2.1 Preparation and Handling

Each vial of VARIZIG contains a minimum potency of 125 IU in 1.2 mL.

Bring VARIZIG to room temperature prior to use.

Inspect VARIZIG for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates.

VARIZIG is for single use only. Discard any unused portion.

Dosing of VARIZIG is based on body weight. Administer a single dose of VARIZIG intramuscularly as recommended in Table 1.

The minimum dose is 62.5 International Units (IU) for small infants under two kilograms body weight; the maximum dose of 625 IU should be administered for all patients greater than 40 kilograms in weight.

Consider a second full dose of VARIZIG for high risk patients who have additional exposures to varicella greater than three weeks after initial VARIZIG administration.

2.2 Administration

For intramuscular use only.

Divide the intramuscular dose and administer in two or more injection sites, depending on patient size. Do not exceed 3 milliliters per injection site.

Inject into the deltoid muscle or the anterolateral aspects of the upper thigh. Due to the risk of sciatic nerve injury, do not use the gluteal region as a routine injection site. If the gluteal region is used, only use the upper, outer quadrant.

To prevent the transmission of infectious agents from one person to another, use a new disposable sterile syringe and needle for each individual patient.

5.1 Thrombotic Events

Thrombotic events may occur during or following treatment with immune globulin products (1, 2, 3). Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

5.2 Coagulation Disorders

Administer VARIZIG intramuscularly only. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, only administer VARIZIG if the expected benefits outweigh the potential risks.

5.3 Hypersensitivity

Severe hypersensitivity reactions may occur following VARIZIG administration. Administer VARIZIG in a setting with appropriate equipment, medication and personnel trained in the management of hypersensitivity, anaphylaxis and shock. In the case of hypersensitivity, discontinue administration of VARIZIG immediately and provide appropriate treatment.

VARIZIG contains trace amounts of IgA (less than 40 micrograms per milliliter). Patients with known antibodies to IgA have a greater risk of severe hypersensitivity and anaphylactic reactions. VARIZIG is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity reactions [see 4 CONTRAINDICATIONS].

5.4 Transmissible Infectious Agents

Because VARIZIG is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The plasma donors are screened for the presence of certain infectious agents and the manufacturing process for VARIZIG includes measures to inactivate and remove certain viruses [see 11 DESCRIPTION]. Despite these measures, products derived from human plasma can still potentially transmit diseases. No cases of transmission of viral diseases, vCJD or CJD have been associated with the use of VARIZIG.

Report all infections thought by a physician to have been transmitted by VARIZIG to Aptevo BioTherapeutics at 1-844-859-6675. Discuss the risks and benefits of this product with the patient before administering it to the patient [see 17 PATIENT COUNSELING INFORMATION].

6.1 Clinical Trial Experience

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

Six hundred and one (n=601) high risk individuals received VARIZIG intramuscularly in two clinical trials which included pregnant women, infants and immunocompromised pediatric and adult patients. The highest incidence of adverse reactions occurred in pregnant women (n=166), including injection site pain (7%), rash (including terms pruritus, rash, rash erythematous, and rash vesicular) (4%), headache (3%), and fatigue (2%). All other adverse reactions occurred in 1% or less of clinical trial subjects within each high risk group. A single incidence of serum sickness (approximately one in 600 patients treated with VARIZIG) was observed in an immunocompromised adolescent patient.

There were eight reported adverse events associated with the coagulation system including, deep vein thrombosis (n=1), disseminated intravascular coagulation (n=1) , intracranial hemorrhage (n=2), coagulopathy (n=2), intraventricular hemorrhage (n=1), and pulmonary hemorrhage (n=1) in 621 subjects in the open-label, Expanded Access Protocol (EAP); the study was not designed to differentiate between adverse events attributed to the underlying medical condition and adverse reactions to VARIZIG.

8.1 Pregnancy

Pregnancy category C. Animal reproduction studies have not been conducted with VARIZIG. It also is not known whether VARIZIG can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. VARIZIG should be given to a pregnant woman only if clearly needed.

The safety and effectiveness of VARIZIG have been evaluated for post-exposure prophylaxis in clinical trials in 166 pregnant women [see 6 ADVERSE REACTIONS and 14 CLINICAL STUDIES].

8.3 Nursing Mothers

It is not known whether VARIZIG is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when VARIZIG is administered to a nursing mother.

8.4 Pediatric Use

The dosing recommendations in the treatment of pediatric patients are by body weight [see 2 DOSAGE AND ADMINISTRATION].

The safety and effectiveness of VARIZIG have been evaluated for post-exposure prophylaxis in the VARIZIG expanded access clinical trial in 374 pediatric patients, including immunocompromised pediatric patients:

• 94 preterm newborns and infants,
• 53 term newborns,
• 45 infants and toddlers,
• 176 children and,
• 43 adolescents.

In the EAP, follow up data were available for 110 VARIZIG treatments in infants (including newborns, pre-term infants, and infants <1 year old). Three severe infections were reported, all three with pox count >100, one of which also had pneumonia and another one also developed probable varicella encephalitis.

8.5 Geriatric Use

Clinical studies of VARIZIG administered intramuscularly for post-exposure prophylaxis did not include sufficient numbers of geriatric subjects (aged 65 and over) to determine whether they respond differently from younger subjects.

Use caution when administering VARIZIG to patients age 65 and over who are judged to be at increased risk of thrombotic events [see 5 WARNINGS AND PRECAUTIONS]. Do not exceed recommended doses and administer VARIZIG intramuscularly only.

8.6 Immunocompromised Patients

In the EAP, both adult (n=37) and pediatric immunocompromised subjects (n=235) were treated. Twelve immunocompromised subjects developed clinical varicella and none developed varicella pneumonitis; however at least five are reported to have received concomitant acyclovir and due to incomplete reporting, it is not known if others also received acyclovir.

12.1 Mechanism of Action

VARIZIG provides passive immunization for non-immune individuals exposed to VZV, reducing the severity of varicella infections (5).

12.3 Pharmacokinetics

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 (Cmax) 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.

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) (6) 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.

16.1 How Supplied

NDC 70504-0126-2: VARIZIG [Varicella Zoster Immune Globulin (Human)] is supplied as a sterile liquid approximately 125 IU of anti-VZV in a 3 mL type 1 glass tubing vial fitted with a 13 mm rubber stopper and a 13 mm flip-off seal, and a package insert.

16.2 Storage and Handling

Store VARIZIG at 2 to 8°C (36 to 46°F). Do not freeze. Do not use after expiration date.