Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Immune sera and immunoglobulins, Specific immunoglobulins, Hepatitis B immunoglobulin.
ATC code: J06BB04

Hepatitis B immunoglobulin contains mainly immunoglobulin G (IgG) with a specifically high content of antibodies against hepatitis B virus surface antigen (HBs).

Clinical efficacy and safety

The open, prospective, single-arm clinical trial enrolled 23 liver transplant recipients, who had been receiving intravenous hepatitis B immunoglobulin prophylaxis and subsequently switched to subcutaneous Zutectra. The weekly subcutaneous dose was 500 IU for patients with bodyweight < 75 kg (a dose increase to 1,000 IU was allowed, if medically required to maintain a safety level of > 100 IU) and 1,000 IU for patients with bodyweight ≥ 75 kg . 2 patients received a higher and 2 patients received a lower dose than recommended by the weight based dosing regimen. Serum anti-
HBs trough levels of 100 IU/L and higher (primary efficacy endpoint) were maintained for all patients 
during the 18 to 24 week trial period. The > 100 IU/L safety margin is the generally accepted level of effective prevention against HBV re-infection in liver transplant patients at risk. No patient experienced HBV re-infection. Self-administration was feasible for most patients.

The mean anti-HBs serum level before switching was 393 ± 139 IU/L. All patients used antiviral medicine.

Using the Clopper Pearson method, the failure rate after 18 weeks was 0 % for patients of the ITT set (95 % CI: [0, 14.8 %]). A failure rate of 0 % was also found for the facultative extension phase (week 24) (95 % CI: [0, 20.6 %])

The objectives of the open, prospective, single-arm clinical trial were the investigation of feasibility of home self-administration (including patient compliance), efficacy and safety of subcutaneous application of Zutectra in a population of stable patients during long-term treatment for prophylaxis against re-infection of a transplanted liver in 66 patients. All patients included in this study had to run through a training period of at least 29 days and home self-administration could start on day 36 at the earliest. With the exception of 6 patients who withdrew prior to day 36, all patients achieved complete hospital and home self-administration. No patient prematurely discontinued the study due to lack of feasibility of home self-treatment. During the 48-weeks treatment phase constant serum HBs antibody concentrations ≥ 100 IU/L were measured in all patients at all assessments with mean values of 312.0 ± 103.5 IU/L at the end of the treatment period. In total, 53/66 patients (80.3 %) used antiviral medication and 13 patients received monotherapy with Zutectra during this study. No hepatitis B re- infection was reported and no patient was tested HBsAg positive during the treatment period of 48 weeks. No serious adverse events were reported to be related to study medication. No fatal case was observed during the study.

The objective of the open, prospective, single-arm clinical trial was the investigation of efficacy and safety of Zutectra for prevention of hepatitis B virus (HBV) re-infection ≥ one week after orthotopic liver transplantation in HBsAg and HBV-DNA negative patients. At the time of transplantation 21 patients (42.9%) were tested positive for HDV, patients with a positive HIV or HCV test were excluded from study participation. 49 patients received subcutaneous injections of Zutectra of 500 IU (1 mL) or 1,000 IU (2 mL) (dose adaptation in exceptional cases up to 1,500 IU) per week or fortnightly according to serum anti-HBs trough levels. The individual treatment duration per patient was planned to be up to 24 weeks after transplantation. No treatment failures occurred during the 6- month study period. Serum HBs antibody concentrations above the minimum safety trough level of >100 IU/L were measured in all patients at all timepoints independent of the type of administration (investigator, caregiver or self-injection), the dose regimen (500 IU, 1,000 IU, 1,500 IU) or the treatment intervals. No clinical signs of a hepatitis B re-infection were observed and no patient was tested HBsAg positive or HBV-DNA positive during the study which confirms that effective protection against Hepatitis B virus re-infection was provided by subcutaneous administration of Zutectra as part of the combination treatment with HBV virostatic therapy 8 – 18 days after orthotopic liver transplantation. One non-serious adverse event was reported to be related to Zutectra (injection site haematoma). No fatal case was observed during the study.

The non-interventional post authorization safety study (PASS 978) enrolled 61 adult patients ≥ 6 months after liver transplantation for hepatitis B induced liver failure. The objective of the study was to evaluate the level of compliance of patients using subcutaneous Zutectra as home self- treatment for preventing hepatitis B re-infection. Patients were to be treated with Zutectra in accordance with the information and dosage given in the SPC. Compliance according to anti-HBs serum levels could be shown for 57 (of 61) patients (93%), with no values below 100 IU/L and a mean anti-HBs serum level of 254.3 IU/L at the final visit. In total, 42/61 patients (68.9 %) used antiviral medication and 19 patients received monotherapy with Zutectra during this study. No treatment failure defined as positive HBV-DNA and HBsAg findings occurred during the entire observation period. No re-infection was observed. No serious adverse reaction was reported. No fatal case was observed during the study.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Distribution
Zutectra is slowly absorbed into the recipient’s circulation and reaches a maximum after a delay of 2-7 days.

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

Elimination
Zutectra has a half-life of about 3-4 weeks. This half-life may vary from patient to patient.