COVID Disease — Baricitinib — Clinical Pathway: All Settings

Active COVID-19, Clinical Pathway — All Settings

Baricitinib

Background

Baricitinib is a long-acting Janus kinase (JAK) inhibitor which reduces T-cell activation. In COVID-19, this activity dampens cytokine signaling, including that of IL-2, IL-6, GM-CSF, IFN-gamma, and IL-10. In addition, through inhibition of cellular kinases involved in endocytosis, baricitinib may inhibit viral entry into the host cell. The FDA has issued an EUA for use of baricitinib in hospitalized patients age 2 years and over with COVID-19 who require supplemental oxygen or more respiratory support. This authorization was based on two studies evaluating its use in hospitalized adults with COVID-19. The first was the ACTT-2   trial, which was a randomized controlled trial comparing the combination of baricitinib + remdesivir to remdesivir alone in hospitalized adults with severe or critical COVID-19. This study demonstrated that time to clinical recovery was reduced by 1 day (7 days vs 8 days) in the baricitinib-treated patients. No statistically significant differences in mortality were detected. Importantly, this trial was conducted early in the pandemic prior to use of dexamethasone, which has since become standard of care. COV-BARRIER   was a second randomized controlled trial that compared baricitinib + standard care to standard care alone in hospitalized adults. Standard of care was dictated by local clinic practice but often included dexamethasone (70 to 74% of patients depending on study arm) and infrequently included remdesivir (18 to 19% depending on study arm). Patients requiring mechanical ventilation at the time of enrollment were not eligible for the study. While there was no difference in the primary composite outcome of progression of disease, there was a reduction in 28-day all-cause mortality in the patients treated with baricitinib (8.1% versus 13.1%). Additional information about baricitinib can be reviewed on the EUA Healthcare Provider Fact Sheet and the
FDA baricitinib package insert.

Indications

Use of baricitinib (in addition to dexamethasone) can be considered on a case-by-case basis in children hospitalized in the ICU who meet all of the following criteria AND in whom the ID and ICU attending agree that therapy is appropriate:

  • Age ≥ 9 years old[1] AND
  • SARS-CoV-2 PCR positive within 72 hours, AND
  • Symptoms attributable to acute COVID-19, AND
  • Within 24 hours of ICU admission or onset of respiratory failure, AND
  • Evidence of hyperinflammation (e.g., elevated CRP[2]), AND
  • At least one of the following:
    • New significant non-invasive mechanical ventilation requirement (e.g., BiPap support with >40% FiO2) or invasive ventilation
    • Rapidly escalating respiratory support needs not yet meeting this requirement
    • Significant increase in baseline mechanical ventilation support
    • Hemodynamic instability despite fluid resuscitation with a vasopressor or extracorporeal support requirement attributable to COVID-19 hyperinflammation

[1] For critically ill children age 2- < 9 years old with acute COVID-19 who otherwise meet the criteria above, use of baricitinib could be considered on a case-by-case basis with extreme caution and in discussion with COVID-19 therapeutics committee (critical care points of contact Katie Chiotos and Julie Fitzgerald), weighing patient acuity and specific comorbidities that may place a patient at higher risk of severe disease. The rationale for suggesting use in children 9 and over is that ARDS or cardiovascular failure related to acute COVID-19 are less common in children under 9 years old vs. older children and adolescents. Further, limited data exist on baricitinib in young children and this drug has not been studied for treatment of COVID-19 in pediatric populations

[2] No specific cut-point for CRP is established. The median CRP reported in the COV-BARRIER study was 6.5 mg/L.

Baricitinib should be administered in combination with dexamethasone unless there is a contraindication to dexamethasone. Clinicians should consider a time-limited (e.g., up to 12-24 hours) trial of dexamethasone and supportive care with observation for clinical improvement prior to administration of baricitinib.

Instructions for ordering providers

After the ID/ICU teams agree that treatment with baricitinib is indicated, the following steps should be completed:

  1. Provide the patient/family with the Patient and Family Fact Sheet (available in English and Spanish).
  2. Obtain informed consent (ICU or ID fellow or attending can obtain consent) – link to consent form is also included in the order
  3. Order baricitinib using the COVID-19 inpatient orderset
  4. Report all medication errors and adverse events (death, serious adverse events[1]) considered potentially related to baricitinib within 7 days of the event to FDA MedWatch  .

[1] Serious adverse events include any of the following occurring while receiving baricitinib:
death, life-threatening event, event resulting in hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.

Baricitinib dosing and administration

Baricitinib comes in tablet form as an immediate release tablet, which can be taken orally or can be crushed, dispersed in water, and given via a NG or G-Tube. Absorption following post-pyloric administration is unknown and is not recommended.

Age group Dose Dose Comment
Less than 2 years Not authorized Not authorized
2 years-less than 9 years 2 mg once daily PO x 14 days or hospital discharge/discharge readiness, whichever occurs first Use with caution, recommend discussion with COVID-19 therapeutics committee (critical care points of contact Katie Chiotos and Julie Fitzgerald)
9 years and older 4 mg once daily PO x 14 days or hospital discharge/discharge readiness, whichever occurs first Dose adjustment is necessary in patients with renal impairment, see table below.

Baricitinib monitoring

  • Baseline CBC and CMP
  • Daily CBC and CMP (attention to absolute lymphocyte count, absolute neutrophil count, platelet count, creatinine, ALT, AST, see below for criteria for drug discontinuation)
  • Baseline Quantiferon Gold and hepatitis B serologies (hepatitis B surface antibody, core antibody, and surface antigen) – results need not be back to start therapy.
  • VTE prophylaxis per COVID-19 pathway guidance (or per ICU standard of care based on patient risk factors if VTE prophylaxis criteria per COVID-19 pathway not met)

Warnings/contraindications

Use with caution in immunocompromised children and children who are receiving other immunosuppressive medications given risk for opportunistic infections and herpesvirus reactivation syndromes. There are adult data suggesting risk of thromboembolic disease with baricitinib, so ensure patient is receiving the appropriate age-based VTE prophylaxis per pathway guidance. Do not use in patients with known active tuberculosis. See table below for lab monitoring parameters and recommended action.

Parameter Value Action
Absolute lymphocyte count (ALC) ≤ 200 cells/uL Not recommended[1]
Absolute neutrophil count (ANC) ≤ 500 cells/uL Not recommended[1]
Platelets > 1,500,000 cells/uL Not recommended
Aminotransferases ALT/AST >5x upper limit of normal or evidence of synthetic dysfunction [coagulopathy, hypoalbuminemia] Not recommended
eGFR 30 - < 60 mL/minute/1.73 m3 9 years or older: 2 mg PO once daily
2 years - < 9 years: 1 mg PO once daily
GFR < 30 ml/minute/1.73 m3 or dialysis Not recommended

[1] Baricitinib has not been studied in patients with lymphopenia or neutropenia. As it is an immune suppressant it may have additional risks when used in patients with lymphopenia/neutropenia. In clinical trials in other populations, life threatening opportunistic infections including fungal and viral have been seen with prolonged use. We would not recommend its use in patients with an ANC < 200/mm3 or ALC < 200/mm3 outside of exceptional circumstances in discussion with intensive care and infectious diseases. Caution should also be used in patients with ANC < 500/mm3, recognizing normal values for ANC vary based on race and ethnicity.

Empiric treatment for Strongyloides

Patients from regions where Strongyloides stercoralis is endemic (e.g., low/middle income countries with tropical climates) should be treated empirically with ivermectin if receiving baricitinib and dexamethasone in discussion with ID, as there are reports of disseminated Strongyloides in patients with COVID-19 treated with immunomodulators. Of note, ivermectin has no activity against COVID-19 and is being used exclusively for Strongyloides in high-risk patients.

Dosing for children > 15 kg and adults
Ivermectin 200 mcg/kg/dose PO daily x 2 days

Vaccines and Baricitinib

Patients should not receive baricitinib if they received a live, attenuated vaccine within the two weeks prior to therapy due to the concern for vaccine strain infection and/or decreased effectiveness of the vaccine. Current guidance from CDC for vaccine administration in patients with altered immunocompetence also recommends live vaccines should be withheld for 3 months following discontinuation of immunosuppressive therapy. The risk versus benefit of administering a live vaccine sooner than 3 months following discontinuation of baricitinib therapy should be evaluated on a case-by-case basis.