Efficacy & Safety

VZ006 - Determined Safety and Efficacy of VARIZIG^® IM or IV to VZIG IM

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Study Design

Phase 3, multicenter, randomized, open-label, active-controlled study in non-immune pregnant women exposed to VZV.

Study Endpoints

The primary endpoint was the incidence of Varicella in high-risk pregnant women treated with VARIZIG IM or IV vs. VZIG IM.

Study Drug: dosage, route of administration

VARIZIG: single dose at 125 IU/ 10 kg IM or 125 IU/ 10 kg IV, up to a maximum dose of 625 IU.

VZIG: single dose at 125 IU/10 kg IM, up to a maximum dose of 625 IU.

Study Population

Pregnant Women, n= 57

VZIG IM n=19
VARIZIG IM n=17
VARIZIG IV n=21

Conducted in 60 pregnant women without immunity to VZV as confirmed by a latex agglutination test.
Of the 60 pregnant patients enrolled in the trial, 57 were included in the per-protocol efficacy analysis.

Safety

The most frequent adverse events overall were pruritus (12%), headache (10%), injection site pain (9%), and nausea (9%). Similar incidences of adverse drug reactions were reported in patients in the standard VZIG group. Other less frequent reactions included myalgia, fatigue, nausea, and flushing.
No severe complications of varicella, including pneumonia, encephalitis, or mortality, were observed.

Efficacy

Fewer patients treated with VARIZIG developed varicella [IM: n=5 (29%); IV: n=6 (29%)] compared to those treated with VZIG IM (n=8, 42%).
The expected rate of varicella in intreated pregnant women after exposure is approximately 70%.
The incidence of clinical varicella was similar across all treatment groups, with an overall incidence of 33% (19/57).
In the subset of 28 subjects with more than 24 hours of exposure to varicella, the incidence of clinical varicella in the combined treatment groups was 64%.

Conclusion

Overall, data collected from study VZ-006 indicated that VARIZIG was as efficacious as VZIG in modifying the course of varicella infection in pregnant women without immunity to VZV.

References: [1] Data on file [2] Koren G, Money D, BoucherM, Aoki F, Petric M, Innocencion G, WoloskM, Remple V, PellandF, Geist R, Ho T, Bar-Oz B, LoebsteinR. Serum concentrations, efficacy, and safety of a new, intravenously administered varicella zoster immune globulin in pregnant women. J Clin Pharmacol. 2002 Mar;42(3):267-74. doi: 10.1177/00912700222011283. PMID: 11865962. [3] Levin MJ, Duchon JM, Swamy GK, Gershon AA (2019): Varicella-zoster immune globulin (VARIZIG®) administration up to 10 days after varicella exposure in pregnant women, immunocompromised participants, and infants: Varicella outcomes and safety results from a large, open-label, expanded access program. PLoS ONE 14(7): e0217749 [4] Varicella-Zoster immune globulin (human) (VARIZIG®) in immunocompromised patients: a subgroup analysis for safety and outcomes from a large, expanded-access program Hayley Gans and Roy F. Chemaly [5] Safety and Varicella Outcomes in In Utero–Exposed Newborns and Preterm Infants Treated With Varicella-Zoster Immune Globulin (VARIZIG®): A Subgroup Analysis of an Expanded-Access Program Jennifer M Duchon, Myron J Levin, Anne A Gershon [6] Safety and varicella outcomes after varicella zoster immune globulin administration in pregnancy Geeta K. Swamy, MD, Sarah K. Dotters-Katz, MD, MMHPE.

VZ009 - Expanded Access Program to Assess and Confirm Efficacy and Safety of Intramuscular VARIZIG^®

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Study Design

Phase 3, open-label, multi-center expanded access program in high-risk individuals exposed to VZV.

Study Endpoints

The primary endpoint was the incidence of clinical varicella in each high-risk population exposed to VZV.

The secondary endpoints included the incidence of varicella-related complication.

Study Drug: dosage, route of administration

VARIZIG: single dose at 125 IU/10 kg body weight, IM, up to a maximum dose of 625 IU.

Study Population

High-risk individuals n=621

Non-immune healthy adults, n=5
Immunocompromised adult and pediatric patients, n=299
Infants, n=152
Pregnant women, n=166

An expanded access program designed to provide VARIZIG, Varicella-Zoster immune globulin (human), to high-risk individuals. 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. 513 subjects had sufficient efficacy data to be included in the primary efficacy population.

Safety

A total of 63 subjects experienced 143 serious AE’s, 7 considered related to VARIZIG (nausea, vomiting, convulsion, headache, abortion spontaneous, serum sickness, and varicella). Only 2 serious adverse events (1 serum sickness and 1 isolated case of varicella) were considered probably related to VARIZIG.
The most common AE (> 3% of subjects) was pyrexia; all reports of pyrexia occurred in immunocompromised subjects, and only 1 report was considered related to VARIZIG.

Efficacy

The overall incidence of clinical varicella was 8.8% for all combined high-risk populations exposed to VZV and treated with VARIZIG.
The secondary endpoints included the incidence of varicella-related complications (pox count >100, pneumonia, encephalitis, and mortality). Overall, complications due to VZV were observed in 4 of 28 cases of clinical varicella in the efficacy population.
1 newborn developed disseminated varicella with pneumonia and encephalitis after intrauterine exposure to VZV; this patient received Acyclovir treatment at birth and received VARIZIG 6 days after birth. When this patient began to exhibit evidence of clinical varicella, acyclovir was administered again.
5 of 35 participants who developed > 100 pox: 2 immunocompromised participants and 3 infants. Each received VARIZIG within 96 hours of exposure to varicella.
- One infant developed both pox counts > 100 pox and encephalitis.
- One newborn infant developed both pox counts > 100 and pneumonia.
- No participants died because of varicella.
Among pregnant women, out of 137 patients who received VARIZIG, 10 developed varicella (7.3%).
In immunocompromised patients, out of 269 who received VARIZIG, 12 developed varicella (4.5%).
In the infants’ subgroup, which includes newborns, preterm, and those under one year, out of 105 patients who received VARIZIG, 12 developed varicella (11.4%).
Several people had more than one dose.
2 healthy non-immune adults were excluded from the efficacy group.

Conclusion

The expanded-access program showed low incidence and severity of varicella in high-risk subjects after VARIZIG administration, as determined by local investigators.

The study lacked a direct comparator, but results were contextualized using historical data from before passive immunization.

Compared to population-specific historical untreated controls, VARIZIG likely reduced the incidence of varicella.

VARIZIG^® Expanded Access Program: Immunocompromised Children and Adults

Safety and Varicella Outcomes in immunocompromised Children and Adults Treated with Varicella-Zoster Immune Globulin (VARIZIG): A Subgroup Analysis of an Expanded-Access Program.

Study Design

Sub-analysis of an open-label, expanded-access program provided VARIZIG to high-risk individuals exposed to VZV.

Study Endpoints

Safety and efficacy analysis of VARIZIG in adults and children with various immunodeficiencies or histories of solid organ transplantation (SOT) or hematopoietic cell transplantation (HCT).

Study Drug: dosage, route of administration

VARIZIG: (125 IU/10 kg, [up to 625 IU]) was administered once intramuscularly Ideally, administration occurred as soon as possible after exposure, but administration could occur within 10 days of exposure.

Study Population

Adults = 40

Children = 263

Safety

VARIZIG’s safety profile was favorable among immunocompromised patients.
Overall, 15 immunocompromised adults (38%) experienced 51 AEs, of which only one AE of nausea was considered related to VARIZIG.  4 adults (10%) experienced 10 serious AEs, none of which were considered related to VARIZIG. There was one death (respiratory failure in a patient with AIDS) in the immunocompromised adult group; this death was considered unrelated to varicella or VARIZIG.
In the group of immunocompromised children, 90 (34%) experienced 402 AEs, of which 53 (13%) were considered related to VARIZIG. The most frequently occurring (in more than one participant) AEs that were considered related to VARIZIG were injection site pain (n = 5,2%), headache (n = 2, 0.8%), and diarrhea (n= 2, 0.8%). There were 42 children (16%) who experienced 93 serious AEs, of which one (serum sickness) was considered related to VARIZIG^®.
Overall, there were 5 deaths, and none of them were considered to be related to varicella or VARIZIG

Efficacy

The overall incidence of varicella was 6% among adults and 7% among children, with the timing of VARIZIG administration not significantly impacting these rates.
Most varicella cases were mild, with only two children developing more than 100 lesions, and no severe complications like pneumonia or encephalitis were reported.
Hospitalizations due to varicella occurred mainly in children with oncologic immunodeficiencies.

Conclusion

The study highlights that VARIZIG is both safe and effective for reducing the severity of varicella in immunocompromised individuals, supporting its use as a critical prophylactic measure after exposure to the virus in these high-risk groups.

This analysis underlines the importance of timely administration, preferably within 96 hours of exposure, to maximize the protective effects of VARIZIG.

VARIZIG^® Expanded Access Program: In Utero-Exposed Newborns and Preterm Infants

Safety and Varicella Outcomes in In Utero–Exposed Newborns and Preterm Infants Treated with Varicella-Zoster Immune Globulin (VARIZIG): A Subgroup Analysis of an Expanded-Access Program.

Study Design

Sub-analysis of an open-label, expanded-access program provided VARIZIG to high-risk individuals exposed to Varicella or Herpes Zoster.

Study Endpoints

Safety and efficacy analysis of VARIZIG in infants exposed to VZV in-utero or in preterm infants.

Study Drug: dosage, route of administration

The initial protocol allowed infants weighing <5 kg to receive a reduced VARIZIG dose (≤62.5 IU).

Study Population

Newborns born to mothers who developed VZV infection within 5 days before birth or within 48 hours after birth, n = 43

preterm infants (<28 weeks’ gestation), n = 80

Infants were followed from initial VARIZIG administration with 3 additional visits through a maximum of 42 days to determine the incidence and severity of varicella and any varicella-related complications (eg, pneumonia, encephalitis, or mortality). Per study definition, varicella cases were considered severe when the lesion count was >100.

Safety

A total of 63 subjects experienced 143 serious AE’s, 7 considered related to VARIZIG (nausea, vomiting, convulsion, headache, spontaneous abortion, serum sickness, and Varicella).
Only 2 serious adverse events (1 serum sickness and 1 isolated case of Varicella) were considered probably related to VARIZIG.
The most common AE (≥ 3% of subjects) was pyrexia; all reports of pyrexia occurred in immunocompromised subjects, and only 1 report was considered related to VARIZIG.

Efficacy

Over 80% of both in utero-exposed newborns and preterm infants received VARIZIG within 96 hours of exposure.
For those with available data, 18% of in utero-exposed newborns developed varicella compared to none of the preterm infants. Specifically, 30% of in utero-exposed newborns whose mothers had varicella developed the disease, but no varicella cases arose from maternal herpes zoster exposure.
3 in utero-exposed infants with varicella had severe outcomes, including encephalitis and pneumonia.
For infants under 5 kg, who received a lower dose of VARIZIG, most did not develop varicella.

Conclusion

The data demonstrated that varicella incidence was low in infants exposed in utero and zero in preterm infants who received post-exposure prophylaxis VARIZIG.

The results further demonstrate safety in both newborn and preterm infant populations and indicate that, across various exposure types and timings, the incidence of varicella and related complications remained low regardless of when a single dose of intramuscular VARIZIG was administered.

VARIZIG^® Expanded Access Program: Pregnant Women

Safety and Varicella Outcomes in Pregnant Women Treated with Varicella-Zoster Immune Globulin (VARIZIG): A Subgroup Analysis of an Expanded-Access Program.

Study Design

1) A randomized, controlled trial (RCT), compared intravenous vs intramuscular administered VARIZIG (625 IU).

2) An open label, expanded-access program (EAP) in which participants received 625 IU of intramuscular VARIZIG in a real-world setting.

Study Endpoints

Safety and efficacy analysis of VARIZIG in pregnant women based on RCT and EAP data.

Study Drug: dosage, route of administration

1) The RCT compared intravenous vs intramuscular administered VARIZIG (625 IU).

2) In the EAP, participants received 625 IU of intramuscular VARIZIG® in a real-world setting.

Study Population

1) The RCT included 60 VZV-seronegative pregnant women, of whom 38 received VARIZIG intramuscularly (n=17) or intravenously (n=21).

2) In the EAP, of 166 pregnant women, full safety data were available for 147 participants, and 137 participants had varicella outcome data.

Safety

Common related adverse events were injection site pain (RCT, 19%; EAP, 3%) and headache (RCT, 7%; EAP, 1%).
No varicella-related pneumonia and no maternal deaths occurred in either study.
Serious adverse events occurred in 2 participants (5%) in the RCT (worsening of asthma and spontaneous abortion), and 5 participants (3%) in the EAP (spontaneous abortion, premature separation of the placenta, congenital anomaly, and fetal growth restriction); none of these serious adverse events were considered related to VARIZIG or varicella.

Efficacy

VZV exposure occurred in a household setting in 68% of cases in the RCT and 47% of cases in the EAP. In the EAP, the following VZV exposures occurred: 58% varicella-zoster, 14% herpes zoster, 19% unspecified, and 8% unknown; VZV type was not specified in the RCT.
Most participants (RCT, 61%; EAP, 81%) received VARIZIG within 96 hours of VZV exposure. Varicella incidence was 29% in the RCT and 7.3% in the EAP.
Varicella incidence was not impacted by the duration of time between VARIZIG administration and VZV exposure nor the trimester of pregnancy.

Conclusion

In the two subgroup analysis of pregnant women who received post-exposure prophylaxis with VARIZIG, the incidence of varicella was low.

Especially compared with findings from a 20-year retrospective study that reported varicella incidence of 42% vs 72% among those who did not receive post-exposure prophylaxis with Varizig.

The incidence of varicella was similar in each study, regardless of the timing of VARIZIG administration after VZV exposure.

Both studies had a similar safety profile, and VARIZIG was well-tolerated.

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Efficacy & Safety

VZ006 - Determined Safety and Efficacy of VARIZIG® IM or IV to VZIG IM

Study Design

Study Endpoints

Study Drug: dosage, route of administration

Study Population

Safety

Efficacy

Conclusion

Important Safety Information

VZ006 - Determined Safety and Efficacy of VARIZIG^® IM or IV to VZIG IM