Human normal immunoglobulin G

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.

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.

Data from prospective clinical trials on the use of human normal immunoglobulin in pregnant women is limited. Therefore, human normal immunoglobulin G 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.

Data from prospective clinical trials on the use of human normal immunoglobulin in breast feeding women is limited. Therefore, human normal immunoglobulin G 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.

Human normal immunoglobulin G has minor influence on the ability to drive and use machines, e.g. dizziness. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

h2 ®. SC administration

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.

Tabulated list of adverse reactions

Adverse Reactions (ARs) have been collected in human normal immunoglobulin G 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 human normal immunoglobulin G obtained from clinical studies and post-marketing surveillance, reporting rate per patient or per infusion:

Paediatric population

Clinical trials with human normal immunoglobulin G showed a similar overall safety profile in paediatric and adult patients with PID. Human normal immunoglobulin G 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 human normal immunoglobulin G in patients ≥65 years of age shows an overall similar safety profile in this age group as in younger patients.

h2 ®. IV administration

PI: The most common adverse reactions observed at a rate of more than 5% in subjects in clinical trials were: headache, abdominal pain, fever, nausea, and fatigue.

Chronic ITP in adults: The most common adverse reactions observed at a rate of more than 5% in subjects in clinical trials were: headache, fever, nausea, vomiting, dizziness, and anemia.

CIDP in adults: The most common adverse reactions observed at a rate of more than 5% in subjects in clinical trials were: headache, fever, dermatitis and blood pressure increased.

The most serious adverse reaction observed with IgG treatment during clinical trials was aseptic meningitis in one subject.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in clinical practice.

Treatment of Primary Humoral Immunodeficiency (PI)

In a prospective, open-label, single-arm, multicenter study in 51 children and adults with PI, subjects received IgG at a dose between 200 to 800 mg/kg body weight every 3 or 4 weeks. Subjects participated in the study for a mean of 360 days. Infusions were initiated at a rate of 1 mg/kg/minute for the first 30 minutes, and, if tolerated, could be advanced to a maximum tolerated rate not exceeding 8 mg/kg/minute. The mean age of subjects was 26.8 years (range: 2 to 65 years).

This study was followed by an extension study that evaluated the safety of IgG administered at higher infusion rates in 21 subjects that successfully had completed the first study. Nineteen of the 21 enrolled patients received IgG up to the maximum allowed infusion rate of 14 mg/kg/minute. In the extension study, medication-related adverse events were reported in 4 of 21 subjects (19%). Adverse reactions occurring in more than 5% of subjects were nausea (9.5%) and headache (9.5%).

In the study in PI, infusion-related adverse events (during or within 72 hours after the end of infusion) were reported in 16 patients (76%) enrolled in the 3-weeks treatment schedule and in 22 patients (73%) in the 4-weeks treatment schedule. Overall, 38 infusions (5%) had at least one adverse event considered related to study medication: 5 infusions (3%) in children, 4 infusions in adolescents (2%), and 29 infusions (8%) in adults. Study medication-related (possible or probable) infusion-related adverse reactions were associated with 35 infusions (5%) (overall); study medication-related headache was noted in 21 infusions (3%).

Table 1. Adverse Reactions* Occurring in more than 5% of Subjects with PI:

^* Any infusional and any study medication related adverse events.

Treatment of Chronic Immune Thrombocytopenia (ITP) in Adults

In a prospective, open-label, single-arm, multicenter study, 40 adult subjects with chronic ITP received IgG at a dose of 2 g/kg, administered daily as 1 g/kg intravenous infusions on 2 consecutive days. 3/40 subjects did not receive a second infusion of IgG due to infusion reactions, including chills, headache, fever and nausea. All subjects except 1 received at least 1 infusion with the highest rate of 8 mg/kg/minute. Pre-medication to alleviate potential adverse drug reactions was not allowed in the study.

There were 67 treatment emergent adverse events (TEAEs) reported in 24 (60%) subjects that were related to administration of IgG. 55 of these adverse events (82%) were infusional adverse events that occurred within 72 hours after start of the infusion. Seven of these adverse events in 2 subjects were severe. These included headache, nausea, vomiting and chills.

When analyzed by infusion, infusion-related adverse events were reported in 33 of the 77 infusions (43%).

Table 2. Adverse Reactions* Occurring in more than 5% of Subjects with Chronic ITP in Adults:

^* Any infusional and any study medication related adverse events.

One out of 40 subjects with ITP treated with IgG developed aseptic meningitis on Day 2 of the infusion. This subject was managed with antibiotics and supportive care with recovery.

Baseline direct Coomb’s test was performed in 39/40 subjects that were treated with IgG. 10/39 (26%) subjects subsequently developed positive Coomb’s test. One subject was not tested at baseline but had positive results on all 3 subsequent visits. Four of these subjects (10%) developed hemolytic anemia after receiving IgG. These resolved spontaneously without any intervention.

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy in Adults

In a prospective, double-blind, randomized, multicenter study, 142 adult subjects with CIDP aged between 18 and 83 years were enrolled and randomized 1:2:1 to receive first a loading dose of 2 g/kg and then 0.5 g/kg, 1.0 g/kg or 2.0 g/kg IgG for 7 maintenance infusions at 3-week intervals during the 24-week Dose-evaluation Phase (mean doses administered – including loading and rescue doses – were 0.91, 1.24 and 1.97 g/kg for 0.5, 1 and 2g/kg group, respectively).

All 142 subjects in this study received at least 1 dose of IgG. The median maximum infusion rate was 0.12 mL/kg/min throughout the study in all dose groups. Seventy-three out of the 142 subjects experienced a total of 209 adverse reactions (AR). Table 3 summarizes the most frequent ARs that occurred in more than 5% of subjects. Generally, the incidence of ARs was similar across the dose groups; the only AR where a dose effect was evident was headache, with an incidence of 2.9% in the 0.5 g/kg group, 14.5% in the 1.0 g/kg group and 23.7% in the 2.0 g/kg group. Pre-medication for AEs was only allowed in subjects who had adverse events during 2 consecutive infusions. During the study 11 subjects (7.75%) received premedication.

Table 3. Adverse Reactions* Occurring in more than 5% of Adult Subjects with CIDP:

^* Any infusional and any study medication related adverse events.

Two serious adverse reactions (headache and vomiting) were reported in one subject but did not lead to discontinuation of IgG.