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Immune Globulins for Post-Exposure Prophylaxis
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Aetna clinical policy bulletin defining medical necessity criteria, continuation criteria, precertification requirements, dosing guidance, and applicable billing codes for various immune globulin products used for post-exposure prophylaxis and treatment (e.g., hepatitis A/B, CMV, Rho-D, rabies, varicella, tetanus, vaccinia, infantile botulism, IGIM/GamaSTAN). This part (1 of 3) includes policy statements, continuation rules, dosing/administration for IGIM, FDA indications/limitations, background and related evidence, and extensive CPT/HCPCS/ICD-10 code lists.
No material clinical or coverage changes in this update.
Coverage Summary
This policy (Clinical Policy Bulletin Number: 0544; status: CURRENT) defines medical necessity, continuation criteria, precertification requirements, dosing/administration guidance, and applicable billing codes for immune globulin products used for post-exposure prophylaxis and treatment. Covered products include intramuscular immune globulin (IGIM, GamaSTAN), cytomegalovirus hyperimmune globulin (CMV-Ig/Cytogam), hepatitis B immune globulin (HBIG), Rho-D immune globulin, rabies immune globulin, varicella/varicella-zoster immune globulin (VZIG/VariZIG), infantile botulism immune globulin (BabyBIG/BIG-IV), vaccinia/vaccinia immune globulin (VIG/VIGIV), tetanus immune globulin, and others. Intended audience includes clinical and billing/operations teams responsible for utilization management, prior authorization, dosing and coding for these products.
Medical-Necessity Criteria
Hepatitis B Immune Globulin - Initial Approval
Aetna considers hepatitis B immune globulin medically necessary when ALL of the following groups/conditions are met or present:
Risk groups (ONE of)
- Infants born to hepatitis B surface antigen (HBsAg)-positive mothers
- Persons with percutaneous or permucosal exposure to HBsAg-positive blood
- Sexual contacts of HBsAg-positive persons
- Household exposure of infants less than 1 year of age to a primary caregiver with acute HBV infection
Other indication (ONE of)
- Prolonged use for prophylaxis of recurrent hepatitis B infection in HBsAg-positive liver transplant recipients
Hepatitis B Immune Globulin - Continuation
Continuation of therapy considered medically necessary when ALL initial criteria are met:
Cytomegalovirus (CMV) Immune Globulin - Initial Approval
Aetna considers CMV immune globulin medically necessary when ANY of the following apply:
ANY of the following
- Treatment of severe CMV disease in transplant recipients
- Prophylaxis of CMV disease in CMV-negative renal transplant recipients receiving a CMV-positive donor organ
- Prophylaxis of CMV disease in lung, liver, pancreas, and heart transplant recipients receiving a CMV-positive donor
CMV Immune Globulin - Continuation
Continuation considered medically necessary when initial criteria are met:
Rho-D Immune Globulin - Initial Approval
Aetna considers Rho-D immune globulin medically necessary when ANY of the following apply:
ANY of the following
- Preventing hemolytic disease of the newborn
- All unsensitized Rh-negative women at 24 to 28 weeks gestation unless father is known to be Rh-negative
- Repeat postpartum dose if an Rh-positive infant is delivered
- Administration after obstetric complications (amniocentesis, chorionic villus sampling, ectopic pregnancy, pregnancy termination, cordocentesis, fetal surgery or manipulation including external version, antepartum placental hemorrhage, antepartum fetal death, miscarriage, stillbirth) in unsensitized Rh-negative women unless father known Rh-negative
- Treatment of Rh-positive persons with idiopathic thrombocytopenic purpura
Rho-D Immune Globulin - Continuation
Continuation considered medically necessary when initial criteria are met:
Rabies Immune Globulin - Initial Approval
Aetna considers rabies immune globulin medically necessary when ANY of the following exposure circumstances apply:
ANY of the following
- Treatment of rabies exposure where the animal has escaped or is known to be rabid at the time of direct exposure or attack
- Post-exposure prophylaxis in the setting of a dog bite if the health status of the dog is unavailable
Rabies Immune Globulin - Continuation
Continuation considered medically necessary when initial criteria are met:
Varicella Zoster Immune Globulin (VZIG) - Initial Approval
Aetna considers VZIG medically necessary when ANY of the following high-risk exposure criteria are met:
ANY of the following
- High-risk individuals with significant exposure per AAP recommendations (immunocompromised without history of chickenpox, susceptible pregnant women, newborn infants whose mother had onset within 5 days before delivery or within 48 hours after delivery, hospitalized premature infants ≥28 weeks gestation whose mother has no history, hospitalized premature infants <28 weeks gestation regardless of maternal history)
- Post-exposure prophylaxis with VariZIG as soon as possible within 10 days after exposure for HIV positive individuals who are susceptible (not vaccinated, no history, or seronegative)
Definition of significant exposures (ONE of)
- Household contacts of infected persons
- Face-to-face indoor play with infected persons
- Hospital contact with infected persons
- Newborn infants whose mothers had onset of chickenpox near time of delivery
Varicella Zoster Immune Globulin - Continuation
Continuation considered medically necessary when initial criteria are met:
Tetanus Immune Globulin - Initial Approval
Aetna considers tetanus immune globulin medically necessary when ALL of the following are met:
ALL of the following
- Non-immunized, incompletely immunized, or remotely immunized persons (last complete vaccination >10 years ago)
- Presence of neglected or tetanus-prone wounds (contaminated, necrotizing, or puncture wounds)
Tetanus Immune Globulin - Continuation
Continuation considered medically necessary when initial criteria are met:
Vaccinia (Smallpox) Immune Globulin - Initial Approval
Aetna considers vaccinia immune globulin medically necessary when ANY of the following apply:
ANY of the following
- Treatment of vaccine complications with severe clinical manifestations (e.g., eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, severe ocular viral implantation)
- Treatment of monkeypox infection
Infantile Botulism Immune Globulin - Initial Approval (BIG-IV/BabyBIG)
Aetna considers BIG-IV (BabyBIG) medically necessary when ALL of the following are met:
ALL of the following
- Member is < 1 year of age
- Diagnosis of infant botulism caused by toxin types A or B
IGIM (GamaSTAN) - Initial Approval
Aetna considers IGIM (GamaSTAN) medically necessary for the following indications when specified criteria are met:
ANY of the following
Hepatitis A criteria (ONE of)
- Member was exposed to hepatitis A virus within the past 2 weeks and is not exhibiting clinical manifestation of diseasewithin past 2 weeks
- Member is at high risk for hepatitis A exposure (e.g., travelers to or workers in high endemicity countries, illicit drug users)
- Measles (Rubeola): Prophylaxis of measles in unvaccinated members who have not had measles previously and were exposed within the past 6 days<= 6 days
Rubella
- Member was recently exposed to rubella
- Member is currently pregnant
Varicella
- Member was exposed to varicella within the past 10 dayswithin past 10 days
- Member is at high risk for severe varicella (e.g., immunocompromised persons, newborns/infants, pregnant women)
- Varicella zoster immune globulin (Varizig) is not available
IGIM (GamaSTAN) - Continuation
Continuation considered medically necessary when initial criteria are met:
Coding
| Z20.5 | Contact with and (suspected) exposure to viral hepatitis |
| Z20.6 | Contact with and (suspected) exposure to human immunodeficiency virus [HIV] |
| Z20.828 | Contact with and (suspected) exposure to other viral communicable diseases |
| 90371 | Hepatitis B immune globulin (HBIg), human, for intramuscular use (CPT) |
| J1571 | Injection, hepatitis B immune globulin (Hepagam B), intramuscular, 0.5 ml |
| J1573 | Injection, hepatitis B immune globulin (Hepagam B), intravenous, 0.5 ml |
| Z20.5 | Contact with and (suspected) exposure to viral hepatitis [Hepatitis B] |
| Z48.23 | Encounter for aftercare following liver transplant |
| Z57.8 | Occupational exposure to other risk factors |
| Z94.4 | Liver transplant status |
| B16.0 - B16.9 | Hepatitis B (acute) |
| B18.0 - B18.1 | Chronic viral hepatitis B |
| B19.10 - B19.11 | Unspecified viral hepatitis B |
| Z86.19 | Personal history of other infectious and parasitic diseases [Not covered for prevention of mother-to-child transmission of hepatitis B virus during pregnancy] |
| 90291 | Cytomegalovirus immune globulin (CMV-IgIV), human, for intravenous use (CPT) |
| J0850 | Injection, cytomegalovirus immune globulin intravenous (human), per vial |
| B25.0 - B25.9 | Cytomegaloviral disease |
| P35.1 | Congenital cytomegalovirus infection |
| Z20.828 | Contact with and (suspected) exposure to other viral communicable diseases [cytomegalovirus] |
| T86.00 - T86.99 | Complications of transplanted organs and tissues |
| Z48.21 - Z48.298 | Encounter for aftercare following organ transplant |
| Z94.0 - Z94.9 | Transplanted organ and tissue status |
| 90384 | Rho(D) immune globulin (RHIg), human, full-dose, for intramuscular use (CPT) |
| 90385 | Rho(D) immune globulin (RHIg), human, mini-dose, for intramuscular use (CPT) |
| 90386 | Rho(D) immune globulin (RHIgIV), human, for intravenous use (CPT) |
| J2788 | Injection, Rho D immune globulin, human, minidose, 50 mcg |
| J2790 | Injection, Rho D immune globulin, human, full dose, 300 mcg |
| J2791 | Injection, Rho D immune globulin, human (Rhophylac), intramuscular or intravenous, 10 IU |
| J2792 | Injection, Rho D immune globulin, intravenous, human, solvent detergent, 100 IU |
| D69.3 | Immune thrombocytopenia purpura |
| 90375 | Rabies immune globulin (RIg), human, for intramuscular and/or subcutaneous use |
| 90376 | Rabies immune globulin, heat-treated (RIg-HT), human, for IM/SC use |
| 90377 | Rabies immune globulin, heat- and solvent/detergent-treated (RIg-HT S/D), human, for IM/SC use |
| Z20.3 | Contact with and (suspected) exposure to rabies [dog bite] |
| 90281 | Immune globulin (Ig), human, for intramuscular use |
| 90396 | Varicella-zoster immune globulin, human, for intramuscular use |
| J1460 | Injection, gamma globulin, intramuscular, 1 cc |
| J1560 | Injection, gamma globulin, intramuscular, over 10 cc |
| Z20.820 | Contact with and (suspected) exposure to varicella |
| B20 | Human immunodeficiency virus [HIV] disease |
| 90393 | Vaccinia immune globulin, human, for intramuscular use |
| B04 | Monkeypox |
| T88.1xx+ | Other complications following immunization, not elsewhere classified |
| Z20.828 | Contact with and (suspected) exposure to other viral communicable diseases [vaccinia (smallpox)] |
| B15.0 | Hepatitis A with hepatic coma |
| B15.9 | Hepatitis A without hepatic coma |
| C88.0 | Waldenstrom macroglobulinemia |
| D80.2 | Selective deficiency of immunoglobulin A [IgA] |
| O98.811 - O98.83 | Other maternal infectious and parasitic diseases complicating pregnancy [cytomegalovirus infection] [in utero] |
| H16.001 - H16.9 | Keratitis (listed as contraindicated for this CPB) |
Provider Actions & Billing Rules
Precertification required for IGIM (GamaSTAN)
Precertification of immune globulin human intramuscular injection (IGIM) (GamaSTAN) is required for all Aetna participating providers and members in applicable plan designs. For Commercial plan precertification call (866) 752-7021 or fax (888) 267-3277. For Medicare Part B plans call (866) 503-0857 or fax (844) 268-7263. Affected billing codes: J1460, J1560, 90281.
- Precertification required for IGIM (GamaSTAN)
Statement of Medical Necessity (SMN) for precertification
As part of prior authorization for IGIM (GamaSTAN), providers should submit a Statement of Medical Necessity (SMN) precertification form via Specialty Pharmacy Precertification to support the request.
Do not administer IGIM intravenously
IGIM (GamaSTAN) is available in single‑dose vials (2 mL and 10 mL) for intramuscular use only. Do not administer IGIM intravenously; product is for intramuscular administration only.
Confirm exposure timing and risk status
For post-exposure indications document timing of exposure relative to specified windows (hepatitis A: within 2 weeks; measles: within 6 days; varicella: within 10 days; rubella in pregnant women: recent exposure) and the member's risk status (pregnancy, immunocompromised status, infant age) to support medical necessity.
Assess susceptibility and exposure
Determine susceptibility by history or serology and document whether a significant exposure occurred per ACIP definitions (household contact, face‑to‑face indoor play, hospital contact, newborn with maternal onset near delivery). For pregnant women, obtain serologic testing (immunofluorescent assay or ELISA) if results can be available within 96 hours; if testing is not feasible consider them susceptible.
Dose selection by patient weight for Varizig
Select Varizig dose based on patient weight using the weight‑based vial dosing table: minimum dose 62.5 IU (0.5 vial) for ≤4.4 lb (≤2.0 kg), typical pediatric steps up to 125–500 IU based on weight, and maximum dose 625 IU (5 vials) for patients >40 kg (≥88.1 lb).
Restricted indications for Vaccinia immunoglobulin
Vaccinia immune globulin should be reserved for treatment of severe vaccine complications with serious manifestations (e.g., eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, severe ocular implantation) and use is limited per CDC guidance due to constrained supplies.
Rabies PEP regimen timing
For rabies post‑exposure prophylaxis in previously unvaccinated persons, give a single RIG dose intramuscularly at time zero and administer rabies vaccine on days 0, 3, 7, and 14. Do not give RIG to previously vaccinated individuals.
Infant botulism treatment window
Administer BIG‑IV (BabyBIG) promptly for infant botulism; clinical trials treated infants within 3 days of admission and benefit was greater when given within 7 days of admission, with reductions in length of hospital and ICU stay and ventilator use.
BabyBIG dosing and administration
BabyBIG is given as a single IV infusion at the recommended dose of 1.5 ml/kg (75 mg/kg). Begin infusion at 0.5 ml/kg/h and if no reaction after 15 minutes increase to 1.0 ml/kg/h (total infusion ~97.5 minutes at the recommended rate).
IVIG/SCIG COVID-19 potency note
IVIG/SCIG lots produced after emergence of SARS‑CoV‑2 showed rapidly increasing anti‑SARS‑CoV‑2 neutralization capacity over time (e.g., mean neutralization 21 IU/ml in Dec 2020 to 506 IU/ml in June 2021). Pharmacokinetic extrapolations estimated possible steady‑state trough neutralizing IgG levels (e.g., ~16 IU/ml based on May 2021 average lot potency; maximum extrapolated trough up to 64 IU/ml).
Background & Definitions
FDA-approved indications and limitations are specified for each product: GamaSTAN (IGIM) is indicated for prophylaxis or modification of hepatitis A, measles (≤6 days post-exposure), varicella (when VZIG unavailable), and rubella in exposed pregnant women, but must not be used for hepatitis B prophylaxis because it is not standardized for anti-HBs titers. IGIM is supplied as a sterile 16.5% protein solution in 2 mL and 10 mL single-dose vials for intramuscular use only and must not be given intravenously. Dosing recommendations for IGIM are weight- and indication-specific (e.g., hepatitis A 0.1 mL/kg within 2 weeks of exposure; measles 0.25 mL/kg within 6 days; varicella 0.6–1.2 mL/kg if VZIG unavailable; rubella 0.55 mL/kg in exposed pregnant women).
| Term | Definition |
|---|---|
| IGIM (GamaSTAN) | |
| Immune globulin (human) intramuscular injection available as a sterile 16.5% protein solution in 2 mL and 10 mL single‑dose vials for intramuscular use only; FDA‑indicated for prophylaxis/modification of hepatitis A, measles, varicella (when VZIG unavailable), and rubella in specified situations; do not administer intravenously. | |
| CMV-Ig (Cytogam) | |
| Cytomegalovirus immune globulin (Cytogam): purified human IgG derived from pooled adult serum selected for high CMV antibody titers, formulated for intravenous use and approved for prophylaxis/treatment of CMV disease in specified solid‑organ transplant recipients. | |
| Significant exposure (VZV) | |
| Face‑to‑face non‑transient contact (experts variably define as ≥5 minutes or >1 hour), household contact, playmate (face‑to‑face indoor) contact, hospital contact, or exposure to contagious lesions; ACIP guidance and AAP recommendations apply when determining significant exposure for VZIG/VariZIG. | |
| VariZIG | |
| Varicella zoster immune globulin product available in the U.S. via expanded access protocol (Varizig); weight‑based intramuscular dosing with minimum dose 62.5 IU (≈0.5 vial for infants ≤4.4 lb) and maximum dose 625 IU (5 vials) for patients >40 kg; ideally administered within 96 hours of exposure but FDA allows up to 10 days post‑exposure. | |
| BabyBIG / BIG-IV | |
| Botulism immune globulin intravenous (human) — BabyBIG (BIG‑IV): human‑derived antitoxin FDA‑approved for treatment of infant botulism (types A and B); given as a single IV infusion (recommended dose 1.5 mL/kg = 75 mg/kg) with specified infusion rate escalation. | |
| VIGIV | |
| Vaccinia immune globulin intravenous (VIGIV): antibody product from vaccinated individuals approved for treatment of severe complications of vaccinia vaccination (e.g., eczema vaccinatum, progressive vaccinia); limited supply and use reserved for severe vaccine complications; effectiveness for monkeypox is not established. |
Evidence Summary
Key evidence summaries: CMV-Ig (Cytogam) has been associated with marked reductions in CMV-related morbidity in transplant recipients and, when combined with ganciclovir, produced substantially lower rates of severe CMV (e.g., liver transplant incidence reduced from 28% to 5%). Meta-analyses of HBIG plus antiviral therapy after liver transplant showed reduced HBV recurrence (RR ~0.38) but no clear patient or graft survival benefit. BabyBIG (BIG-IV) randomized and open-label studies demonstrated clinically significant reductions in hospital length of stay, ICU time and mechanical ventilation duration for infant botulism when given promptly (single IV infusion 1.5 mL/kg). VariZIG expanded-access data (n=507) showed low varicella rates and similar effectiveness when administered ≤96 hours versus up to 10 days post-exposure; product is available in the U.S. via an expanded access/IND protocol. IVIG/SCIG lots produced after emergence of SARS-CoV-2 showed increasing neutralization capacity (mean rise from ~21 IU/mL to ~506 IU/mL Dec 2020–June 2021) with PK extrapolations estimating possible steady-state troughs (~16 IU/mL to 64 IU/mL). Current monkeypox guidance is low-quality and antivirals are preferred; VIGIV is suggested by some guidelines for severe immunosuppressed cases but effectiveness for MPX is not established.
Definitions
IGIM (GamaSTAN): Immune globulin (human) intramuscular injection available as a 16.5% protein solution in 2 mL and 10 mL single-dose vials for intramuscular use only.
CMV-Ig (Cytogam): Cytomegalovirus immune globulin, human — purified IgG derived from pooled adult human serum selected for high CMV antibody titers, formulated for intravenous administration to raise anti-CMV titers and reduce severe CMV disease in transplant recipients.
Significant exposure (VZV): Face-to-face non-transient contact (definitions vary — commonly ≥5 minutes or >1 hour), household contact, playmate contact, or exposure to contagious lesions; ACIP/AAP criteria define exposures that warrant VZIG/VariZIG.
VariZIG: Varicella zoster immune globulin available in the U.S. via an expanded access protocol (VariZIG 125 IU vials); dosing is weight-based (minimum 62.5 IU for ≤4.4 lb; maximum 625 IU for ≥88.1 lb) and administered intramuscularly; ideal administration within 96 hours but FDA allows up to 10 days post-exposure.
BabyBIG / BIG-IV: Human-derived botulism immune globulin intravenous approved for infant botulism types A and B; given as a single IV infusion 1.5 mL/kg (75 mg/kg) with infusion rate escalation from 0.5 to 1.0 mL/kg/h if tolerated.
VIGIV: Vaccinia immune globulin intravenous — antibody product from vaccinated individuals approved for treatment of severe complications from vaccinia vaccination; limited supply and not proven effective for monkeypox.
Revision History
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