VARIZIG Solution for injection Ref.[27439] Active ingredients: Human varicela zoster immunoglobulin

In a comparative pharmacokinetic clinical trial, 35 volunteers were administered an intramuscular dose of 12.5 IU/kg of VARIZIG (n=18) or the comparator product VZIG (n=17). The dose of 12.5 IU/kg of VZIG or VARIZIG given to the subjects was based on the assumption that the potency was similar for both products. For the bioequivalence analysis, a potency correction factor was applied (concentrations of VARIZIG were multiplied by 2.3) to account for higher measured potency of the comparator product. The mean peak concentration (C_max) of varicella antibodies occurred within five days of administration for both products (Table 3). In the trial, baseline levels of anti-VZV antibodies ranged from 0 to 720 mIU/mL, therefore baseline levels were taken into account for pharmacokinetic calculations, to better represent the indicated population. After potency correction, baseline correction, and exclusion of subjects with baseline values of anti-VZV antibody levels of >200 mIU/mL, the two products were pharmacokinetically comparable.

Table 3. Pharmacokinetic Comparison of VARIZIG and VZIG:

^* Potency and subgroup analysis were implemented for pharmacokinetic calculations. Study subjects with elevated baseline anti-VZV levels (>200 mIU/mL) from both treatment groups were excluded from pharmacokinetic calculations.
^** The half-life is expected to vary from patient to patient.

14.1 Pregnant Women Exposed to Varicella Zoster Virus

A randomized, open-label, multicenter, active controlled clinical trial was conducted in 60 pregnant women without immunity to VZV as confirmed by a latex agglutination test. Patients were stratified on the basis of time from first exposure to varicella as follows:

• one to four days post-exposure and,
• five to 14 days post-exposure.

The women were randomized into one of three study arms as follows:

• a single intravenous dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VARIZIG,
• a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VARIZIG or,
• a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VZIG (licensed comparator product).

Patients were followed for 42 days.

Incidence of clinical varicella was similar across all treatment groups with an overall incidence of 33%; however, in the subset of 28 subjects with more than 24 hours exposure to varicella, the incidence of clinical varicella in the combined treatment groups was 64%.

Mean weighted constitutional illness scores (CIS) () were similar across all groups and none of the subjects had serious complications of varicella. The small number of subjects in each treatment stratum and the lack of agreed upon pre-specified hypothesis testing precluded formal statistical comparisons between groups.

14.2 High Risk Patients Exposed to Varicella Zoster Virus

An open-label, Expanded Access Protocol (EAP) conducted in the United States of America was designed to provide VARIZIG to high risk individuals who were exposed to varicella zoster virus (VZV). Although the study was not designed to evaluate efficacy, the objective of the study was to further assess and confirm the safety and efficacy of intramuscular injection of VARIZIG in the prevention or reduction of severity of complications from varicella infections in the indicated high risk populations. Initially, enrolment was limited to allow treatment with VARIZIG only within 96 hours of exposure, but the protocol was amended to expand the treatment window to 10 days post-exposure.

The incidence of clinical varicella (chickenpox lesions), was compared to predefined historical reference rates. The incidence of severe varicella complications, including pneumonia, encephalitis, severe varicella with pox counts >100 pox, mortality and all complications was also evaluated. The overall incidence of clinical varicella was evaluated in an interim analysis, where 10% (31/311) of high risk individuals exposed to VZV and treated with VARIZIG for all combined populations, for whom complete or partial efficacy data was available. Clinical varicella was observed in 8.4% (13/154) of immunocompromised pediatric and adult patients, in 6.8 % (5/74) of pregnant women, in 14.8% (12/81) of infants and one healthy adult (Table 4). Clinical varicella was more common after prolonged VZV exposure. The final report confirmed the efficacy results in the interim analysis (Table 5). In addition, a comparison of the incidence of varicella based on treatment window revealed that treatment between 5 and 10 days post-exposure was no different from treatment within 96 hours.

Table 4. Comparison of Varicella Incidence in Subjects Treated with VARIZIG to Historical Incidence of Varicella in Untreated Individuals – Interim analysis:

¹ n = number of VARIZIG doses for post-exposure prophylaxis of varicella in efficacy population.
² One sample two-sided exact binomial test.
^* Statistically significant (α=0.05).

Table Updated Summary of Incidence of Varicella in Subjects Treated with VARIZIG – Final Report:

¹ n = number of VARIZIG doses for post-exposure prophylaxis of varicella in efficacy population