Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Horizon Therapeutics Ireland DAC, 70 St. Stephens Green, Dublin 2, D02 E2X4, Ireland
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Inebilizumab can cause infusion-related reactions and hypersensitivity reactions, which can include headache, nausea, somnolence, dyspnoea, fever, myalgia, rash, or other symptoms. Infusion-related reactions were most common with the first infusion, but were observed during subsequent infusions. Although rare, serious infusion reactions did occur in clinical trials of inebilizumab (see section 4.8).
Premedication with a corticosteroid (e.g., methylprednisolone 80-125 mg intravenous or equivalent), an antihistamine (e.g., diphenhydramine 25-50 mg orally or equivalent), and an anti-pyretic (e.g., paracetamol 500-650 mg orally or equivalent) should be administered (see section 4.2). A 2-week course of oral corticosteroids (plus a 1-week taper) was administered at the start of inebilizumab treatment in the pivotal study (see section 5.1).
The patient should be monitored for infusion-related reactions. Management recommendations for infusion reactions depend on the type and severity of the reaction. For life-threatening infusion reactions, treatment should be stopped immediately and permanently, and appropriate supportive treatment should be administered. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
The patient should be monitored for infusion reactions for at least one hour after the completion of the infusion.
Inebilizumab causes reduction in peripheral blood lymphocyte count and Ig levels consistent with the mechanism of action of B-cell depletion. Reduction of neutrophil counts were also reported. Therefore, inebilizumab may increase the susceptibility to infections (see section 4.8).
A recent (i.e. within 6 months) complete blood cell count including differentials and immunoglobulins should be obtained before initiation of inebilizumab. Assessments of CBC including differentials and immunoglobulins are also recommended periodically during treatment and after discontinuation of treatment until B-cell repletion. Prior to every infusion of inebilizumab, it should be determined whether there is a clinically significant infection. In case of infection, infusion of inebilizumab should be delayed until the infection resolves. Patients should be instructed to promptly report symptoms of infection to their physician. Treatment discontinuation should be considered if a patient develops a serious opportunistic infection or recurrent infections if Ig levels indicate immune compromise.
The most common infections reported by inebilizumab-treated NMOSD patients across the randomised controlled period (RCP) and the open-label period (OLP) included urinary tract infection (26.2%), nasopharyngitis (20.9%), upper respiratory tract infection (15.6%), influenza (8.9%), and bronchitis (6.7%).
Risk of HBV reactivation has been observed with other B-cell-depleting antibodies. Patients with chronic HBV were excluded from clinical trials with inebilizumab. HBV screening should be performed in all patients before initiation of treatment with inebilizumab. Inebilizumab should not be administered to patients with active hepatitis due to HBV who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients who are chronic carriers of HBV [HBsAg+] should consult a liver disease expert before starting and during treatment (see section 4.3).
Patients positive for HCV were excluded from clinical trials with inebilizumab. Baseline screening for HCV is required to detect and start treatment prior to initiating inebilizumab treatment.
Prior to initiating inebilizumab, patients should be evaluated for active tuberculosis and tested for latent infection. For patients with active tuberculosis or positive tuberculosis screening without a history of appropriate treatment, infectious disease experts should be consulted before starting treatment with inebilizumab.
PML is an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV) that typically occurs in patients who are immunocompromised, and that may lead to death or severe disability. JCV infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies.
In inebilizumab clinical trials, one subject died following the development of new brain lesions for which a definitive diagnosis could not be established. However, the differential diagnosis included atypical NMOSD attack, PML, or acute disseminated encephalomyelitis.
Physicians should be vigilant for clinical symptoms or Magnetic Resonance Imaging (MRI) findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
At the first sign or symptom suggestive of PML, treatment with inebilizumab should be suspended until PML has been excluded. Further evaluation, including consultation with a neurologist, MRI scan preferably with contrast, cerebrospinal fluid testing for JC viral DNA, and repeat neurological assessments, should be considered. If confirmed, treatment with inebilizumab should be discontinued.
Cases of late onset of neutropenia have been reported (see section 4.8). Although some cases were Grade 3, the majority of cases were Grade 1 or 2. Cases of late onset of neutropenia have been reported at least 4 weeks after the latest infusion of inebilizumab. In patients with signs and symptoms of infection, measurement of blood neutrophils is recommended.
Patients in a severely immunocompromised state must not be treated until the condition resolves (see section 4.3).
Inebilizumab has not been tested together with other immunosuppressants. If combining it with another immunosuppressive therapy, consider the potential for increased immunosuppressive effects.
Patients with a known congenital or acquired immunodeficiency, including HIV infection or splenectomy, have not been studied.
All immunisations should be administered according to immunisation guidelines at least 4 weeks prior to initiation of inebilizumab. The efficacy and safety of immunisation with live or live-attenuated vaccines following inebilizumab therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.
Infants of mothers exposed to inebilizumab during pregnancy should not be administered live or live-attenuated vaccines before confirming recovery of B-cell counts in the infant. Depletion of B cells in these exposed infants may increase the risks from live or live-attenuated vaccines. Non-live vaccines, as indicated, may be administered prior to recovery from B-cell and Ig-level depletion, but consultation with a qualified specialist should be considered to assess whether a protective immune response was mounted.
The time to B-cell repletion following administration of inebilizumab is not known. B-cell depletion below the lower limit of normal was maintained in 94% of patients for at least 6 months following treatment.
As a precautionary measure, it is preferable to avoid the use of inebilizumab during pregnancy and in women of childbearing potential not using contraception (see section 4.6). Patients should be instructed that if they are pregnant or plan to become pregnant while taking inebilizumab, they should inform their healthcare provider. Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) while receiving Uplizna and for 6 months after the last administration of Uplizna.
Immunomodulatory medicinal products may increase the risk of malignancy. On the basis of limited experience with inebilizumab in NMOSD (see section 4.8), the current data do not seem to suggest any increased risk of malignancy. However, the possible risk for the development of solid tumours cannot be excluded at this time.
This medicinal product contains 48.3 mg sodium per dose, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
No interaction studies have been performed.
The primary elimination pathway for therapeutic antibodies is clearance by the reticuloendothelial system. Cytochrome P450 enzymes, efflux pumps, and protein-binding mechanisms are not involved in the clearance of therapeutic antibodies. Therefore, the potential risk of pharmacokinetic interactions between inebilizumab and other medicinal products is low.
The efficacy and safety of immunisation with live or live-attenuated vaccines following inebilizumab therapy has not been studied. The response to vaccination could be impaired when B cells are depleted. It is recommended that patients complete immunisations prior to the start of inebilizumab therapy (see section 4.4).
Inebilizumab has been tested, and is intended to be used, as monotherapy for this indication. No data are available on the safety or efficacy of combining inebilizumab with other immunosuppressants. In the pivotal study, a 2-week course of oral corticosteroids (plus a 1-week taper) was given to all subjects following the first administration of inebilizumab.
Concomitant usage of inebilizumab with immunosuppressants, including systemic corticosteroids, may increase the risk of infection. The effects of inebilizumab on B cells and immunoglobulins may persist for 6 months or longer following its administration.
When initiating inebilizumab after other immunosuppressive therapies with prolonged immune effects or initiating other immunosuppressive therapies with prolonged immune effects after inebilizumab, the duration and mode of action of these medicinal products should be taken into account because of potential additive immunosuppressive effects (see section 5.1).
Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) while receiving Uplizna and for 6 months after the last administration of Uplizna.
There are limited amount of data from the use of inebilizumab in pregnant women. Inebilizumab is a humanised IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier.
Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell-depleting antibodies during pregnancy.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity; however, they have shown a B-cell depletion in the foetal livers of progeny (see section 5.3).
Treatment with inebilizumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus.
In case of exposure during pregnancy, depletion of B cells may be expected in newborns due to the pharmacological properties of the product and findings from animal studies (see section 5.3). The potential duration of B-cell depletion in infants exposed to inebilizumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown (see sections 4.4 and 5.1). Consequently, newborns should be monitored for B-cell depletion and vaccinations with live virus vaccines, such as Bacillus Calmette-Guérin (BCG) vaccine, should be postponed until the infant’s B-cell count has recovered (see section 4.4).
The use of inebilizumab in women during lactation has not been studied. It is unknown whether inebilizumab is excreted in human milk. In humans, excretion of IgG antibodies in milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards. Consequently, a risk to the breast-fed child cannot be excluded during this short period. Afterwards, Uplizna could be used during breast feeding if clinically needed. However, if the patient was treated with Uplizna up to the last few months of pregnancy, breast feeding can be started immediately after birth.
There are limited data on the effect of inebilizumab on human fertility; however, studies in animals have shown reduced fertility. The clinical significance of these nonclinical findings is not known (see section 5.3).
The pharmacological activity and adverse reactions reported to date suggest that inebilizumab has no or negligible influence on the ability to drive and use machines.
The most frequently reported adverse reactions by inebilizumab-treated patients were urinary tract infection (26.2%), nasopharyngitis (20.9%), upper respiratory tract infection (15.6%), arthralgia (17.3%), and back pain (13.8%) across both the RCP and OLP. The most frequently reported serious adverse reactions by inebilizumab-treated patients across the RCP and OLP were infections (11.1%) (including urinary tract infections (4.0%), pneumonia (1.8%)) and NMOSD (1.8%).
Adverse reactions reported in the clinical trial of inebilizumab in NMOSD are listed in Table 2 according to the following frequency categories: 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), not known (cannot be estimated from the available data).
Table 2. Adverse reactions:
| MedDRA System Organ Class | Adverse reaction | Frequency |
|---|---|---|
| Infections and infestations | Urinary tract infection, respiratory tract infection, nasopharingitis, influenza | Very Common |
| Pneumonia, cellulitis, herpes zoster, sinusitis | Common | |
| Sepsis, subcutaneous abscess, bronchiolitis | Uncommon | |
| Blood and lymphatic system disorders | Lymphopenia, Neutropenia, Late-onset neutropenia | Common |
| Musculoskeletal and connective tissue disorders | Arthralgia, back pain | Very Common |
| Investigations | Immunoglobulins decreased | Very Common |
| Injury, poisoning and procedural complications | Infusion-related reaction | Very Common |
Inebilizumab can cause infusion-related reactions, which can include headache, nausea, somnolence, dyspnoea, fever, myalgia, rash, or other symptoms. All patients were given premedication. Infusion reactions were observed in 9.2% of NMOSD patients during the first course of inebilizumab compared to 10.7% of placebo-treated patients. Infusion-related reactions were most common with the first infusion but were observed during subsequent infusions. The majority of infusion-related reactions reported in inebilizumab-treated patients were either mild or moderate in severity.
An infection was reported by 74.7% of NMOSD patients treated with inebilizumab across the RCP and OLP. The most common infections included urinary tract infection (26.2%), nasopharyngitis (20.9%), and upper respiratory tract infection (15.6%), influenza (8.9%), and bronchitis (6.7%).
Serious infections reported by more than one inebilizumab-treated patient were urinary tract infection (4.0%) and pneumonia (1.8%). See section 4.4 for action to be taken in case of infection.
During the RCP, no opportunistic infections occurred in either treatment group, and a single Grade 4 infectious adverse reaction (atypical pneumonia) occurred in a patient treated with inebilizumab. During the OLP, 2 inebilizumab-treated patients (0.9%) experienced an opportunistic infection (one of which was not confirmed) and 3 inebilizumab-treated patients (1.4%) experienced a Grade 4 infectious adverse reaction. See section 4.4 for action to be taken in case of infection.
Consistent with its mechanism of action, average immunoglobulin levels decreased with inebilizumab use. At the end of the 6.5-month RCP, the proportion of patients with levels below the lower limit of normal was as follows: IgA 9.8% inebilizumab and 3.1% placebo, IgE 10.6% inebilizumab and 12.5% placebo, IgG 3.8% inebilizumab and 9.4% placebo, and IgM 29.3% inebilizumab and 15.6% placebo. A single adverse reaction of IgG decreased was reported (Grade 2, during the OLP). The proportion of inebilizumab-treated patients with IgG levels below the lower limit of normal at year 1 was 7.4% and at year 2 was 9.9%. With a median exposure of 3.2 years, the frequency of moderate IgG reduction (300 to <500 mg/dL) was 14.2% and the frequency of severe IgG reduction (<300 mg/dL) was 3.6%.
After 6.5 months of treatment, neutrophil counts between 1.0-1.5 x109/L (Grade 2) were observed in 7.5% of inebilizumab-treated patients versus 1.8% of placebo-treated patients. Neutrophil counts between 0.5-1.0 x109/L (Grade 3) were observed in 1.7% of inebilizumab-treated patients versus 0% of placebo-treated patients. Neutropenia was generally transient and was not associated with serious infections.
After 6.5 months of treatment, a reduction in lymphocyte counts was observed more commonly in patients treated with inebilizumab than placebo: lymphocyte counts between 500 - <800/mm³ (Grade 2) were observed in 21.4% of inebilizumab-treated patients versus 12.5% of placebo-treated patients. Lymphocyte counts between 200 - <500/mm³ (Grade 3) were observed in 2.9% of inebilizumab-treated patients versus 1.8% of placebo-treated patients. This finding is consistent with the mechanism of action of B-cell depletion since B cells are a subset of the lymphocyte population.
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.
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