Baricitinib

Usage

• Medical Conditions: Baricitinib is prescribed for the treatment of:

  • Moderately to severely active rheumatoid arthritis (RA) in adult patients who have had an inadequate response or intolerance to one or more disease-modifying anti-rheumatic drugs (DMARDs). It can be used as monotherapy or in combination with methotrexate.
  • Severe alopecia areata in adults.
  • Hospitalized adult and pediatric (2 years and older) patients with COVID-19 requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) (under Emergency Use Authorization).

• Pharmacological Classification: Janus kinase (JAK) inhibitor, Immunomodulator, Anti-inflammatory.

• Mechanism of Action: Baricitinib selectively inhibits JAK1 and JAK2 enzymes, which play a crucial role in cytokine signaling pathways involved in inflammation. By inhibiting these enzymes, baricitinib reduces inflammation and modulates the immune response, thereby alleviating symptoms of the targeted diseases.

Alternate Names

• International Nonproprietary Name (INN): Baricitinib
• Brand Names: Olumiant

How It Works

• Pharmacodynamics: Baricitinib primarily targets intracellular JAK1 and JAK2, key components of signaling pathways utilized by various cytokines associated with inflammation and immune responses. By blocking these enzymes, baricitinib interrupts the downstream cascade that leads to inflammation, thus reducing the symptoms of RA and alopecia areata. In COVID-19, it inhibits the inflammatory response associated with severe disease.

• Pharmacokinetics:

  • Absorption: Baricitinib is rapidly absorbed after oral administration, reaching peak plasma concentrations within 1 hour. Food does not significantly affect absorption.
  • Metabolism: Baricitinib undergoes minimal metabolism, primarily by CYP3A4.
  • Elimination: Primarily eliminated via renal excretion (approximately 75%), with the remainder eliminated in feces. The half-life is approximately 12-13 hours.

• Mode of Action: Baricitinib binds to JAK1 and JAK2, inhibiting their activity. This prevents the phosphorylation of STAT proteins, which would otherwise translocate to the cell nucleus and activate the transcription of genes involved in inflammation.

• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Baricitinib is a selective inhibitor of JAK1 and JAK2 enzymes. It does not significantly inhibit other JAK family members or other kinase families. It does not directly modulate neurotransmitters.

• Elimination Pathways: Primarily renal excretion (about 75%) and to a lesser extent hepatic elimination (fecal excretion).

Dosage

Standard Dosage

Adults:

• Rheumatoid Arthritis: 2 mg orally once daily. Can be increased to 4 mg once daily if the response is inadequate.
• Alopecia Areata: 2 mg orally once daily. Can be increased to 4 mg once daily if the response is inadequate. For extensive scalp hair loss, consider starting with 4 mg. Once an adequate response is achieved, the dosage may be reduced to 2 mg once daily.
• COVID-19: 4 mg orally once daily for 14 days or until hospital discharge, whichever occurs first.

Children:

• COVID-19 (2 years and older):
  • 9 years and older: 4 mg once daily.
  • 2 to less than 9 years: 2 mg once daily.

Special Cases:

• Elderly Patients (≥65 years or ≥75 years): A starting dose of 2 mg once daily may be appropriate due to higher risk of adverse events.
• Patients with Renal Impairment: Dose adjustments are necessary.
  • RA: Moderate impairment (eGFR 30 to <60 mL/min/1.73 m²): 1 mg once daily. Severe impairment (eGFR <30 mL/min/1.73 m²): Not recommended.
  • Alopecia Areata: Moderate impairment: If recommended dose is 2 mg, reduce to 1 mg. If recommended dose is 4 mg, reduce to 2 mg. Severe impairment: not recommended.
  • COVID-19: Mild to moderate impairment, dose reductions based on eGFR. Severe impairment, acute kidney injury, end-stage renal disease: Not recommended.
• Patients with Hepatic Dysfunction: No adjustment needed for mild or moderate impairment. Not recommended for severe impairment.
• Patients with Comorbid Conditions: Patients with a history of infections or thromboembolic events may benefit from a lower starting dose (2 mg) or closer monitoring.

Clinical Use Cases

Baricitinib’s primary clinical use is for the chronic conditions mentioned above (RA, alopecia areata). Its use in COVID-19 is for hospitalized patients with specific oxygen requirements. There is no standard dosage for intubation, surgical procedures, or general ICU use outside of the approved COVID-19 indication.

Dosage Adjustments

Dose adjustments are based on renal function, concomitant medications (strong OAT3 inhibitors like probenecid), age, and other individual patient factors (e.g., history of infections).

Side Effects

Common Side Effects:

• Upper respiratory tract infections (nasopharyngitis, sinusitis)
• Headache
• Nausea
• Elevated liver enzymes
• Acne

Rare but Serious Side Effects:

• Serious infections (including tuberculosis)
• Thrombosis (deep vein thrombosis, pulmonary embolism)
• Malignancy (lymphoma)
• Hypersensitivity reactions

Long-Term Effects:

• Potential for increased risk of infections with prolonged use.
• Potential long-term effects on lipid profile and liver function.

Adverse Drug Reactions (ADR):

• Angioedema
• Anaphylaxis

Contraindications

• Hypersensitivity to baricitinib
• Pregnancy
• Active tuberculosis

Drug Interactions

• CYP450 Interactions: Baricitinib is minimally metabolized by CYP3A4; thus, significant interactions with CYP3A4 inhibitors/inducers are unlikely.
• Other Interactions:
  • Concomitant use with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants (e.g., azathioprine, cyclosporine) is not recommended due to the risk of increased immunosuppression.
  • Strong OAT3 inhibitors (e.g., probenecid) can increase baricitinib exposure, requiring dosage adjustments.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Contraindicated in pregnancy. May cause fetal harm.
• Breastfeeding: Not recommended during breastfeeding.

Drug Profile Summary

• Mechanism of Action: Selective JAK1/JAK2 inhibitor, modulating immune response and reducing inflammation.
• Side Effects: Common: Upper respiratory infections, headache, acne. Serious: Infections, thrombosis, malignancy.
• Contraindications: Pregnancy, active tuberculosis, hypersensitivity.
• Drug Interactions: Avoid use with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants. OAT3 inhibitors require dosage adjustments.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy and not recommended while breastfeeding.
• Dosage: RA/Alopecia Areata: 2-4 mg once daily. COVID-19: 4 mg (adults), or 2/4 mg (children) Adjustments needed for renal impairment and other factors.
• Monitoring Parameters: Complete blood counts (CBC), liver enzymes, renal function, lipid profile.

Popular Combinations

• Baricitinib is often used in combination with methotrexate in RA patients if methotrexate alone is not sufficient.
• Other DMARD combinations might be considered, though combining with biologic DMARDs is not recommended.

Precautions

• General Precautions: Evaluate for infections, TB, hepatitis B/C before and during treatment. Monitor blood counts, liver and renal function. Assess for cardiovascular risk factors.
• Specific Populations: Pregnancy: Contraindicated. Breastfeeding: Not recommended. Children: For COVID-19 only under specific criteria. Elderly: Increased risk of adverse events, start with 2 mg.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Baricitinib?

A: The recommended dose varies based on the condition: - RA/Alopecia areata: 2 mg once daily, potentially increasing to 4 mg. - COVID-19: Adults: 4 mg once daily. Children: 2 mg or 4 mg once daily depending on age.

Q2: What are the common side effects of Baricitinib?

A: Common side effects include upper respiratory infections, headache, nausea, acne, and elevated liver enzymes.

Q3: Is Baricitinib safe during pregnancy?

A: No. Baricitinib is contraindicated during pregnancy due to potential risks to the fetus.

Q4: Can I take Baricitinib if I have kidney problems?

A: Dosage adjustments are necessary for patients with renal impairment. It’s not recommended for severe renal impairment.

Q5: Does Baricitinib interact with other medications?

A: Yes. Avoid concurrent use of Baricitinib with other JAK inhibitors, biologic DMARDs, or potent immunosuppressants. Dose adjustment is required with strong OAT3 inhibitors.

Q6: How does Baricitinib work?

A: Baricitinib works by selectively inhibiting JAK1 and JAK2 enzymes, reducing inflammation and modulating the immune response.

Q7: What should I monitor in patients taking Baricitinib?

A: Monitor complete blood counts, liver enzymes, renal function, and lipid profile regularly.

Q8: What are the serious side effects of Baricitinib?

A: Serious side effects can include serious infections, thrombosis, and malignancy. Patients should be monitored closely for any signs of these complications.

Q9: Can Baricitinib be used in children?

A: Baricitinib is authorized for use in children 2 years and older hospitalized with COVID-19 requiring supplemental oxygen or respiratory support.

Q10: When should I consider dose adjustment for Baricitinib?

A: Dose adjustment should be considered for patients with renal impairment, elderly patients, those with a history of recurrent infections, and those taking strong OAT3 inhibitors.