HIZENTRA Solution for injection Ref.[27859] Active ingredients: Human normal immunoglobulin G

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.

Hizentra is for subcutaneous use only. If Hizentra is accidentally administered into a blood vessel, patients could develop shock.

The recommended infusion rate given under section 4.2 should be adhered to. Patients should be closely monitored and carefully observed for any adverse events 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 treatment has been stopped for more than eight weeks.

Potential complications can often be avoided by ensuring that patients:

• are not sensitive to human normal immunoglobulin, by initially injecting the product slowly (see section 4.2);
• are carefully monitored for any symptoms throughout the infusion period. In particular, patients naïve to human normal immunoglobulin, patients switched from an alternative 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 reactions.

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

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment should be administered.

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 switched to Hizentra 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. Caution should be exercised in patients with pre-existing risk factors for thrombotic events (such as 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. Patients should be sufficiently hydrated before use of immunoglobulins.

Aseptic Meningitis Syndrome (AMS)

AMS has been reported with use of IVIg or SCIg. The syndrome usually begins within several hours to 2 days following immune globulin treatment. 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 causes of meningitis. Discontinuation of immunoglobulin treatment may result in remission of AMS within several days without sequelae.

Information on safety with respect to 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 HIV, HBV and HCV and for the non-enveloped viruses HAV and 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.

Interference with serological testing

After infusion 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 allo-antibodies (Coombs' test).

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per vial/syringe, that is to say essentially ‘sodium-free’.

Paediatric population

The same warnings and precautions apply to the paediatric population.

Elderly

The same warnings and precautions apply to the elderly.

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 same interactions may occur in the paediatric population.

Elderly

The same interactions may occur in the elderly.

Pregnancy

Data from prospective clinical trials on the use of human normal immunoglobulin in pregnant women is limited. Therefore, Hizentra should only be given with caution to pregnant women. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus or the neonate are to be expected.

Continued treatment of the pregnant woman ensures a passive immunity for the neonate.

Breast-feeding

Data from prospective clinical trials on the use of human normal immunoglobulin in breast feeding women is limited. Therefore, Hizentra should only be given with caution to breast-feeding mothers. Clinical experience with immunoglobulins suggests however that no harmful effects on the neonate are to be expected. Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate.

Fertility

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

Hizentra 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 safety profile

Adverse reactions such as chills, headache, 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.

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

Tabulated list of adverse reactions

Adverse Reactions (ARs) have been collected in Hizentra clinical trials from 7 phase III studies in patients with primary immunodeficiency (n=231), 2 phase IV studies in patients with PID (n=74), 1 phase III study (n=115), and 1 extension study (n=82) in patients with CIDP (total N=502 patients; 26,646 infusions). The ADRs reported in these clinical studies are summarised and categorised according to the MedDRA System Organ Class (SOC and Preferred Term level) and frequency below.

Frequency per patient or per infusion has been evaluated using the following criteria: 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). For spontaneous post-marketing ADRs, the reporting frequency is categorised as unknown. Within each frequency grouping, the adverse reactions are presented in the order of decreasing frequency.

Frequency of Adverse Drug Reactions (ADR) associated with Hizentra obtained from clinical studies and post-marketing surveillance, reporting rate per patient or per infusion:

Paediatric population

Clinical trials with Hizentra showed a similar overall safety profile in paediatric and adult patients with PID. Hizentra was not evaluated in clinical studies in paediatric patients with CIDP who were under the age of 18.

Elderly

The same adverse reactions may occur in the elderly. Information available from clinical trials showed no difference in the safety profile of patients ≥65 years of age than of younger patients.

Postmarketing experience with Hizentra in patients ≥65 years of age shows an overall similar safety profile in this age group as in younger patients.

Please refer to section 4.4 for details on risk factors and monitoring recommendations.

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 national reporting system listed in Appendix V.

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