UPLIZNA

/ Amgen

Initial doses: The recommended loading dose is 300 mg (3 vials of 100 mg) intravenous infusion followed 2 weeks later by a second 300 mg intravenous infusion.
Maintenance doses: The recommended maintenance dose is 300 mg intravenous infusion every 6 months. Inebilizumab is for chronic treatment.
See prescribing information for full details

Monotherapy for the treatment of adult patients with neuromyelitis optica spectrum disorders (NMOSD) who are anti-aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive.

* Hypersensitivity to the active substance(s) or to any of the excipients.
* Severe active infection, including active chronic infection such as hepatitis B
* Active or untreated latent tuberculosis
* History of progressive multifocal leukoencephalopathy (PML)
* Severely immunocompromised state
* Active malignancies

Infusion-related reactions and hypersensitivity
nebilizumab 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.
Before the infusion
Premedication with a corticosteroid an antihistamine and an anti-pyretic should be administered. A 2-week course of oral corticosteroids (plus a 1-week taper) was administered at the start of inebilizumab treatment in the pivotal study
During the infusion
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.
After the infusion
The patient should be monitored for infusion reactions for at least one hour after the completion of the infusion.
Infections
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. 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%).
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.
Hepatitis B virus reactivation
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.
Hepatitis C virus
Baseline screening for HCV is required to detect and start treatment prior to initiating inebilizumab treatment.
Tuberculosis
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.
Progressive multifocal leukoencephalopathy (PML)
JCV infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies.
Clinical symptoms or Magnetic Resonance Imaging (MRI) findings suggestive of PML should be closely monitored. Typical symptoms of PML are diverse, progress over days to weeks, and may include progressive weakness on one side of the body, clumsiness of the limbs, vision disturbances, and cognitive changes such as impaired thinking, memory, or orientation, potentially leading to confusion and personality changes. At the first sign or symptom suggestive of PML, treatment with inebilizumab should be suspended until PML is ruled out. If PML is confirmed, inebilizumab treatment should be discontinued.
Late neutropenia
Cases of late onset of neutropenia have been reported. Although some cases were Grade 3, most 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.
Treatment of severely immunocompromised patients
Patients in a severely immunocompromised state must not be treated until the condition resolves.
Inebilizumab has not been tested together with other immunosuppressants. If combining it with another immunosuppressive therapy, consider the potential for increased immunosuppressive effects.
Vaccinations
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. 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.
B-cell repletion time
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.
Pregnancy
As a precautionary measure, it is preferable to avoid the use of inebilizumab during pregnancy and in women of childbearing potential. Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) while receiving this medical product and for 6 months after the last administration.
Malignancy
Immunomodulatory medicinal products may increase the risk of malignancy. Based on limited experience with inebilizumab in NMOSD, 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.
See prescribing information for full details.

Very Common: urinary tract infection, respiratory tract infection, nasopharyngitis, influenza, arthralgia, back pain, immunoglobulins decreased, infusion-related reaction.
Common: pneumonia, cellulitis, herpes zoster, sinusitis, lymphopenia, neutropenia, late-onset neutropenia
See prescribing information for full details.

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.
Vaccinations
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.
Immunosuppressants
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 considered because of potential additive immunosuppressive effects.
See prescribing information for full details.

Pregnancy: 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. Treatment with inebilizumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus. 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.
Lactation: 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, this medical product could be used during breast feeding if clinically needed. However, if the patient was treated with inebilizumab up to the last few months of pregnancy, breast feeding can be started immediately after birth.

The highest dose of inebilizumab tested in autoimmune patients was 1200 mg, administered as two 600 mg intravenous infusions separated by 2 weeks. The adverse reactions were similar to what was observed in the inebilizumab pivotal clinical study.
There is no specific antidote in the event of an overdose; the infusion should be interrupted immediately and the patient should be observed for infusion-related reactions. The patient should be closely monitored for signs or symptoms of adverse reactions and supportive care instituted as required.