Immune Globulins for Post-Exposure Prophylaxis

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:

Member meets all initial medical necessity criteria

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:

Member meets all initial medical necessity criteria

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:

Member meets all initial medical necessity criteria

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:

Member meets all initial medical necessity criteria

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

Varicella Zoster Immune Globulin - Continuation

Continuation considered medically necessary when initial criteria are met:

Member meets all initial medical necessity criteria

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:

Member meets all initial medical necessity criteria

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

IGIM (GamaSTAN) - Continuation

Continuation considered medically necessary when initial criteria are met:

Member (including new members requesting authorization) meets all initial medical necessity criteria

Coding

Covered HCPCS for IGIM (GamaSTAN)HCPCSCovered

J1460	Injection, gamma globulin, intramuscular, 1 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]
J1560	Injection, gamma globulin, intramuscular, over 10 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]

Covered CPT for IGIM and relatedCPTCovered

90281	Immune globulin (Ig), human, for intramuscular use
90399	Unlisted immune globulin
96372	Therapeutic, prophylactic, or diagnostic injection; subcutaneous or intramuscular

Hepatitis A ICD-10 - covered for exposureICD-10Covered

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

Hep A CPT/HCPCS specificmixedCovered

90281	Immune globulin (Ig), human, for intramuscular use
90399	Unlisted immune globulin
J1460	Injection, gamma globulin, intramuscular, 1 cc
J1560	Injection, gamma globulin, intramuscular, over 10 cc

Hepatitis B codes (covered if selection criteria met)mixedCovered

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

Hepatitis B ICD-10 - not covered (disease codes)ICD-10Not Covered

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]

Cytomegalovirus codesmixedCovered

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

Rho-D Immune Globulin HCPCS/CPTmixedCovered

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

Rabies Immune Globulin codesCPTCovered

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]

Varicella Zoster Immune Globulin codesmixedCovered

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

Tetanus Immune Globulin codesmixedCovered

90389	Tetanus immune globulin (TIg), human, for intramuscular use (CPT)
J1670	Injection tetanus immune globulin, human, up to 250 units
M72.6	Necrotizing fasciitis
T20.00x+ - T25.799+	Burns and corrosions of external body surface

Rubeola (Measles) Immune Globulin codesmixedCovered

90281	Immune globulin (Ig), human, for intramuscular use
90399	Unlisted immune globulin
J1460	Injection, gamma globulin, intramuscular, 1 cc
J1560	Injection, gamma globulin, intramuscular, over 10 cc
Z20.828	Contact with and (suspected) exposure to other viral communicable diseases [rubeola (measles)]

Rubella Immune Globulin codesmixedCovered

90281	Immune globulin (Ig), human, for intramuscular use
90399	Unlisted immune globulin
J1460	Injection, gamma globulin, intramuscular, 1 cc
J1560	Injection, gamma globulin, intramuscular, over 10 cc
Z20.4	Contact with and (suspected) exposure to rubella

Vaccinia (Smallpox) Immune Globulin codesmixedCovered

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)]

Infantile Botulism Immune Globulin codesmixedCovered

90288	Botulism immune globulin, human, for intravenous use [BabyBIG or BIG-IV]
A48.51	Infant botulism
96365	Intravenous infusion, initial, up to 1 hour
96366	Intravenous infusion, each additional hour

ICD-10 codes contraindicated/not covered for this CPBICD-10Not Covered

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

Prior Authorization

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)

Documentation Required

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.

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.

OpenPayer

Immune Globulins for Post-Exposure Prophylaxis

Coverage Summary

Medical-Necessity Criteria

Coding

Provider Actions & Billing Rules

Background & Definitions

Evidence Summary

Definitions

Revision History