Baricitinib (Olumiant) is a Janus Kinase inhibitor that is indicated for the treatment of patients with moderately to severely active Rheumatoid arthritis who have an inadequate response to conventional and Biological DMARDs including TNF (Tumor necrosis Alfa) inhibitor therapy.

Baricitinib (Olumiant) Uses:

It is indicated for the treatment of adult patients with moderately to severely active Rheumatoid Arthritis Who have an inadequate response to one or more TNF inhibitor therapies. Limitations of Use:

• It is not indicated in combination with other JAK inhibitors, Biologic DMARDs (Disease-Modifying Anti-Rheumatic Drugs), or other immunosuppressants such as Azathioprine and cyclosporine.

Update: FDA Approved Baricitinib (Olumiant) in combination with Remdesivir for COVID-19 infection:

On 19th November, FDA approved Baricitinib (Olumiant) in combination with Remdesivir (Veklury) for the treatment of patients with COVID-19 infection fulfilling the following criteria:

• Adult and pediatric patients who are 2 years of age or older,
• those who require supplemental oxygen,
• Patients on invasive mechanical ventilation, or
• Patients requiring extracorporeal membrane oxygenation (ECMO).

The Baricitinib-Remdesivir combination therapy reduces the time to recovery within 29 days after treatment initiation compared to placebo. Monotherapy is not approved.

Patrizia Cavazzoni, M.D., acting director of the FDA’s Center for Drug Evaluation and Research said:

"The FDA’s emergency authorization of this combination therapy represents an incremental step forward in the treatment of COVID-19 in hospitalized patients, and FDA’s first authorization of a drug that acts on the inflammation pathway" [Ref]

Data supporting the use of Baricitinib in combination with remdesivir in patients with COVID-19 infection came from a study conducted by the National Institute of Allergy and Infectious Diseases (NIAID). The study included more than a thousand patients. One group received Baricitinib + Remdesivir while the other group received Placebo + Remdesivir. Important results include:

• The median time to recovery in the Baricitinib-Remdesivir combo was seven days while the median time to recovery in the controlled group was eight days.
• The odds of patients dying or progressing to require mechanical ventilation was higher in the control group compared to the Baricitinib-Remdesivir group at day 29.
• The odds of clinical improvement at day-15 was higher in patients who received the drug combo compared to the control group.

Baricitinib (Olumiant) Dose in Adults:

Baricitinib (Olumiant) Dose in Rheumatoid Arthritis:

• The recommended dose of Olumiant in RA is 2 mg orally once a day.
• It may be used as monotherapy or in combination with other DMARDs or Methotrexate.

Note:

• Avoid using the drug in patients with active infection and those with an absolute lymphocyte count of fewer than 500 cells/mm³, absolute neutrophil counts of fewer than 1000 cells/mm³, or hemoglobin level less than 8 g/dL.
• Before treatment initiation, investigate the patient for active or latent tuberculosis. Those with latent tuberculosis should be treated following recommended guidelines before initiating treatment with Olumiant.

Baricitinib (Olumiant) Dosage adjustment in patients with cytopenias and serious infections:

• Withhold the treatment in patients who develop a serious infection until the disease is controlled.
• Dosage adjustment in patients with lymphopenia, neutropenia, and anemia are given in the following tables:

Dosage Adjustment in Patients with Low Absolute Lymphocyte Count:
Lab Value (cells/mm³)	Recommendation
ALC greater than or equal to 500	Maintain dose
ALC less than 500	Interrupt OLUMIANT until ALC greater than or equal to 500

Dosage Adjustment in Patients with Low Absolute Neutrophil Count (ANC):
Lab Value (cells/mm³)	Recommendation
ANC greater than or equal to 1000	Maintain dose
ANC less than 1000	Interrupt OLUMIANT until ANC greater than or equal to 1000

Dosage Adjustment in Patients with Low hemoglobin Values
Lab Value (g/dL)	Recommendation
Greater than or equal to 8	Maintain dose
Less than 8	Interrupt OLUMIANT until hemoglobin greater than or equal to 8

Baricitinib (Olumiant) Overdosage:

• The drug is considered very safe. In clinical trials, single doses of 40 mg and multiple doses of up to 20 mg daily for 10 days have been administered without dose-limiting toxicity.
• After the administration of a single dose of 40 mg, 90% of the administered dose is excreted within 24 hours.
• Patients should be monitored for the clinical features of any adverse events and treated appropriately.

Dosage modification due to Drug interactions:

Patients taking strong Organic Anion Transporter 3 (OAT3) inhibitors, such as probenecid should avoid taking Olumiant.

Use in Children:

Not indicated.

Pregnancy Risk Category: N

• It is not known if it has been used in pregnancy. 
• Placental transfer is possible due to the drug's low molecular weight.

Use during Breastfeeding:

• It is unknown whether the drug will be excreted into breastmilk. 
• Because of possible adverse drug reactions in infants, the manufacturer suggests that you stop breastfeeding. 
• It has a low molecular mass and can be excreted in breastmilk.

Baricitinib (Olumiant) Dose in Kidney impairment:

Impaired renal functions could significantly affect drug exposure. The manufacturer recommends avoiding it in patients with an estimated GFR of less than 60 ml/minute.

Baricitinib (Olumiant) Dose in Hepatic Impairment:

• In patients with mild to moderate hepatic impairment (Child Class A and B), dosage adjustment is not recommended.
• The drug has not been studied in patients with severe hepatic impairment (Child Class C).
• It should be avoided in patients with severe hepatic impairment.

Side effects of Baricitinib (Olumiant):

Infection:

• Infection (29%; serious infection: 1%)

Respiratory:

• Upper respiratory tract infection

Less Common Side effects of Baricitinib (Olumiant) (1 - 10%):

Gastrointestinal:

• Nausea

Hepatic:

• Increased serum alanine aminotransferase (≥3 x ULN)
• increased serum aspartate aminotransferase (≥3 x ULN)

Infection:

• Herpes zoster infection

Uncommon Side effects of Baricitinib:

Cardiovascular:

• Arterial thrombosis

Dermatologic:

• Acne vulgaris

Hematologic & oncologic:

• Malignant lymphoma,
• malignant neoplasm,
• neutropenia

Baricitinib Side effects (Frequency not defined):

Cardiovascular:

• Venous thrombosis (including deep vein thrombosis and pulmonary embolism)

Endocrine & metabolic:

• Increased HDL cholesterol,
• increased LDL cholesterol,
• increased serum cholesterol,
• increased serum triglycerides

Gastrointestinal:

• Esophageal candidiasis

Genitourinary:

• Urinary tract infection

Hematologic & oncologic:

• Anemia,
• lymphocytopenia

Infection:

• Bacterial infection,
• BK virus,
• candidiasis,
• cryptococcosis,
• cytomegalovirus disease,
• fungal infection,
• histoplasmosis,
• mycobacterium infection,
• opportunistic infection,
• viral infection

Neuromuscular & skeletal:

• Increased creatine phosphokinase in blood specimen

Renal:

• Increased serum creatinine

Respiratory:

• Infection due to an organism in genus Pneumocystis, pneumonia, tuberculosis

Miscellaneous:

• Reactivation of viral disease

Postmarketing Adverse effects of Olumiant:

Dermatologic:

• Skin rash,
• urticaria

Gastrointestinal:

• Gastrointestinal perforation

Hematologic & oncologic:

• Skin carcinoma

Hypersensitivity:

• Angioedema,
• hypersensitivity reaction

Contraindications to Baricitinib (Olumiant):

• The manufacturer's labeling does not contain any contraindications.

Warnings and precautions

Severe Infections - US Boxed Warnings

• Olumiant has been shown to cause serious fungal and viral infections in patients with Rheumatoid arthritis.
• These are the most commonly reported infections:
  • Pneumonia
  • Herpes Zoster
  • Infections of the urinary tract
• Olumiant therapy has been associated with a number of other potential infections, including:
  • Mycobacterium tuberculosis,
  • Multidermatomal herpes zoster,
  • Esophageal candidiasis,
  • Pneumocystosis,
  • Acute histoplasmosis
  • Cryptococcosis
  • Cytomegalovirus (and
  • Infection with the BK virus
• Patients who had disseminated diseases were often on immunosuppressants like methotrexate and corticosteroids.
• Olumiant should not be used on patients with a severe infection or localized infection.
• Patients with:
  • Recurrent or chronic infections
  • Tuberculosis patients
  • Patients who have had a history of serious infections or opportunistic infections
  • Patients who have lived in or traveled to areas where tuberculosis or mycosis are endemic.
  • Patients who have an underlying condition may be more susceptible to infection.
• Patients must be monitored closely for signs and symptoms of infection during treatment.
• If the patient has a serious infection, it is important to withhold treatment and initiate appropriate investigations.
• If the patient is on antimicrobial therapy for a mild or moderate infection, but is not improving, treatment must be withheld.
• Until the infection is under control, olumiant treatment should be stopped.

TuberculosisUS Boxed Warnings

• All patients who are considering treatment with Baricitinib, (Olumiant), must be tested for active or latent tuberculosis before they can begin treatment.
• Before treatment can be initiated, patients must be treated with the antimycobacterial therapy recommended.
• Olumiant should not be given to patients with active tuberculosis.
• Anti-tuberculosis treatment may be considered for patients with a history of ineffective course of treatment or who cannot be confirmed to have an appropriate course of treatment. It may also be considered for patients with a negative latent TB test but who are at risk for developing TB infection.
• To help you make the right anti-TB treatment decision, it is possible to consult an infectious disease specialist or a doctor who is experienced in diagnosing and treating TB.
• Patients should be closely monitored for signs and symptoms of tuberculosis, even if they have not been tested for latent tuberculosis.

Viral activation:

• The treatment may result in the reactivation of viral infections, including herpes zoster.
• You should stop treating the virus until it is gone.
• Since these patients were not included in the clinical trials, it is unknown if hepatitis B and C viral activation can occur.
• If a patient is found to have Hepatitis B/C, treatment should be stopped immediately and the patient must be referred to a hepatologist. Before initiating treatment, all patients must be screened for Hepatitis B or C.

Malignancy and Lymphoproliferative Diseases:US Boxed Warnings

• Treatment increases the risk of developing a malignant condition. Patients with a malignant condition should weigh the risks and benefits before starting treatment.

Non-melanoma skin tumors:

• Patients should be examined regularly for non-melanoma, especially if they are at higher risk.

Thrombosis:US Boxed Warnings

• Baricitinib treatment (Olumiant), has been shown to increase the incidence of deep vein thrombosis, pulmonary embolism and other forms of thrombosis.
• Studies have also shown arterial thrombosis in clinical studies. Thrombotic episodes can be fatal and serious. Patients at higher risk of thrombosis should be cautious with Olumiant (Baricitinib).
• If the patient experiences any symptoms that indicate thrombosis, it is important to get prompt treatment.

Gastrointestinal Perforations:

• Treatment has been associated with cases of gastrointestinal perforations. It is unknown if JAK inhibitors play a direct role in the treatment of these patients.
• Patients with underlying conditions such as diverticulosis can increase their risk of gastrointestinal perforations. Patients should be monitored closely. Patients who experience abdominal pain after treatment should be evaluated immediately for GI perforation.

Laboratory Abnormalities​​​​​​​

• Neutropenia:
  • The increased incidence of neutropenia is linked to treatment (ANC less than 1000 cells/mm3). Patients with neutropenia should not receive treatment.
  • The ANC should always be determined at baseline and every other month thereafter. Adjustment of dosage may be necessary (see Adult dose).
• Lymphopenia:
  • Clinical trials showed that lymphopenia was less than 500 cells per day in patients who received the treatment. Increased infection was associated with lymphopenia.
  • If the patient is suffering from lymphopenia, treatment must be stopped immediately.
  • At baseline, absolute lymphocyte counts should always be measured. They can also be taken periodically thereafter or when clinically indicated. Patients with an ALC below 500 cells/mm3 may need to adjust their dosage (see dosing adjustments).
• Anemia:
  • Clinical trials showed that the treatment caused anemia in comparison to placebo.
  • Olumiant should not be used on patients with hemoglobin levels below 8 gm/dl. Hemoglobin should always be checked at baseline, and then periodically thereafter or when clinically indicated. You may need to adjust the dosage (see adult dosing).
• Liver Enzyme Elevations
  • Transaminitis is often associated with olumiant therapy. Clinical trials have shown that ALT levels exceeding 5 times the normal limit and AST levels exceeding 10 times the normal limit were reported.
  • At baseline, liver function tests should be performed. To determine the cause of liver injury in patients, it is important to perform appropriate investigations. The treatment should be stopped if liver toxicities are secondary to the drug.
• Lipid Elevations
  • Olumiant treatment may lead to an increase in lipid parameters, including total cholesterol, LDL (low density lipoproteins) and HDL (high density lipoprotein cholesterol).
  • Before treatment begins, and 12 weeks later, it is important to determine your lipid profile.
  • Hyperlipidemia patients should be treated promptly

Vaccinations:

• Live vaccines should not be administered to Olumiant patients.
• All patients should have their immunizations up-to-date before treatment can begin.

Monitoring Parameters:

• Lymphocyte, neutrophil, hemoglobin, platelet counts, and liver function tests at baseline and periodically thereafter.
• Lipid profile at 12 weeks after treatment initiation and periodically thereafter.
• Investigate for viral hepatitis before treatment initiation
• Observe for the clinical signs and symptoms of infections, tuberculosis in particular,  during and after the treatment.
• Observe for abdominal symptoms
• Periodically examine the skin in patients who are at an increased risk for skin cancer.

How to administer Baricitinib (Olumiant)?

• It is administered orally with or without meals.
• Administration with a high fat-meal may slightly delay the time for the drug to reach the peak plasma concentration.
• The patients may chew the tablets if they are not able to swallow the tablets whole.
• The tablets may also be dispersed in a small amount of liquid (5 - 10 ml) such as water, milk, green tea, or soup).
• The tablets disperse in about five minutes. Ensure to ingest the full contents of the mixture.
• A small amount of food can be added to the liquid mixture. Ensure to consume the entire mixture at one time.

Mechanism of Action of Baricitinib (Olumiant):

• Baricitinib inhibits the Janus Kinase pathway.
• JAKs, intracellular enzymes, are activated by growth factor receptor interactions and cytokines on cell surface membranes. 
• JAKs activate STATs (Signal Transferrers and Activators for Transcription). 
• STATs regulate intracellular activity as well as gene expression.
• JAK enzymes transmit cytokine signals via pairing (e.g. JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/JAK2, JAK2/TYK2, JAK2/JAK2, JAK2/TYK2).
• Baricitinib inhibits JAKs, which prevents activation or phosphorylation of STATs. 
• It has a higher inhibitory power at JAK1, JAK2, TYK2 & TYK2 but a lower inhibitory potential at JAK3.
• The signal transmission induced from cytokines by JAKs is also inhibited when STATs are blocked. 
• It also lowers serum levels of Immunoglobulins, primarily IgG and IgM, Interleukin-6, as well as C-reactive protein.
• You can observe the immunoglobulin response 12 weeks after starting treatment and it will continue for 52 weeks.
• The C-reactive proteins levels can drop as soon as one week after being administered and they persist throughout dosing.

When to reach plasma peak concentrations

• After the drug is administered, it takes approximately one hour for plasma to reach its peak concentration.

Steady-State Plasma Concentration

• With minimal accumulation following once-daily drug administration, steady-state plasma concentrations can be achieved in 2 to 3 days.

Absorption

• Consuming high amounts of fat meals may cause it to be less absorbable.
• The mean AUC and Cmx might be reduced by 11% or 18%, respectively. 
• It takes approximately half an hour to reach maximum serum concentration.

Bioavailability

• It is bioavailable at approximately 80%.

Protein-binding:

• 50% of the drug is bound by plasma proteins (45% to serum proteins).

Half-life elimination:

• It takes approximately 12 hours.

Metabolism

• It is metabolized in liver primarily by CYP3A4.

Excretion

• Urine: 75% (65% as an unchanged drug);
• Feces: 20% (5% unchanged drug).

International Brand Names of Baricitinib:

• Olumiant (Eli lilly)

Baricitinib Brand Names in Pakistan:

It is not available in Pakistan.

Correct Spelling: Baricitinib Incorrect spelling: Bericitinib, Barecitinib, Baricetinib, Baricitnib