing the commonly pathogenic meningococcal serogroups. Patients must be vaccinated or revaccinated according to current national guidelines for vaccination use. If the patient is being switched from eculizumab treatment, physicians should verify that meningococcal vaccination is current according to national guidelines for vaccination use.

Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Cases of serious meningococcal infections/sepsis have been reported in patients treated with ravulizumab. Cases of serious or fatal meningococcal infections/sepsis have been reported in patients treated with other terminal complement inhibitors. All patients should be monitored for early signs of meningococcal infection and sepsis, evaluated immediately if infection is suspected, and treated with appropriate antibiotics. Patients should be informed of these signs and symptoms and steps should be taken to seek medical care immediately. Physicians should provide patients with a patient information brochure and a Patient card.

Immunization

Prior to initiating ravulizumab therapy, it is recommended that PNH and aHUS patients initiate immunizations according to current immunization guidelines.

Vaccination may further activate complement. As a result, patients with complement-mediated diseases, including PNH and aHUS, may experience increased signs and symptoms of their underlying disease, such as haemolysis. Therefore, patients should be closely monitored for disease symptoms after recommended vaccination.

Patients below the age of 18 years old must be vaccinated against Haemophilus influenzae and pneumococcal infections, and strictly need to adhere to the national vaccination recommendations for each age group.

Other systemic infections

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.

Infusion reactions

Administration of ravulizumab may result in infusion reactions and allergic or hypersensitivity reactions (including anaphylaxis). In clinical trials with PNH and aHUS, [(6 out of 487 patients with PNH), and (4 of 89 patients with aHUS)] patients experienced infusion reactions which were mild in severity and transient [e.g., lower back pain, drop in blood pressure, elevation in blood pressure, limb discomfort, drug hypersensitivity (allergic reaction), and dysgeusia (bad taste)]. In case of infusion reaction, infusion of ravulizumab should be interrupted and appropriate supportive measures should be instituted if signs of cardiovascular instability or respiratory compromise occur.

Treatment discontinuation for PNH

If patients with PNH discontinue treatment with ravulizumab, they should be closely monitored for signs and symptoms of serious intravascular haemolysis, identified by elevated LDH (lactate dehydrogenase) levels along with sudden decrease in PNH clone size or haemoglobin, or re-appearance of symptoms such as fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. Any patient who discontinues ravulizumab should be monitored for at least 16 weeks to detect haemolysis and other reactions. If signs and symptoms of haemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ravulizumab.

Treatment discontinuation for aHUS

There are no specific data on ravulizumab discontinuation. In a long-term prospective observational study, discontinuation of complement C5 inhibitor treatment (eculizumab) resulted in a 13.5-fold higher rate of TMA recurrence and showed a trend toward reduced renal function compared to patients who continued treatment.

If patients must discontinue treatment with ravulizumab, they should be monitored closely for signs and symptoms of TMA on an on-going basis. However, monitoring may be insufficient to predict or prevent severe TMA complications.

TMA complications post-discontinuation can be identified if any of the following is observed:

• At least two of the following laboratory results observed concurrently: a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ravulizumab treatment; an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ravulizumab treatment; or, an increase in serum LDH of 25% or more as compared to baseline or to nadir during ravulizumab treatment (results should be confirmed by a second measurement)
• any one of the following symptoms of TMA: a change in mental status or seizures or other extra-renal TMA manifestations including cardiovascular abnormalities, pericarditis, gastrointestinal symptoms/diarrhoea; or thrombosis.

If TMA complications occur after ravulizumab discontinuation, reinitiation of ravulizumab treatment should be considered, beginning with the loading dose and maintenance dose (see section 4.2).

Sodium content

Ultomiris 300 mg/3 mL and 1,100 mg/11 mL concentrates for solution for infusion

Once diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, this medicinal product contains 0.18 g sodium per 72 mL at the maximal dose, equivalent to 9.1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Ultomiris 300 mg/30 mL concentrate for solution for infusion

Once diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, this medicinal product contains 2.65 g sodium per 720 mL at the maximal dose, equivalent to 133% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

No interaction studies have been performed.

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.

Women of childbearing potential

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

Pregnancy

There are no clinical data from the use of ravulizumab in pregnant women. Nonclinical reproductive toxicology studies were not conducted with ravulizumab (see section 5.3). 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 (see section 5.3).

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

Breast-feeding

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.

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.

Ultomiris 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 (see section 4.4).

Tabulated list of adverse reactions

Table 5 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.

Table 5. 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. Please refer to section 4.4 for information on prevention and treatment of suspected meningococcal infection. 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%).

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Dilution should only use sodium chloride 9 mg/mL (0.9%) solution for injection as diluent.