Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Hansa Biopharma AB, P.O. Box 785, 220 07 Lund, Sweden
Infusion-related reactions have been reported with imlifidase administration in clinical studies (see section 4.8). If any serious allergic or anaphylactic reaction occurs, imlifidase therapy should be discontinued immediately and appropriate therapy initiated. Mild or moderate infusion-related reactions occurring during imlifidase treatment can be managed by temporarily interrupting the infusion, and/or by administration of medicinal products, such as antihistamines, antipyretics and corticosteroids. An interrupted infusion can be restarted when the symptoms have abated.
For kidney transplantation, ongoing serious infections of any origin (bacterial, viral or fungal) are considered a contraindication, and chronic infections such as HBV or HIV have to be well controlled. The temporary reduction of IgG by imlifidase must be taken into consideration.
The most common infections in patients with hypogammaglobulinemia are respiratory tract infections. Therefore, in addition to the standard of care infection prophylaxis in kidney transplantation in general (against Pneumocystis carinii, cytomegalovirus and oral candida), all patients should also receive prophylactic oral antibiotics covering respiratory tract pathogens for 4 weeks. Should a patient for any reason not be transplanted after imlifidase treatment, prophylactic oral antibiotics covering respiratory tract pathogens should still be given for 4 weeks.
Use of imlifidase and T-cell depleting induction therapy with or without memory B-cell depleting therapies may increase the risk of reactivation of live-attenuated vaccines and/or latent tuberculosis.
Due to the reduced IgG levels after treatment with imlifidase, there is a risk for a temporary reduction of vaccine protection for up to 4 weeks following imlifidase treatment.
AMR may occur as a consequence of rebound of donor-specific antibodies (DSA). Patients with very high levels of DSA before transplantation are more likely to experience early AMR that requires intervention. Most patients in the clinical studies had rebound of DSA that peaked between 7 and 21 days after imlifidase treatment, and AMR occurred in approximately 30% of the patients. All patients with AMR in clinical studies were successfully managed with standard of care treatment. The re-appearance of DSAs and increased risk of AMR in highly sensitised patients require physician’s previous experience from managing sensitised patients, resources and preparedness to diagnose and treat acute AMRs according to standard clinical practice. Management of patients should include close monitoring of HLA antibodies and serum or plasma creatinine as well as readiness to perform biopsies when AMR is suspected.
There is very limited experience in patients with a confirmed positive T-cell CDC-crossmatch test before imlifidase treatment (see section 5.1).
The potential influence of anti-imlifidase antibodies (ADA) on the efficacy and safety of a second imlifidase dose given within 24 hours of the first is expected to be negligible, since the production of ADA in response to the first dose has not yet started to develop.
Each clinic should follow its standard protocol for confirmation of crossmatch conversion from positive to negative. If complement-dependent cytotoxicity crossmatch (CDCXM) is used, the following needs to be considered to avoid false positive results: IgM has to be inactivated to be able to specifically assess the cytotoxic capacity of IgG. The use of an anti-human globulin (AHG) step should be avoided. If used, it should be confirmed that the AHG is directed against the Fc-part and not against the Fab-part of the IgG. Use of AHG, directed against the Fab-part, will not allow correct readout of a CDCXM in an imlifidase-treated patient.
Imlifidase is a cysteine protease that specifically cleaves IgG. As a consequence, IgG-based medicinal products may be inactivated if given in connection with imlifidase. Antibody-based medicinal products cleaved by imlifidase include, but are not limited to basiliximab, rituximab, alemtuzumab, adalimumab, denosumab, belatacept, etanercept, rabbit anti-thymocyte globulin (rATG) and intravenous immunoglobulin (IVIg) (see section 4.5 for recommended time intervals between administration of imlifidase and antibody-based medicinal products).
IVIg may contain neutralising antibodies against imlifidase, which may inactivate imlifidase if IVIg is given before imlifidase (see section 4.5).
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
Imlifidase specifically cleaves IgG; the species specificity results in degradation of all subclasses of human and rabbit IgG. As a consequence, medicinal products based on human or rabbit IgG may be inactivated if given in connection with imlifidase. Antibody-based medicinal products cleaved by imlifidase include, but are not limited to basiliximab, rituximab, alemtuzumab, adalimumab, denosumab, belatacept, etanercept, rATG and IVIg.
Imlifidase does not degrade equine anti-thymocyte globulin and no time interval between administrations needs to be considered. Eculizumab is not cleaved by imlifidase at the recommended dose level.
Table 1. Recommended time intervals for administration of antibody-based medicinal products after administration of imlifidase:
| Medicinal product | Recommended time interval after administration of 0.25 mg/kg imlifidase |
|---|---|
| equine anti-thymocyte globulin, eculizumab | No time interval needed (can be administered concomitantly with imlifidase) |
| intravenous immunoglobulin (IVIg) | 12 hours |
| alemtuzumab, adalimumab, basiliximab, denosumab, etanercept, rituximab | 4 days |
| rabbit anti-human thymocyte globulin (rATG), belatacept | 1 week |
Also, IVIg may contain neutralising antibodies against imlifidase, which may inactivate imlifidase if IVIg is given before imlifidase. The half-life of IVIg (3-4 weeks) should be considered before imlifidase administration to patients treated with IVIg. In clinical studies, IVIg was not administered within 4 weeks before imlifidase infusion.
There are no data from use of imlifidase in pregnant women since pregnancy is a contraindication to kidney transplantation.
Studies in rabbits do not indicate direct or indirect harmful effects of imlifidase with respect to embryonic/foetal development (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of imlifidase during pregnancy.
It is unknown whether imlifidase is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued before imlifidase exposure.
No specific studies on fertility and postnatal development have been conducted (see section 5.3).
Not relevant.
The most common serious adverse reactions in clinical studies were pneumonia (5.6%) and sepsis (3.7%). The most common adverse reactions were infections (16.7%) (including pneumonia (5.6%), urinary tract infection (5.6%) and sepsis (3.7%)), infusion site pain (3.7%), infusion related reactions (3.7%), alanine aminotransferase increased (3.7%), aspartate aminotransferase increased (3.7%), myalgia (3.7%), headache (3.7%) and flushing (3.7%).
The adverse reactions described in this section were identified in the clinical studies (N=54). The adverse reactions are presented according to MedDRA system organ class and frequency category. The frequency categories are defined as follows: 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:
Very common: Bacterial and viral infection
Common: Abdominal infection, Adenovirus infection, Catheter site infection, Infection, Influenza, Parvovirus infection, Pneumonia, Postoperative wound infection, Sepsis, Upper respiratory tract infection, Urinary tract infection, Wound infection
Common: Anaemia
Common: Transplant rejection
Common: Dizziness postural, Headache
Common: Scleral haemorrhage, Visual impairment
Common: Sinus tachycardia
Common: Flushing, Hypertension, Hypotension
Common: Dyspnoea
Common: Rash
Common: Myalgia
Common: Feeling hot, Infusion site pain
Common: Alanine aminotransferase (ALT) increased, Aspartate aminotransferase (AST) increased
Common: Infusion related reactions
In the clinical studies, 16.7% of the patients experienced an infection. Nine infections were serious and assessed as related to imlifidase in the clinical studies, where of 5 started within 30 days after imlifidase treatment. Eight of the 9 related serious infections had a duration of less than 30 days. The incidence and pattern (including infectious agent) of serious or severe infections were not different from those observed in kidney-transplanted patients in general (see section 4.4).
Infusion-related reactions, including dyspnoea and flushing were reported in 5.6% of the patients, one resulting in interruption of the imlifidase infusion and the patient not being transplanted. Except for one event of mild rash, all infusion-related reactions started on the day of imlifidase infusion and resolved within 90 minutes (see section 4.4).
Myalgia was reported for 2 patients (3.7%) in the clinical studies. One of the patients had severe myalgia without any findings of muscle damage.
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.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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