Clesrovimab-cfor (Enflonsia)

Number: 1088

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Brand Selection for Medically Necessary Indications for Commercial Medical Plans

According to Aetna commercial benefit plans, health care services are considered not medically necessary if they are more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that member’s illness, injury or disease. Aetna commercial plans may require a trial of a lower-cost drug (preferred medication) that is at least as likely to produce equivalent therapeutic results before approving coverage for a higher-cost drug within the same therapeutic class. For a list of preferred drugs, refer to the Aetna Commercial Clinical Program Summary.

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses clesrovimab-cfor (Enflonsia) for commercial medical plans. 

1. Criteria for Initial Approval

   Aetna considers the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recommendations for a single intramuscular injection of clesrovimab-cfor (Enflonsia) medically necessary for the prevention of lower respiratory tract disease (LRTD) caused by the respiratory syncytial virus (RSV) when any of the following criteria is met:

   1. For infants less than 8 months old born during or entering their first RSV season and the following criteria are met: (For maternal RSV vaccine, see CPB 1027 - Respiratory Syncytial Virus (RSV) Vaccine)

      1. One of the following criteria is met:

         1. Maternal RSV vaccine was not received or maternal RSV vaccine status is unknown; or
         2. Maternal RSV vaccine was received and infant was born less than 14 days after maternal vaccination; or 
         3. Maternal RSV vaccine was received in a prior pregnancy; and
            

      2. Infant has not previously received a clesrovimab-cfor, nirsevimab-alip, or palivizumab dose; or

   2. Per the CDC’s ACIP, most infants will only need protection from either the maternal RSV vaccine (Pfizer’s bivalent RSVpreF, Abrysvo) or infant immunization (clesrovimab), but not both. For maternal RSV vaccine with Abrysvo, see CPB 1027 - Respiratory Syncytial Virus (RSV) Vaccine. However, there may be circumstances for which infant immunization with clesrovimab can be considered when maternal RSV vaccine was received 14 or more days prior to birth or was received during a previous pregnancy. The following indications may be considered per clinical judgment of the healthcare provider and infant has not previously received a clesrovimab-cfor, nirsevimab-alip, or palivizumab dose before or during their first RSV season:

      1. When pregnant individual may not have mounted an adequate immune response to vaccination (e.g., members with immunocompromising conditions) or have conditions associated with reduced transplacental antibody transfer (e.g., members living with HIV infection); or
      2. Infant who has had cardiopulmonary bypass, extracorporeal membrane oxygenation (ECMO), or exchange transfusion leading to loss of RSV antibodies; or
      3. Infant with substantially increased risk for severe RSV disease (e.g., hemodynamically significant congenital heart disease, intensive care admission, and requiring oxygen at discharge); or

   3. For infants undergoing cardiac surgery with cardiopulmonary bypass, ECMO, or exchange transfusion during or entering their first RSV season, an additional dose of Enflonsia may be administered as soon as the child is stable after surgery to ensure adequate clesrovimab-cfor serum levels.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Related Policies 

   1. CPB 0155 - Ribavirin (Virazole) Inhalation
   2. CPB 0318 - Palivizumab (Synagis)
   3. CPB 1027 - Respiratory Syncytial Virus (RSV) Vaccine
   4. CPB 1038 - Nirsevimab-alip (Beyfortus)

Dosage and Administration

Enflonsia is a sterile, preservative-free, solution containing 105 mg of clesrovimab-cfor that is supplied in a single-dose prefilled syringe for intramuscular (IM) injection.

The recommended dose for neonates and infants born during or entering their first RSV season is 105 mg administered as a single IM injection by a healthcare provider.

For infants undergoing cardiac surgery with cardiopulmonary bypass during or entering their first RSV season, an additional 105 mg dose administered as an IM injection is recommended as soon as the infant is stable after surgery to ensure adequate clesrovimab-cfor serum levels. 

Source: Merck & Co., 2025

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
90382	Respiratory syncytial virus, monoclonal antibody, seasonal dose, 0.7 mL, for intramuscular use
Other CPT codes related to the CPB:
90380	Respiratory syncytial virus, monoclonal antibody, seasonal dose; 0.5 mL dosage, for intramuscular use
90381	Respiratory syncytial virus, monoclonal antibody, seasonal dose; 1 mL dosage, for intramuscular use
90678	Respiratory syncytial virus vaccine, preF, subunit, bivalent, for intramuscular use
90679	Respiratory syncytial virus vaccine, preF, recombinant, subunit, adjuvanted, for intramuscular use
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96380	Administration of respiratory syncytial virus, monoclonal antibody, seasonal dose by intramuscular injection, with counseling by physician or other qualified health care professional
96381	Administration of respiratory syncytial virus, monoclonal antibody, seasonal dose by intramuscular injection
ICD-10 codes covered if selection criteria are met:
B20	Human immunodeficiency virus [HIV] disease
B97.4	Respiratory syncytial virus as the cause of diseases classified elsewhere
Q20.0 - Q28.9	Congenital malformations of the circulatory system
Z29.11	Encounter for prophylactic immunotherapy for respiratory syncytial virus (RSV)
Z95.1	Presence of aortocoronary bypass graft
Z99.81	Dependence on supplemental oxygen

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Enflonsia is a respiratory syncytial virus (RSV) F protein-directed fusion inhibitor indicated for the prevention of RSV lower respiratory tract disease in neonates and infants who are born during or entering their first RSV season.

Respiratory syncytial virus (RSV) is an enveloped single-stranded, negative-sense ribonucleic acid (RNA) virus of the Pneumovirdae family that can cause acute respiratory tract illness in persons of all ages. RSV is considered a common respiratory pathogen typically resulting in self-limited, mild, cold-like symptoms that can last around one to two weeks. However, for some people, the virus can lead to an infection that spreads to the lower respiratory tract, causing bronchiolitis or pneumonia, resulting in a severe or life-threatening illness. Those who are most vulnerable for severe infection include infants (especially premature infants), older adults (especially those 65 years and older), people with certain comorbid conditions (e.g., cardiac and pulmonary disease), and those who are immunocompromised. In most parts of the United States, RSV circulation is seasonal, typically starting during the fall and peaking in the winter. It is transmitted from person to person through close contact with someone who is infected.

Currently, there is not a "vaccine" readily available to prevent RSV in infants and children less than 2 years of age. However, since 1998, palivizumab, a humanized monoclonal antibody against the RSV F glycoprotein, has been available for the prevention of serious RSV lower respiratory tract disease in children, but only for those at high risk of RSV disease, and is only administered during RSV season. In July 2023, the FDA approved nirsevimab-alip (Beyfortus) (Sanofi Pasteur and AstraZeneca), a monoclonal antibody against the RSV F glycoprotein with an extended half-life, to protect all infants through their first RSV season. Approval also included use for children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. Palivizumab and nirsevimab are classified as an immunoprophylactic drug, not a vaccine. They act similarly to a vaccine; however, instead of prompting the immune system to develop antibodies to the virus (considered active immunization), they deliver the antibodies directly to the bloodstream (considered passive immunization).

Clesrovimab-cfor is a respiratory syncytial virus F protein-directed fusion inhibitor, a fully human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody produced in recombinant Chinese hamster ovary (CHO) cells. Passive immunity is provided by clesrovimab-cfor, which targets the extracellular domain of the RSV fusion (F) protein to prevent fusion of the viral and cellular membranes and viral entry. Clesrovimab-cfor is branded as Enflonsia (Merck & Co., Inc.).

In June 2025, the FDA granted approval to Merck's Enflonsia (clesrovimab-cfor) for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants who are born during or entering their first RSV season. Enflonsia is a long-acting monoclonal antibody (mAb) designed to provide direct, rapid and durable protection through 5 months, a typical RSV season, with the same 105 mg intramuscular (IM) dose regardless of body weight. A typical RSV season usually spans autumn to spring of the next year.

FDA approval was based the CLEVER trial, a Phase 2b/3 randomized, double-blind, placebo-controlled, multi-site, international trial (Trial 004), evaluating a single dose of Enflonsia administered to in early and moderate preterm infants (greater than or equal to 29 to less than 35 weeks gestational age [GA]) and late preterm and full-term infants (greater than or equal to 35 weeks GA). Participants were randomized 2:1 to receive either a single 105 mg dose of Enflonsia (n= 2411) or saline placebo (n=1203) by IM injection. The primary endpoint was the incidence of medically attended RSV-associated lower respiratory tract infection (MALRI) through 150 days post-dose. The trial demonstrated a reduction in incidence of RSV-associated MALRI requiring greater than or equal to 1 indicator of lower respiratory infection or severity compared to placebo through 5 months by 60.5% (95% CI: 44.2, 72.0, p<0.001) (incidence rates: Enflonsia, 0.026; placebo, 0.065). The trial also met its key secondary endpoint, a reduction in RSV-associated hospitalizations through 5 months by 84.3% (95% CI: 66.7, 92.6, p<0.001) (incidence rates: Enflonsia, 0.004; placebo, 0.024), showing increasing efficacy with increasing disease severity.

FDA approval is also supported by results from the Phase 3 SMART trial (MK-1654-007) which evaluated the safety and efficacy of Enflonsia versus palivizumab in infants at increased risk for severe RSV disease.

The SMART trial (Trial 007) was a randomized, partially-blind, palivizumab-controlled, multi-site, international trial that evaluated the efficacy of Enflonsia in early (<29 weeks GA) or moderate preterm infants (≥29 to ≤35 weeks GA), and infants with chronic lung disease of prematurity or congenital heart disease of any GA, who are at increased risk for severe RSV disease. Participants were randomized to receive Enflonsia or palivizumab by IM injection. Participants randomized to Enflonsia received a single 105 mg dose on Day 1 followed by a dose of placebo one month later; 15 mg/kg palivizumab was administered on Day 1 and every month thereafter for a total of 3 to 5 doses. The efficacy of Enflonsia in infants at increased risk for severe RSV disease—including those born prematurely or with chronic lung disease of prematurity or congenital heart disease—was established through extrapolation from Trial 004 to Trial 007, based on comparable pharmacokinetic exposure profiles. In Trial 007, the incidence of RSV-associated MALRI through 150 days post-dose was 3.6% (95% CI: 2.0–6.0) in the Enflonsia group and 2.9% (95% CI: 1.5–5.2) in the palivizumab group, indicating similar effectiveness. Likewise, the incidence of RSV-associated hospitalization was 1.3% (95% CI: 0.4–2.9) for Enflonsia and 1.5% (95% CI: 0.5–3.2) for palivizumab, supporting the use of Enflonsia as a comparable alternative in this high-risk population.

Labeled warnings and precautions include risk of hypersensitivity, including anaphylaxis, which have been observed with other human immunoglobulin G1 (IgG1) monoclonal antibodies. The most common adverse reactions were injection-site erythema (3.7%), injection-site swelling (2.7%) and rash (2.3%).

The safety and effectiveness of Enflonsia have not been established in children older than 12 months of age.

Enflonsia can be given concomitantly with childhood vaccines. There is no information regarding co-administration of Enflonsia with other immunoglobulin products. Moreover, there are no data regarding substitution of Enflonsia for palivizumab once prophylaxis treatment is initiated with palivizumab for the RSV season. 

Clesrovimab-cfor may interfere with some immunologically-based RSV diagnostic assays (i.e., rapid antigen tests) as observed in laboratory studies. Confirmation using a reverse transcriptase polymerase chain reaction (RT-PCR) assay is recommended when rapid antigen assay results are negative and clinical observations are consistent with RSV infection.  

Enflonsia is not indicated for use in females of reproductive potential.

Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) 

On April 16, 2025, the ACIP proposed clinical considerations for clesrovimab, which include the following (with comparison to nirsevimab) (Jones, 2025):

• Clesrovimab and nirsevimab recommendations would be the same for use in infants younger than 8 months of age born during or entering their first RSV season. No preferential recommendation for use of clesrovimab versus nirsevimab;
• Only nirsevimab recommended for children ages 8 through 19 months who are at increased risk of severe RSV disease and entering their second RSV season;
• For clesrovimab or nirsevimab, one dose for infants younger than 8 months of age born during or entering their first RSV season (administration during October through March in most of the continental U.S.) if:
  
  
  • The mother did not receive RSV vaccine during pregnancy
  • The mother’s RSV vaccination status is unknown
  • The infant was born less than 14 days after maternal RSV vaccination
    
    
• Most infants will not need both maternal vaccination and an RSV antibody
• When RSV antibody may be considered for infants born to vaccinated mothers:
  
  
  • Born to mothers who may not mount an adequate immune response to vaccination (e.g., immunocompromising conditions)
  • Born to mothers who have conditions associated with reduced transplacental antibody transfer (e.g., living with HIV infection)
  • Infants who have procedures leading to loss of maternal antibodies (e.g., cardiopulmonary bypass, extracorporeal membrane oxygenation [ECMO], exchange transfusion)
  • Infants with substantially increased risk for severe RSV disease (e.g., hemodynamically significant congenital heart disease, ICU admission with oxygen requirement at discharge) 
    
    

• Timing of administration:

  • For infants born October through March

    • Administer in the first week of life—ideally during the birth hospitalization
    • Infants with prolonged birth hospitalizations due to prematurity or other causes should be immunized shortly before or promptly after discharge
    • If not given in the hospital, administer in outpatient settings
      
      
  • For infants born April through September - Optimal timing is shortly before the RSV season begins (i.e., October through November)
  • In jurisdictions with differing RSV seasonality (e.g., Alaska, southern Florida, Puerto Rico, and other jurisdictions with tropical climates), providers should follow state, local, or territorial guidance on the timing of administration
  • Recommendations for the timing of infant RSV antibody administration are flexible
    
    
    • Recommended that CDC provide national recommendations with flexibility for state and local jurisdictions but avoid providing region-specific recommendations due to the complexity of implementation
    • Making annual changes to the timing of RSV antibody administration would be complicated for jurisdictions and providers
      
      

  • Health care providers may use clinical judgment to determine when to give infant RSV antibodies outside of October through March.

On June 26, 2025, the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) voted to recommend clesrovimab-cfor as an option for the prevention of RSV lower respiratory tract disease (LRTD) in infants younger than 8 months of age who are born during or entering their first RSV season. The ACIP also voted to include clesrovimab-cfor in the Vaccines for Children Program.

The ACIP’s recommendation for clesrovimab-cfor is provisional and will be official once reviewed and finalized by the CDC Director or the Health and Human Services Secretary (in the absence of a CDC Director).

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References