4.1. Therapeutic indications

Idefirix is indicated for desensitisation treatment of highly sensitised adult kidney transplant patients with positive crossmatch against an available deceased donor. The use of Idefirix should be reserved for patients unlikely to be transplanted under the available kidney allocation system including prioritisation programmes for highly sensitised patients.

4.2. Posology and method of administration

Treatment should be prescribed and supervised by specialist physicians experienced in the management of immunosuppressive therapy and of sensitised renal transplant patients.

Imlifidase is restricted to hospital use only.

Posology

The dose is based on patient body weight (kg). The recommended dose is 0.25 mg/kg administered as a single dose preferably within 24 hours before transplantation. One dose is adequate for crossmatch conversion in the majority of patients but, if needed, a second dose can be administered within 24 hours after the first dose.

After treatment with imlifidase, crossmatch conversion from positive to negative should be confirmed before transplantation (see section 4.4).

Premedication with corticosteroids and antihistamines should be given to reduce the risk of infusion reactions in accordance with transplant centre routines.

Since respiratory tract infections are the most common infections in patients with hypogammaglobulinemia, prophylactic oral antibiotics covering respiratory tract pathogens should be added to the standard of care for 4 weeks (see section 4.4).

Patients treated with imlifidase should, in addition, receive standard of care induction T-cell depleting agents with or without B-cell depleting agents (see section 5.1), i.e. imlifidase does not eliminate the need for standard of care immunosuppressive therapy.

Special populations

Elderly patients

Data on the use in patients older than 65 years are limited, but there is no evidence to suggest that dose adjustment is required in these patients.

Hepatic impairment

The safety and efficacy of imlifidase in patients with moderate or severe hepatic impairment have not been established. No data are available.

Paediatric population

The safety and efficacy of imlifidase in children and adolescents 0 to 18 years of age have not been established. No data are available.

Method of administration

Idefirix is for intravenous use only following reconstitution and dilution.

The entire, fully diluted infusion should be administered over a period of 15 minutes and must be administered with an infusion set and a sterile, inline, non-pyrogenic, low protein binding filter (pore size of 0.2 μm). Following administration, it is recommended that the intravenous line is flushed with 0.9% (9 mg/ml) solution of sodium chloride for infusion to ensure administration of the complete dose. Do not store any unused portion of the solution for infusion for re-use.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Ongoing serious infection.

- Thrombotic thrombocytopenic purpura (TTP). Patients with this blood disorder may be at risk of developing serum sickness.

4.4. Special warnings and precautions for use

Infusion-related reactions

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.

Infection and infection prophylaxis

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.

Vaccinations

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.

Antibody-mediated rejection (AMR)

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 anti-HLA (human leukocyte antigen) antibodies and serum or plasma creatinine as well as readiness to perform biopsies when AMR is suspected.

Patients with positive T-cell complement-dependent cytotoxicity (CDC) crossmatch test

There is very limited experience in patients with a confirmed positive T-cell CDC-crossmatch test before imlifidase treatment (see section 5.1).

Immunogenicity

The potential influence of anti-imlifidase antibodies (anti-drug 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.

Confirmation of crossmatch conversion

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 after imlifidase treatment: IgM has to be inactivated to be able to specifically assess the cytotoxic capacity of IgG and 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.

Antibody-based medicinal products

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).

Information on excipients

Idefirix contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

Idefirix contains 0.5 mg of polysorbate 80 in each mL. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the 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/fetal development (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Idefirix during pregnancy.

Breast-feeding

It is unknown whether imlifidase is excreted in human milk. A risk to the breast-fed child cannot be excluded.

Breast-feeding should be discontinued before Idefirix exposure.

Fertility

No specific studies on fertility and postnatal development have been conducted (see section 5.3).

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

Summary of the safety profile

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%).

Tabulated list of adverse reactions

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

MedDRA system organ class

Adverse reaction/

Frequency

Very common

Common

Infections and infestations

Bacterial and viral infection

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

Blood and lymphatic system disorders

Anaemia

Immune system disorders

Transplant rejection

Nervous system disorders

Dizziness postural

Headache

Eye disorders

Scleral haemorrhage

Visual impairment

Cardiac disorders

Sinus tachycardia

Vascular disorders

Flushing

Hypertension

Hypotension

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Skin and subcutanous tissue disorders

Rash

Musculoskeletal and connective tissue disorders

Myalgia

General disorders and administration site conditions

Feeling hot

Infusion site pain

Investigations

Alanine aminotransferase (ALT) increased

Aspartate aminotransferase (AST) increased

Injury, poisoning and procedural complications

Infusion-related reactions

Description of selected adverse reactions

Infections

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, whereof 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

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

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 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 Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is no experience with doses higher than the recommended. In the event of an overdose, the patient should be monitored closely and treated symptomatically.

No specific antidote exists, but depletion of IgG can be restored by administration of IVIg.