2.1 Dosage

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.

 

Table 1 VARIZIG Dose and Volume of Administration

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 Reconstitution

Reconstitute VARIZIG according to Table 2. Only use the accompanying Sterile Diluent with aseptic technique throughout. Reconstitute shortly before use.

 

Table 2 Recommendations for Reconstitution of VARIZIG

To reconstitute:

1.

Remove caps from the Sterile Diluent and VARIZIG vials.

2.

Wipe exposed central portion of each rubber stopper with suitable disinfectant.

3.

Withdraw 1.25 milliliter of the Sterile Diluent using a suitable syringe and needle.

4.

Inject diluents slowly into the VARIZIG vial at an angle so that the liquid is directed onto the inside glass wall of the vial containing the freeze-dried pellet.

5.

Wet pellet by gently tilting and inverting the vial. Avoid frothing. Gently swirl upright vial until dissolved (less than ten minutes). Do not shake.

•

Inspect VARIZIG visually for particulate matter and discoloration prior to administration.

•

Do not use if turbid and/or discoloration is observed.

•

Reconstituted product can be stored for up to 12 hours at 2 to 8°C (36 to 46ºF) prior to use.

•

Do not freeze. Solutions that have been frozen should not be used.

VARIZIG is for single use only. Partially used vials, including the remaining Sterile Diluent, should be discarded.

2.3 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 [see4 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 [see11 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 Cangene Corporation at 1-800-768-2304. 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.

Three hundred and seventy seven 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=90), including injection site pain (9%), headache (4%), chills (2%) 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 400 patients treated with VARIZIG) was observed in an immunocompromised adolescent patient.

There were six reported adverse events related to the coagulation system (one deep vein thrombosis) in 372 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.

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 [see2 DOSAGE AND ADMINISTRATION]. The safety and effectiveness of VARIZIG have been evaluated for post-exposure prophylaxis in the VARIZIG expanded access clinical trial in 265 pediatric patients, including immunocompromised pediatric patients:

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70 preterm newborns and infants

•

38 term newborns

•

28 infants and toddlers

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99 children and

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30 adolescents.

In the EAP, follow up data were available for 81 VARIZIG treatments in 78 infants (including newborns, pre-term infants, and infants <1 year old). Two severe infections were reported, with pox count >100. One of these patients 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, eight immunocompromised subjects developed clinical varicella, and none developed varicella pneumonitis; however five are reported to have received concomitant 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 4). 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.

14.1Pregnant 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.

16.1How Supplied

NDC 53270-0125-2: VARIZIG [Varicella Zoster Immune Globulin (Human)] is supplied as a kit in a carton box containing approximately 125 IUof anti-VZV supplied freeze-dried in a 6 mL type 1 glass tubing vial fitted with a 20 mm rubber lyophilization stopper and a 20 mm flip-off seal, one single dose vial of Sterile Diluent, non-pyrogenic for reconstitution of VARIZIG 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. Use the product within 12 hours of reconstitution if stored at 2 to 8°C.