Generic Name: varicella zoster immune globulin

Uses

Postexposure Prophylaxis of Varicella Zoster Virus (VZV)

Postexposure prophylaxis to prevent or reduce severity of varicella (chickenpox) in pregnant women who do not have evidence of varicella immunity and were exposed to VZV within the last 4 days (96 hours).

Postexposure prophylaxis to prevent or reduce severity of varicella in neonates† whose mothers had signs and symptoms of varicella at the time of delivery (i.e., from 5 days before to 2 days after delivery). Such neonates are at risk of severe, potentially fatal varicella and should receive VZIG regardless of whether the mother received VZIG.

Postexposure prophylaxis to prevent or reduce severity of varicella in certain premature neonates† exposed to VZV during neonatal period. VZIG recommended for exposed premature neonates born at <28 weeks of gestation or with birthweight ≤1 kg, regardless of maternal history of varicella or varicella vaccination. Also recommended for exposed premature neonates born at ≥28 weeks of gestation if mother does not have evidence of varicella immunity.

Postexposure prophylaxis to prevent or reduce severity of varicella in immunocompromised children† or immunocompromised adults† who do not have evidence of varicella immunity and were exposed to VZV within the last 4 days (96 hours). This includes those with primary or acquired immunodeficiency disorders (including HIV infection), neoplastic disease, and those receiving immunosuppressive therapy. Individuals receiving immune globulin IV (IGIV) replacement therapy (≥400 mg/kg once monthly) are likely to be protected from VZV and probably do not require VZIG if last IGIV dose was administered ≤3 weeks before exposure.

VZIG provides temporary passive immunity and may prevent or reduce severity of VZV infection if administered within 4 days (96 hours) after exposure. May not be effective if administered >4 days (>96 hours) after exposure.

Active immunization with varicella vaccine preferred for postexposure prophylaxis in most immunocompetent individuals exposed to VZV who have not previously received age-appropriate vaccination with varicella vaccine and do not have evidence of varicella immunity.

Passive immunization with VZIG recommended for postexposure prophylaxis in individuals without evidence of varicella immunity if varicella vaccine is contraindicated or cannot be used and exposed individual is at risk for severe disease and complications (e.g., pregnant women, neonates, immunocompromised individuals).

VZIG not indicated for postexposure prophylaxis in healthy term infants exposed postnatally or in susceptible immunocompetent children, adolescents, or adults.

When varicella vaccine is contraindicated or cannot be used and VZIG is unavailable (cannot be obtained within 96 hours of exposure), consider use of IGIV as an alternative since it contains anti-VZV.

Decisions to administer VZIG should be made on an individual basis and depend on whether patient lacks evidence of varicella immunity, exposure is likely to result in infection, and patient is at greater risk for varicella complications than the general population.

ACIP states that evidence of varicella immunity includes documentation of age-appropriate vaccination against varicella, laboratory evidence of immunity or laboratory confirmation of prior varicella, birth in the US before 1980 (except pregnant women, immunocompromised individuals, health-care personnel), diagnosis or verification of history of varicella by health-care provider, or diagnosis or verification of history of herpes zoster (shingles, zoster) by health-care provider. Individuals without such evidence should be considered susceptible.

ACIP states that exposures likely to result in varicella in individuals without evidence of immunity are those that involve direct contact (i.e., face-to-face contact with an infectious person while indoors). Some experts suggest use of VZIG be considered if duration of close contact was >5 minutes, others define close contact as >1 hour. Those with continuous exposure to household members with varicella or disseminated ter are at greatest risk for infection. For hospital contacts, substantial exposure consists of sharing the same hospital room or direct face-to-face contact with an infectious person.

VZIG has not been shown to be useful for treatment of clinical varicella or herpes zoster or for preventing disseminated zoster and is not recommended for such use.

Dosage and Administration

Administration

Administer by IV or IM injection.

Monitor patient for adverse effects for at least 20 minutes after administration of VZIG. (See Cautions.)

Do not mix with any other drug or solution.

Do not administer concomitantly with varicella vaccine. (See Specific Drugs and Laboratory Tests under Interactions.)

IV Administration

If a preexisting catheter must be used for the IV injection, flush line with 0.9% sodium chloride for injection prior to giving VZIG dose.

Reconstitution

Add 2.5 mL of diluent supplied by the manufacturer to the vial of lyophilized powder using a suitable syringe and needle. Inject diluent slowly at an angle so that liquid is directed onto the wall of the vial. Wet pellet by gently tilting and inverting vial. Avoid frothing. Gently swirl upright vial until pellet dissolves; do not shake.

Inspect visually for particulate matter and discoloration. Solution should be clear or slightly opalescent; do not use if it is cloudy or contains deposits.

Reconstituted solution for IV administration contains 50 units/mL.

Reconstituted solution may be stored for up to 12 hours at 2–8°C. (See Storage under Stability.) Allow solution to warm to room or body temperature before use.

Rate of Administration

Inject directly into a vein over 3–5 minutes.

IM Administration

Administer IM into deltoid muscle or anterolateral aspect of upper thigh.

Because of risk of injection-associated injury to the sciatic nerve, use gluteal region only when necessary and use only the upper, outer quadrant.

Reconstitution

Add 1.25 mL of diluent supplied by the manufacturer to the vial of lyophilized powder using a suitable syringe and needle. Inject diluent slowly at an angle so that liquid is directed onto the wall of the vial. Wet pellet by gently tilting and inverting vial. Avoid frothing. Gently swirl upright vial until pellet dissolves; do not shake.

Inspect visually for particulate matter and discoloration. Solution should be clear or slightly opalescent; do not use if it is cloudy or contains deposits.

Reconstituted solution for IM administration contains 100 units/mL.

Reconstituted solution may be stored for up to 12 hours at 2–8°C. (See Storage under Stability.) Allow solution to warm to room or body temperature before use.

Dosage

Pediatric Patients

Postexposure Prophylaxis of Varicella Zoster Virus (VZV)

Neonates (Including Premature Neonates)

IV or IM

Single dose of 125 units/10 kg of body weight (up to 625 units).†

Give dose within 4 days (96 hours) of exposure to VZV, preferably as soon as possible.†

Susceptible Immunocompromised Children or Adolescents <18 Years of Age

IV or IM

Single dose of 125 units/10 kg of body weight (up to 625 units).†

Give dose within 4 days (96 hours) of exposure to VZV, preferably as soon as possible.†

Adults

Postexposure Prophylaxis of Varicella Zoster Virus (VZV)

Susceptible Pregnant Women

IV or IM

Single dose of 125 units/10 kg of body weight (up to 625 units).

Give dose within 96 hours of exposure to VZV, preferably as soon as possible.

Susceptible Immunocompromised Adults

IV or IM

Single dose of 125 units/10 kg of body weight (up to 625 units).†

Give dose within 4 days (96 hours) of exposure to VZV, preferably as soon as possible.†

Prescribing Limits

Pediatric Patients

Minimum dose is 125 units; maximum dose is 625 units.

Adults

Minimum dose is 125 units; maximum dose is 625 units.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations. (See Geriatric Use under Cautions.)

Cautions

Contraindications

• Hypersensitivity to VZIG or any ingredient in the formulation or component of the container.
• History of anaphylactic or other severe systemic reactions to immune globulins.
• Known immunity to VZV (i.e., previous varicella infection or age-appropriate vaccination with varicella vaccine).
• IgA deficiency. (See Selective IgA Deficiency under Cautions.)

Warnings/Precautions

Warnings

Risk of Transmissible Agents in Plasma-derived Preparations

Because VZIG is prepared from pooled human plasma, it is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and HIV infection, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).

Improved donor screening, viral-inactivation procedures (e.g., solvent/detergent treatment), and/or filtration procedures have reduced, but not completely eliminated, risk of pathogen transmission with plasma-derived preparations.

The manufacturing process for VZIG includes a solvent/detergent inactivation process and a filtering procedure to remove both enveloped and non-enveloped viruses.

Because no purification method has been shown to be totally effective in removing the risk of viral infectivity from plasma-derived preparations and because new blood-borne viruses or other disease agents may emerge which may not be inactivated by the manufacturing process or the chemical (solvent/detergent) treatment procedures currently used, administer VZIG only when a benefit is expected.

Any infection believed to have been transmitted by VZIG should be reported to the manufacturer at 800-768-2304.

Sensitivity Reactions

Hypersensitivity Reactions

Although not reported to date with VZIG, anaphylaxis reported rarely following administration of other human immune globulins.

Weigh potential benefit of VZIG against potential for hypersensitivity reactions.

Epinephrine and other appropriate therapy should be readily available in case anaphylaxis occurs.

If hypotension or a hypersensitivity reaction (e.g., anaphylaxis) occurs, immediately discontinue VZIG and institute appropriate therapy (e.g., epinephrine) as indicated.

Selective IgA Deficiency

Individuals with IgA deficiency may have antibodies to IgA or may develop such antibodies following administration of VZIG preparations containing IgA. Hypersensitivity (including anaphylactic reactions) may occur.

VariZIG^® contains trace amounts (<40 mcg/mL) of IgA. As little as 15 mcg of IgA per mL of blood product may elicit an anaphylactic reaction in individuals with IgA deficiency.

General Precautions

Administration Precautions

Administer under supervision of a qualified health professional experienced in use of passive immunizing agents and management of pregnant women exposed to VZV.

Administer in clinical settings with adequate diagnostic and treatment facilities readily available to manage therapy and any possible complications.

Monitor patient for adverse effects for at least 20 minutes after administration of VZIG.

Thrombotic Events

Thrombotic events reported in patients receiving IGIV. Patients at risk for such events include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity.

Potential for thrombotic events is significantly lower with VZIG than with IGIV because of differences in amount of protein infused, volume infused, and relative health of the patient population receiving VZIG.

Although risk for thrombotic events with VZIG appears to be extremely low, use caution in those at risk for hyperviscosity (e.g., those with cryoglobulins, fasting chylomicronemia/markedly high triglycerides, monoclonal gammopathies). IM administration of VZIG may be preferred instead of IV administration in such patients since thrombotic events have only been reported following IV administration of immune globulins.

Renal Effects

Renal dysfunction, acute renal failure, osmotic nephrosis, proximal tubular nephropathy, and death reported in patients receiving IGIV. Patients at increased risk for IGIV-associated acute renal failure include those receiving known nephrotoxic drugs and those with any degree of preexisting renal insufficiency or with diabetes mellitus, volume depletion, sepsis, or paraproteinemia.

Adverse renal effects occur most frequently with IGIV preparations stabilized with sucrose and given in dosages providing ≥400 mg of sucrose daily. VZIG does not contain sucrose as a stabilizer and contains lower amounts of protein than IGIV preparations.

Transfusion-related Acute Lung Injury

Transfusion-related acute lung injury (noncardiogenic pulmonary edema) reported in patients receiving IGIV. Typically occurs within 1–6 hours after the IGIV infusion and is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever.

The potential for severe respiratory complications is significantly lower with VZIG than with IGIV because of differences in amount of protein infused, volume infused, and relative health of the patient population receiving VZIG.

Although risk for severe respiratory complications with VZIG appears to be extremely low, use caution in those with preexisting respiratory conditions. IM administration of VZIG may be preferred instead of IV administration in such patients since severe respiratory adverse events have only been reported following IV administration of immune globulins.

Monitor for adverse pulmonary reactions. If transfusion-related acute lung injury is suspected, perform appropriate tests for the presence of antineutrophil antibodies in both the product and patient serum. Manage with oxygen therapy with adequate ventilatory support.

Individuals with Altered Immunocompetence

May be administered to individuals immunosuppressed as the result of disease or immunosuppressive therapy.

Immunocompromised individuals without evidence of varicella immunity are at high risk of severe or disseminated varicella and generally should receive VZIG for postexposure prophylaxis.

VZIG is recommended for postexposure prophylaxis in individuals without evidence of varicella immunity who are immunosuppressed because they are receiving corticosteroid therapy (prednisone or equivalent) in a dosage ≥2 mg/kg daily or ≥20 mg daily.

VZIG is recommended for postexposure prophylaxis in HIV-infected children and adults (including pregnant women) without evidence of varicella immunity.

Not indicated for individuals who previously received age-appropriate varicella vaccination and subsequently became immunocompromised as the result of disease or immunosuppressive therapy later in life.

Bone marrow transplant recipients should be considered susceptible to varicella, regardless of previous history of varicella or varicella vaccination in themselves or in their donors. However, those who develop varicella or herpes zoster after transplantation should be considered immune to varicella.

Limitations of Effectiveness

May prevent or modify varicella if given within 4 days (96 hours) of exposure. Immune globulins not effective once disease is established.

Use of VZIG for postexposure prophylaxis in pregnant women exposed to VZV may prevent or reduce severity of varicella in the woman, but such prophylaxis in the mother does not prevent fetal infection.

In some patients, VZIG may not prevent varicella and may prolong the incubation period from 10–21 days to ≥28 days. Closely observe patient for signs and symptoms of varicella for 28 days after exposure; immediately initiate antiviral therapy if signs or symptoms of varicella occur.

Passive immunization with VZIG only provides short-term protection against VZV (see Duration of Immunity under Cautions). Unless varicella vaccine is contraindicated, patients who receive VZIG for postexposure prophylaxis should receive active immunization with the vaccine ≥5 months after VZIG. (See Specific Drugs and Laboratory Tests under Interactions.) Varicella vaccine is not needed if the patient developed varicella despite administration of VZIG.

Duration of Immunity

Duration of protection against VZV following administration of VZIG unknown. Single dose of VZIG provides passive immunity to VZV that should last about 3 weeks.

Administer a second dose of VZIG if another exposure to VZV occurs in a susceptible individual at high risk who cannot receive varicella vaccine.

Serologic Testing

After a dose of VZIG, passively-acquired anti-VZV may interfere with serologic tests used to determine immunity to VZV for ≥3 months. (See Specific Drugs and Laboratory Tests under Interactions.)

Because some patients who receive VZIG for postexposure prophylaxis may have asymptomatic varicella infections, some experts recommend follow-up serologic testing ≥2 months after VZIG to determine immune status in case a subsequent exposure occurs. Other experts suggest that serologic tests are unreliable in immunocompromised individuals and asymptomatic infections in such individuals may not confer lasting protection; these experts recommend use of VZIG in immunocompromised individuals after subsequent VZV exposure regardless of serologic test results.

When serologic testing is performed to determine immune status after natural varicella, positive antibody results are reliable but negative antibody results may not be reliable.

Specific Populations

Pregnancy

Category C.

A decision to use VZIG for postexposure prophylaxis of VZV in a pregnant woman should be made on an individual basis taking into consideration the woman's health status, type of exposure, and likelihood of previously unrecognized varicella infection.

Because of potential risks to the neonate from exposure to VZV infection, pregnancy is not considered a contraindication to use of VZIG when indicated.

ACIP states there are no known risks associated with use of immune globulins for passive immunization in pregnant women.

Lactation

Not known whether VZIG is distributed into milk; use caution.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Although specific studies evaluating currently available VZIG in pediatric patients not available, previously available preparations of VZIG have been effective in at-risk pediatric populations and similar efficacy is likely.

ACIP and AAP recommend use of VZIG in neonates† whose mothers had signs and symptoms of varicella at the time of delivery (i.e., from 5 days before to 2 days after delivery) and in certain premature infants†. ACIP and AAP also recommend use of VZIG in susceptible immunocompromised children† exposed to VZV. (See Postexposure Prophylaxis of Varicella Zoster Virus [VZV] under Uses.)

Geriatric Use

Safety and efficacy not established in geriatric individuals >65 years of age. Data not available to date regarding use in this age group.

Common Adverse Effects

Pain at injection site, headache, rash, chills, fever, vomiting, nausea, arthralgia, low back pain, allergic reactions.

Interactions

Live Vaccines

Antibodies present in immune globulins, including VZIG, may interfere with the immune response to certain live virus vaccines (e.g., measles virus vaccine live, mumps virus vaccine live, rotavirus vaccine live oral, rubella virus vaccine live, varicella virus vaccine live); these vaccines should not be administered simultaneously with or for specified intervals before or after administration of VZIG. (See Specific Drugs and Laboratory Tests under Interactions.) There is no evidence that immune globulin preparations interfere with the immune response to yellow fever virus vaccine live, typhoid vaccine live oral, influenza virus vaccine live intranasal, or poliovirus vaccine live oral (OPV; no longer commercially available in the US).

Inactivated Vaccines and Toxoids

Immune globulins, including VZIG, are not expected to have a clinically important effect on the immune response to inactivated vaccines or toxoids; inactivated vaccines, recombinant vaccines, polysaccharide vaccines, and toxoids may be administered simultaneously with (using different syringes and different injection sites) or at any interval before or after administration of VZIG. Neonates who received VZIG at birth can receive age-appropriate inactivated vaccines according to the usually recommend childhood immunization schedule.

Specific Drugs and Laboratory Tests

Pharmacokinetics

Absorption

Bioavailability

Following IV administration of VZIG, peak serum concentrations of immune globulin are attained in <3 hours.

Following IM administration of VZIG, bioavailability is expected to be almost 100%. Anti-VZV antibodies are detected within 2–3 days and peak within 3–7 days.

Although concentrations of passively-acquired antibody are higher and achieved more quickly following IV administration than IM administration, levels of circulating antibodies over time are expected to be similar with both routes.

Distribution

Extent

Following IV administration of VZIG, anti-VZV is expected to be quickly distributed between plasma and extravascular spaces.

Not known whether VZIG is distributed into milk.

Elimination

Metabolism

Immune globulins are metabolized in the reticuloendothelial system.

Half-life

Half-life of hyperimmune globulins generally is about 18–24 days following IV administration and 24–30 days following IM administration. Half-life is expected to show interindividual variation.

Anti-VZV antibodies persist for ≥6 weeks after a single dose of VZIG. Protection against VZV may last approximately 3 weeks.

Stability

Storage

Parenteral

Powder, for Injection

2–8°C. Do not freeze.

After reconstitution, store for up to 12 hours at 2–8°C.

Does not contain thimerosal or any other preservatives.

Actions

• Currently available VZIG is a lyophilized preparation of purified IgG fraction containing anti-VZV prepared from plasma of healthy adults with high titers of anti-VZV.
• Potency of VZIG is expressed in international units by comparison to the WHO international anti-VZV immune globulin reference preparation.
• Primary VZV infection results in varicella (chickenpox); reactivation of infection results in herpes zoster.
• Varicella usually is self-limited in otherwise healthy children. In neonates or immunocompromised children or adults, varicella is associated with a high risk of severe or disseminated disease (e.g., pneumonia, encephalitis, multiple organ system involvement) and death.
• Maternal-fetal transmission of VZV can cause congenital varicella syndrome resulting in low birthweight, cutaneous scarring, limb hypoplasia, microcephaly, cortical atrophy, chorioretinitis, cataracts, and other anomalies and may result in fetal death. Congenital varicella syndrome occurs most frequently in infants born to women who had varicella at about 13–20 weeks of gestation. Severe neonatal infection, including fatalities, can occur when varicella develops in neonates born to women who had onset of varicella from 5 days before to 2 days after delivery.
• Varicella is highly contagious; the secondary infection rate is 85% in healthy, susceptible individuals exposed through household contact. Individuals usually are contagious from 1–2 days before rash onset through 5–6 days after rash onset. Immunocompromised individuals may be contagious for a longer period of time, presumably because their immune system is depressed allowing viral replication to persist.
• In susceptible pregnant women exposed to varicella, postexposure prophylaxis with VZIG decreases the rate of infection to about 30%. Although use of VZIG in susceptible pregnant women may prevent or ameliorate clinical disease in the mother, such prophylaxis in the mother does not appear to prevent viremia, fetal infection, congenital varicella syndrome, or varicella in her neonate.
• When VZIG postexposure prophylaxis is used in neonates exposed to VZV in utero within 7 days of delivery, the rate of infection is not substantially decreased compared with neonates who do not receive postexposure prophylaxis; however the incidence of severe neonatal varicella and fatal outcomes is substantially decreased in those who do become infected.
• In susceptible immunocompromised children exposed to VZV, postexposure prophylaxis with VZIG decreases, but does not eliminate, the risk of infection (attack rate following such prophylaxis is decreased to ≤60%); however, VZIG substantially decreases the incidence of severe varicella in those who do become infected.

Advice to Patients

• Advise patient and/or patient's parent or guardian of the risks and benefits of VZIG.
• Advise patient and/or patient's parent or guardian that VZIG is prepared from pooled human plasma. Although improved donor screening and viral-inactivating and purification procedures used in manufacture of plasma-derived preparations have reduced the risk of pathogen transmission, VZIG is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and HIV infection, and theoretically may carry a risk of transmitting the causative agent of CJD or vCJD.
• Advise patients that allergic or anaphylactic reactions to VZIG are rare, but these reactions can occur in individuals with a history of allergy to blood products or with IgA deficiency. Importance of informing clinician of any prior allergic reactions to blood products or prior diagnosis of IgA deficiency.
• Because VZIG may impair the immune response to certain live virus vaccines (e.g., measles vaccine, mumps vaccine, rotavirus vaccine, rubella vaccine, varicella vaccine), importance of informing clinician of any recent vaccinations.
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

VZIG is no longer commercially available in the US, but is available under an IND expanded access protocol. Contact the distributor, FFF Enterprises, at 800-843-7477 for information regarding the IND protocol and how to obtain VZIG.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions June 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.