Xembify 200 mg/mL solution for subcutaneous injection

Replacement therapy in adults, children and adolescents (0-18 years) in:

• Primary immunodeficiency syndromes (PID) with impaired antibody production (see section 4.4).

• Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (CLL) in whom prophylactic antibiotics have failed or are contra-indicated.

• Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients.

• Hypogammaglobulinaemia in patients pre- and post- allogeneic haematopoietic stem cell transplantation (HSCT).

Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

Posology

The dose and dose regimen are dependent on the indication.

Replacement therapy

The product should be administered via the subcutaneous route.

In replacement therapy the dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dose regimens are given as a guideline.

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6 g/L and aim to be within the reference interval of serum IgG for age. A loading dose of at least 0.2 to 0.5 g/kg (1 to 2.5 mL/kg) body weight (bw) may be required. This may need to be divided over several days, with a maximal daily dose of 0.1 to 0.15 g/kg bw.

After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals (approximately once per week) to reach a cumulative monthly dose of the order of 0.4 - 0.8 g/kg bw. Each single dose may need to be injected at different anatomic sites.

Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dose and aim for higher trough levels.

Elderly

As the dose is given by body weight and adjusted to the clinical outcome of the above mentioned conditions, the dose in the elderly population is not considered to be different from that in patients 18 to 65 years of age.

In clinical studies Xembify was evaluated in 5 subjects with PID >65 years of age and no specific dose adjustments were necessary to achieve the desired serum IgG levels.

Paediatric population

The posology in children and adolescents (0-18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome in replacement therapy indications.

Xembify was evaluated in 43 paediatric subjects with PID aged 2 to 16 years (inclusive), which included 28 subjects 12 years of age or younger. No paediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.

Method of administration

For subcutaneous use only.

Subcutaneous infusion for home treatment must be initiated and monitored by a health care professional experienced in the guidance of patients for home treatment. Infusion pumps appropriate for subcutaneous administration of immunoglobulins can be used. The patient or a caregiver must be instructed in the use of an infusion pump, the infusion techniques, the keeping of treatment diary, recognition of and measures to be taken in case of severe adverse reactions.

Xembify may be injected into sites such as abdomen, thigh, upper arm, and lateral hip.

The recommended initial infusion rate depends on the individual needs of the patient. Adjustment of the infusion rate and infusion volume per site is based on subject tolerablility.

It is recommended to use an initial administration speed of 10 mL/hr/infusion site. If well tolerated (see section 4.4), the rate of administration may be increased at intervals of at least 10 minutes to a maximum of 20 mL/hr/infusion site for paediatric patients and to a maximum of 25 mL/hr/infusion site for adults for the initial two infusions.

If well tolerated (see section 4.4 ) for two infusions, the infusion speed can gradually be increased to 35 mL/hr/site.

More than one pump can be used simultaneously. The amount of product infused into a particular site varies. In infants and children infusion sites may be changed every 5-15 mL. In adults doses over 30 mL may be divided according to patient preference. There is no limit to the number of infusion sites. Infusion sites should be at least 5 cm apart. The infusion sites should be rotated and avoid bony prominences.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4). Xembify must not be given intravascularly or intramuscularly.

Patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.

IgA deficient patients with antibodies against IgA and history of hypersensitivity to human immune globulin treatment.

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.

If Xembify is accidentally administered into a blood vessel patients could develop shock.

The recommended infusion rate given under section 4.2 must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.

Certain adverse reactions may occur more frequently in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion.

Potential complications can often be avoided by:

• initially injecting the product slowly (not to exceed 25 mL/hr/site);

• ensuring that patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients naïve to human normal immunoglobulin, patients switched from an alternative immunoglobulin product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs.

All other patients should be observed for at least 20 minutes after administration.

In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the adverse reaction. Allergic or anaphylactic type reactions require immediate discontinuation.

In case of shock, standard medical treatment for shock should be implemented.

Hypersensitivity

True allergic reactions are rare. They can particularly occur in patients with anti-IgA antibodies who should be treated with particular caution. Patients with anti-IgA antibodies, in whom treatment with subcutaneous IgG products remains the only option, should be treated with Xembify only under close medical supervision.

Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

Thromboembolism

Arterial and venous thromboembolic events including myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism have been associated with the use of immunoglobulins. Patients should be sufficiently hydrated before use of immunoglobulins. Caution should be exercised in patients with preexisting risk factors for thrombotic events (such as use of estrogens, advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilization, severely hypovolemic patients, patients with diseases which increase blood viscosity).

Patients should be informed about first symptoms of thromboembolic events including shortness of breath, pain and swelling of a limb, focal neurological deficits and chest pain and should be advised to contact their physician immediately upon onset of symptoms.

Aseptic Meningitis Syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with subcutaneous immunoglobulin treatment; the symptoms usually begin within several hours to 2 days following treatment. AMS may occur more in females than in males. AMS is characterised by the following signs and symptoms: severe headache, neck stiffness, drowsiness, fever, photophobia, nausea, and vomiting. Patients exhibiting signs and symptoms of AMS should receive a thorough neurological examination, including CSF studies, to rule out other cases of meningitis. Discontinuation of immunoglobulin treatment may result in remission of AMS within several days without sequelae.

Patients should be informed about first symptoms of AMS. AMS may occur more frequently in the context of high doses and/or rapid infusion.

Renal dysfunction/failure

Severe renal adverse reactions have been reported in patients receiving immune globulin treatment, particularly those products containing sucrose (Xembify does not contain sucrose). These include acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis. Factors that increase the risk of renal complications include, but are not limited to preexisting renal insufficiency, diabetes mellitus, hypovolemia, concomitant nephrotoxic medicinal products, age over 65, sepsis, hyperviscosity and paraproteinemia.

Patients with renal impairment should be monitored as well, in particular patients with preexisting renal insufficiency or risk of acute renal failure.

Interference with serological testing

After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies for example the direct antiglobulin test (DAT, direct Coombs' test). In case of high doses or non-O blood group haemolysis can occur, thus monitoring is recommended.

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation / removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C (HCV) virus, and for the non-enveloped hepatitis A virus (HAV). The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

It is strongly recommended that every time that Xembify is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Paediatric population

The listed warnings and precautions apply to both adults and children.

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this medicinal product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year.

Therefore, patients receiving measles vaccine should have their antibody status checked.

Paediatric population

The listed interactions apply to both adults and the paediatric population.

Elderly

The listed interactions apply to the elderly.

Pregnancy

The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers.

Immunoglobulin products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.

Breast-feeding

Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry.

Fertility

Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

Xembify has minor influence on the ability to drive and use machines, e.g. dizziness (see section 4.8). Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

Summary of the safety profile

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.

Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

Local reactions at infusion sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash, may frequently occur.

For safety information with respect to transmissible agents, see section 4.4.

Tabulated list of adverse reactions

The safety of Xembify administered subcutaneously was evaluated in two prospective, open-label, phase 3, non-controlled multicentre studies in 110 male or female subjects, ages 2-72 years with primary immune deficiency (PID) previously treated with IVIg/SCIg. Forty-nine (49) subjects were in the North American study and 61 subjects in the European study.

Across both studies eight subjects discontinued Xembify due to adverse reactions, all were mild or moderate in severity except for aortic valve incompetence due to congenital anomaly.

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to 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). Within each frequency grouping the adverse reactions are presented in the order of decreasing seriousness (all non-serious).

Frequency of Adverse Reactions (ADRs) with Xembify in 1% or more of Subjects and per infusion in the clinical studies

^a The frequency per subject is calculated using the number of subjects with ADRs excluding infections for which there was at least a possibility of causal relationship with Xembify divided by the total number of subjects.

^b The frequency per infusion is calculated using the number of infusions associated with ADRs excluding infections for which there was at least a possibility of causal relationship with Xembify divided by the total number of infusions.

Postmarketing experience

The following adverse reactions have been identified and reported during the postmarketing use of Xembify: local infusion site reaction such as erythema and swelling, dyspnoea, fatigue, pain, nausea and headache. It is not always possible to reliably estimate the frequency of these reactions.

Paediatric population

Frequency, type and severity of adverse reactions in paediatric population are expected to be the same as in adults.

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.

Consequences of an overdose are not known.

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for extravascular administration, ATC code: J06BA01

Mechanism of action

Xembify supplies a broad spectrum of opsonizing and neutralizing immunoglobulin G (IgG) antibodies against bacterial, viral, parasitic, and mycoplasmal agents and their toxins. The role of these antibodies and the mechanism of action of Xembify are not fully understood.

Pharmacodynamic effects

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

Clinical efficacy in PID

In the European study, a total of 61 subjects with primary immunodeficiency syndromes aged between 2 years and 69 years were treated with Xembify for up to 52 weeks. The mean dose administered each week was 125.5 mg/kg bw. Sustained IgG trough levels with mean concentration of 947.64 mg/dL were thereby achieved during the treatment period. Subjects received a total of 3045 weekly Xembify infusions. The annual rate of serious bacterial infections (SBIs) was 0.017 per subject-year (1-sided 99% upper confidence limit 0.036), which reflected one subject with pneumonia treated with oral antibiotics as an outpatient with resolution in 4 days.

In the North American study, a total of 49 subjects with primary immunodeficiency syndromes aged between 2 years and 72 years were treated with Xembify for up to 24 weeks. The mean dose administered each week was 178.9 mg/kg bw. Sustained IgG trough levels with a mean concentration of 1244.84 mg/dL were thereby achieved during the treatment period. Subjects received in total 1053 weekly Xembify infusions. The annual rate of SBIs during Xembify treatment was 0.049 per subject-year (1-sided 99% upper confidence limit 0.110), which reflected one subject with sepsis due to cat bite.

Paediatric population

The safety and effectiveness of Xembify have been established in paediatric subjects. Xembify was evaluated in 28 paediatric subjects with PID aged 2 years to 12 years of age (inclusive) and in 15 paediatric subjects aged older than 12 years to less than 17 years. There were no differences in the pharmacokinetics, safety and efficacy profiles as compared with adult subjects. No paediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. No differences were seen in the pharmacodynamic properties between adult and paediatric study patients with PID.

The European Medicines Agency has waived the obligation to submit the results of studies with Xembify in all subsets of the paediatric population in primary immunodeficiency for preterm and/or term newborn infants (0-27 days) and for infants and toddlers (28 days to 23 months). See 4.2 for information on paediatric use.

Elderly

No overall differences in safety or efficacy were observed between PID subjects >65 years and PID subjects 18 to 65 years of age. In the clinical studies Xembify was evaluated in 5 patients with PID >65 years of age.

Absorption

Following subcutaneous administration of Xembify, peak serum levels are achieved after approximately three days.

Distribution

Weekly dosing

In a clinical trial with Xembify (n = 61) in Europe, the subjects achieved sustained IgG trough levels (median 909.10 mg/dL) over a period of 52 weeks when receiving median weekly doses of 113.0 mg/kg bw. Data from the clinical trial of Xembify show that serum IgG trough levels can be maintained by dosing regimens of 400 mg to 848 mg/kg bw/4 weeks.

Summary of Steady-State Trough Concentrations of Total IgG during the Previous Regimen and SC Phases (IgG Population)

The pharmacokinetics of Xembify were evaluated in the phase 3 efficacy and safety study in 27 adult patients with PID. The pharmacokinetic results are presented in the table below.

Pharmacokinetic Parameters of Serum Total IgG for Xembify (PK Population)

Once weekly, biweekly or more frequent dosing (2-7 times per week)

Pharmacokinetic (PK) characterization of biweekly or more frequent dosing of Xembify was undertaken using population PK-based modelling and simulation. Serum IgG concentration data consisted of 1841 samples from 95 unique paediatric and adult subjects with PID. Compared with weekly administration, PK modelling and simulation predicted that administration of Xembify on a biweekly basis at double the weekly dose results in overlapping IgG exposure across an entire 2-week interval. In addition, PK modelling and simulation predicted that for the same total weekly dose, Xembify infusions given 2-7 times per week (frequent dosing) results also in overlapping IgG exposure across the entire treatment interval.

Elimination

IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

Paediatric population

There are no theoretical or observed differences in the action of immunoglobulins in children compared to adults.

Immunoglobulins are a normal constituent of the human body. Non-clinical data reveal no special risk for humans based on toxicology testing.

Glycine (E 640)

Polysorbate 80 (E 433)

Water for injections

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

3 years

Once the vial has been opened, it is recommended that the solution should be used immediately.

• Store in a refrigerator (2 ºC – 8 ºC).

• Do not freeze.

• Keep the vial in the outer carton in order to protect from light.

• Administer as soon as possible after Xembify is transferred from the vial into a syringe.

For storage conditions after first opening of the medicinal product, see section 6.3.

5, 10, 20, or 50 mL of solution in a clear glass vial with a chlorobutyl stopper, an aluminum overseal, plastic top and shrink band that guarantee the intactness of packaging.

Pack sizes:

1 or 10 vials containing 1 g human normal immunoglobulin in 5 mL solution for subcutaneous injection

1, 10 or 20 vials containing 2 g human normal immunoglobulin in 10 mL solution for subcutaneous injection

1 or 20 vials containing 4 g human normal immunoglobulin in 20 mL solution for subcutaneous injection

1 or 10 vials containing 10 g human normal immunoglobulin in 50 mL solution for subcutaneous injection

Each carton contains 1, 10 or 20 vials Xembify and 1 Patient Information Leaflet.

Not all pack sizes may be marketed.

The medicinal product should be brought to room or body temperatures (20 ºC to 37 ºC) before use.

Do not shake.

Products should be inspected visually prior to administration. Solutions that are discoloured, cloudy or have deposits should not be used.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Instructions for use

For subcutaneous infusion only.

Prior to use, allow the solution to reach room or body temperatures (20 ºC to 37 ºC).

Do not shake.

Follow the steps below and use aseptic technique to administer Xembify.

1. Inspect the vials: inspect for clarity, color, and expiration date.

2. Prepare for infusion:

Gather supplies: Xembify vial(s), ancillary supplies, sharps container, patient's treatment diary/logbook, and the infusion pump.

Prepare a clean work area.

Wash hands.

3. Remove the protective cap from the vial to expose the central portion of the stopper.

4. Wipe the stopper with alcohol and allow to dry.

6. Use Xembify as soon as practicable, to avoid the potential formation of particles caused by siliconized syringes.

7. Follow the manufacturer's instructions for preparing the pump and administration tubing. Be sure to prime the administration tubing to ensure that no air is left in the tubing or needle by filling the tubing/needle with Xembify.

12. Repeat priming and needle insertion steps using a new needle, administration tubing and a new infusion site. Secure the needle in place by applying sterile gauze or transparent dressing over the site.

13. For the initial two infusions, the infusion speed will start at 10 mL per hour per infusion site. If well tolerated and you do not experience side effects (see section 4.4), the speed may be increased every 10 minutes to a maximum of 20 mL per hour per infusion site for children and adolescents, and 25 mL per hour per infusion site for adults. If well tolerated for two infusions, the infusion speed can gradually be increased to 35 mL per hour per infusion site.

Ensure that the infusion sites are at least 5 cm apart for patients of all ages. The number of infusion sites is at healthcare provider discretion. In adults doses over 30 mL may be divided according to patient preference. There is no limit to the number of infusion sites.

Children will require less total volume for a specific Xembify dose (mg/kg body weight) than adults. The healthcare provider may choose a smaller volume/site for children and/or fewer infusion sites to achieve the target total dose, depending on the needs of the child.

The total dose volume of Xembify is divided by the desired volume (mL/site) to obtain number of infusion sites to be used.

14. Record information about the infusion (e.g., lot number, expiration date, dose, date, time, infusion site location(s), side effects) in a patient treatment record or infusion log.

15. Discard the needle(s) and infusion line(s) in an appropriate container. Follow the manufacturer's instructions for storage of the infusion pump.

16. Discard partially used vial(s).