Baricitinib

Registered South African indications:

• Moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs
• Coronavirus disease 2019 (COVID-19) in hospitalised patients who require supplemental oxygen

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or to any of its excipients
• Pregnancy
• Breastfeeding
• Severe renal impairment
  - Rheumatoid arthritis: CrCl <30ml/min
  - COVID-19: CrCl <15ml/min
• Active tuberculosis and other active infections
  (See additional prescribing points)

International manufacturer recommendations

• Hypersensitivity to the active ingredient or to any of its excipients
• Pregnancy

Cautions

South African manufacturer recommendations

• Renal impairment
  - Rheumatoid arthritis: Moderate (CrCl 30-60ml/min)
  - COVID-19: Moderate to severe (CrCl 15-60ml/min)
• Severe hepatic impairment
• Elderly
  - ≥65 years of age previously treated with both biologic and conventional disease-modifying anti-rheumatic drugs (DMARDs)
  - ≥75 years (Rheumatoid arthritis)
• Hepatitis B infection
  - Expression of hepatitis B virus (HBV) DNA
• Hepatitis C infection
• Absolute Neutrophil Count (ANC) <1 x 10⁹ cells/L
• Absolute Lymphocyte Count (ALC) <0.5 x 10⁹ cells/L
• Haemoglobin <8g/dL
• Herpes zoster
• Herpes simplex
• Use with live, attenuated vaccines during, or immediately prior to, baricitinib therapy
• Patients not up to date with all immunisations in the current immunisation guidelines
• Risk factors for deep venous thrombosis (DVT) and pulmonary embolism (PE)
  - Older age
  - Obesity
  - Medical history of DVT/PE
  - Patients undergoing surgery and immobilisation
• Patients with COVID-19 with
  - ALC <0.2 x 10⁹ cells/L
  - ANC <1 x 10⁹ cells/L
  - Haemoglobin <8g/dL
• Diverticular disease
  (See additional prescribing points)
• Patients chronically treated with concomitant medications associated with an increased risk of diverticulitis
  - Nonsteroidal anti-inflammatory drugs
  - Corticosteroids
  - Opioids
• Coadministration with immunosuppressants, such as methotrexate or corticosteroids
• Coadministration with biologic DMARDs or other Janus kinase (JAK) inhibitors
• Coadministration with potent immunosuppressive medicines, such as azathioprine, tacrolimus, ciclosporin

International manufacturer recommendations

• Breastfeeding
• Moderate to severe renal impairment (CrCl ≤60ml/min)
• Severe hepatic impairment
• Elderly
  - ≥65 years of age and previously treated with both biologic and conventional DMARDs 
  - ≥75 years
• Active, chronic or recurrent infections
• Active or untreated latent tuberculosis
• Herpes zoster
• Herpes simplex
• Hepatitis B infection
  - Expression of hepatitis B virus (HBV) DNA
• Hepatitis C infection
• ANC <1 x 10⁹ cells/L
• ALC <0.5 x 10⁹ cells/L
• Haemoglobin <8g/dL
• Use with live, attenuated vaccines during, or immediately prior to, baricitinib therapy
• Risk factors for DVT and PE 
  - Older age
  - Obesity
  - Medical history of DVT/PE
  - Patients undergoing surgery and immobilisation
• Diverticular disease
  (See additional prescribing points)
• Patients chronically treated with concomitant medications associated with an increased risk of diverticulitis
  - Nonsteroidal anti-inflammatory drugs
  - Corticosteroids
  - Opioids
• Coadministration with biologic DMARDs
• Coadministration with biologic immunomodulators
• Coadministration with other Janus kinase (JAK) inhibitors
• Coadministration with potent immunosuppressive medicinal products such as azathioprine, tacrolimus and ciclosporin

Forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

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Treatment should be initiated by doctors experienced in the diagnosis and treatment of conditions for which baricitinib is indicated

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South African manufacturer recommendations

Moderate to severe active rheumatoid arthritis in patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (Additional agent may be required) 

• Oral (tab): 4mg, dly

- ≥ 75 years
- History of chronic or recurrent infections
- Achieved sustained control of disease activity with 4mg daily and are eligible for dose tapering

• Oral (tab): 2mg, dly

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Baricitinib may be used as monotherapy or in combination with methotrexate

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Use of baricitinib in combination with other Janus Kinase (JAK) inhibitors, biologic disease-modifying anti-rheumatic medicines (DMARDs), or with potent immunosuppressants such as azathioprine and ciclosporin, has not been studied, and is not recommended

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Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) <0.5 x 10⁹ cells/L, an absolute neutrophil count (ANC) <1 x 10⁹ cells/L, or who have a haemoglobin value <8g/dL. Treatment may be initiated once values have improved above these limits

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Coronavirus disease 2019 (COVID-19)
- In hospitalised patients who require supplemental oxygen

• Oral (tab): 4mg, dly; Treatment duration: 14 days (or until hospital discharge, whichever occurs first)

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Baricitinib may be used with or without corticosteroids and with or without remdesivir

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For treatment initiation, there is limited information on the use of baricitinib in patients with an ALC <0.2 x 10⁹ cells/L, ANC <1 x 10⁹ cells/L or haemoglobin <8g/dL

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Venous thromboembolism (VTE) prophylaxis is recommended unless contraindicated

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See additional prescribing points for alternate administration routes for patients with COVID-19

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International manufacturer recommendations

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Treatment should not be initiated in patients with an ALC <0.5 x 10⁹ cells/L, an ANC <1 x 10⁹ cells/L, or who have a haemoglobin value <8g/dL. Treatment may be initiated once values have improved above these limits

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Moderate to severe active rheumatoid arthritis in patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (Additional agent may be required) 

• Oral (tab): 4mg, dly

- ≥ 75 years
- History of chronic or recurrent infections
- Achieved sustained control of disease activity with 4mg daily and are eligible for dose tapering

• Oral (tab): 2mg, dly

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Baricitinib may be used as monotherapy or in combination with methotrexate

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Moderate to severe atopic dermatitis in patients who are candidates for systemic therapy (Additional agent may be required) 

• Oral (tab): 4mg, dly

- ≥ 75 years
- History of chronic or recurrent infections
- Achieved sustained control of disease activity with 4mg daily and are eligible for dose tapering

• Oral (tab): 2mg, dly

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Baricitinib can be used with or without topical corticosteroids. The efficacy of baricitinib can be enhanced when given with topical corticosteroids

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Topical calcineurin inhibitors may be used, but should be reserved for sensitive areas only, such as the face, neck, intertriginous and genital areas

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Consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic benefit after 8 weeks of treatment

Forms avail. in SA and covered in this monograph: tab

Paed. dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Moderate to severe active rheumatoid arthritis in patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (Additional agent may be required) 

• Not established for use in children under 18 years

Coronavirus disease 2019 (COVID-19)
- In hospitalised patients who require supplemental oxygen

Younger than 10 years

• Not established for use

10 years and older

• See adult dosage

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International manufacturer recommendations

Moderate to severe active rheumatoid arthritis in patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs 
Moderate to severe atopic dermatitis in patients who are candidates for systemic therapy 

• Not established for use in children under 18 years

Pregnancy

South African manufacturer recommendations

• Contraindicated
• Rheumatoid Arthritis: Barcitinib is contraindicated during pregnancy. The JAK/STAT pathway has been shown to be involved in cell adhesion and cell polarity which can affect early embryonic development
• Studies in animals have shown reproductive toxicity. Baricitinib was teratogenic in rats and rabbits. Animal studies indicate that baricitinib may have an adverse effect on bone development in utero at higher dosages
• Women of childbearing potential have to use effective contraception during and for at least 1 week after treatment. If a patient becomes pregnant while taking baricitinib the parents should be informed of the potential risk to the foetus
• COVID-19: The woman must be fully informed of the potential foeto-toxicity of baricitinib and the potential efficacy benefits to herself. An appropriate treatment decision can then be made

International manufacturer recommendations

• Contraindicated
• Baricitinib is contraindicated during pregnancy
• The JAK/STAT pathway has been shown to be involved in cell adhesion and cell polarity which can affect early embryonic development. There are no adequate data from the use of baricitinib in pregnant women
• Studies in animals have shown reproductive toxicity. Baricitinib was teratogenic in rats and rabbits. Animal studies indicate that baricitinib may have an adverse effect on bone development in utero at higher dosages
• Women of childbearing potential have to use effective contraception during and for at least 1 week after treatment. If a patient becomes pregnant while taking baricitinib the parents should be informed of the potential risk to the foetus

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• Women who are breastfeeding should not use baricitinib. It is unknown whether baricitinib/ metabolites are excreted in human milk. Available pharmacodynamic/ toxicological data in animals have shown excretion of baricitinib in milk
• A risk to newborns/infants cannot be excluded

International manufacturer recommendations

• Caution; not recommended
• It is unknown whether baricitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of baricitinib in milk
• A risk to newborns/infants cannot be excluded and baricitinib should not be used during breastfeeding. A decision must be made whether to discontinue breastfeeding or to discontinue baricitinib therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

• Studies in animals suggest that treatment with baricitinib has the potential to decrease female fertility while on treatment, but there was no effect on male spermatogenesis

Renal Impairment

South African manufacturer recommendations

- Moderate to severe active rheumatoid arthritis

• Mild (CrCl>60ml/min): No dose adjustment recommended
• Moderate (CrCl 30-60ml/min): Caution; dose adjustment recommended
  Oral (tab): 2mg, dly
• Severe (CrCl<30ml/min): Contraindicated 

- Coronavirus disease 2019 (COVID-19)

• Mild (CrCl>60ml/min): No dose adjustment recommended
• Moderate (CrCl 30-60ml/min): Caution; dose adjustment recommended
  Oral (tab): 2mg, dly
• Severe (CrCl 15-30ml/min): Caution; dose adjustment recommended
  Oral (tab): 2mg, 48hrly
• Severe (CrCl<15ml/min): Contraindicated 

International manufacturer recommendations

• Mild (CrCl >60ml/min): No dose adjustment recommended
• Moderate (CrCl 30-60ml/min): Caution; dose adjustment recommended
  Oral (tab): 2mg, dly
• Severe (CrCl <30ml/min): Not recommended for use

Hepatic Impairment

South African manufacturer recommendations

- Moderate to severe active rheumatoid arthritis

• Mild to moderate: No dose adjustment recommended
• Severe: Not recommended for use

- Coronavirus disease 2019 (COVID-19)

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available

International manufacturer recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Not recommended for use

Elderly

South African manufacturer recommendations

- Moderate to severe active rheumatoid arthritis

• Caution; dose adjustment recommended
  ≥75 years: Oral (tab): 2mg, dly
  Clinical experience in patients ≥75 years is very limited and in these patients, a starting dose of 2mg is appropriate

- Coronavirus disease 2019 (COVID-19)

• No dose adjustment recommended
  Clinical experience in patients ≥75 years is limited

International manufacturer recommendations

• Caution; dose adjustment recommended
  ≥75 years: Oral (tab): 2mg, dly
  Clinical experience in patients ≥75 years is very limited and in these patients, a starting dose of 2mg is appropriate

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache

Cardiovascular Disorders

• Deep vein thrombosis

Respiratory Disorders

• Upper respiratory tract infections
• Pneumonia
• Pulmonary embolism

Gastrointestinal Disorders

• Gastroenteritis
• Nausea
• Abdominal pain
• Diverticulitis

Hepatobiliary Disorders

• Increased alanine transaminase ≥3 x ULN
• Increased aspartate aminotransferase ≥3 x ULN

Genitourinary Disorders

• Urinary tract infections

Endocrine and Metabolic Disorders

• Hypercholesterolaemia
  -Elevations in LDL cholesterol, HDL cholesterol and total cholesterol
• Hypertriglyceridaemia
• Increased weight

Musculoskeletal Disorders

• Increased creatine phosphokinase >5 x ULN

Skin and Subcutaneous Tissue Disorders

• Rash
• Acne
• Swelling face
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Herpes zoster
• Herpes simplex
• Thrombocytosis >600 x 10⁹ cells/L
• Neutropaenia <1 x 10⁹ cells/L

• Immunosuppressive medicinal products
• Biologic disease-modifying anti-rheumatic drugs
• Biologic immunomodulators
• Other Janus kinase (JAK) inhibitors
• Azathioprine
• Tacrolimus
• Ciclosporin
• Strong OAT3 inhibitors (See additional prescribing points)
• Probenecid
• Leflunomide
• Teriflunomide

• Full blood count
• Hepatic function
• Lipid profile
• Viral hepatitis status

Additional observations

• Signs and symptoms of infections (including tuberculosis)
• Abdominal symptoms
• Skin examinations

WARNING: SERIOUS INFECTIONS, MALIGNANCY AND THROMBOSIS Patients treated with baricitinib are at risk of developing serious infections that may lead to hospitalization or death and undesirable effects. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt treatment with baricitinib until the infection is controlled Reported infections include: Active tuberculosis which may present with pulmonary or extra pulmonary disease. Patients should be tested for latent tuberculosis before initiating treatment with baricitinib and during therapy. Treatment for latent infection should be considered prior to baricitinib use Invasive fungal infection, including candidiasis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease Bacterial, viral and other infections due to opportunistic pathogens. The risks and benefits of treatment with baricitinib should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection

Coadministration with organic anion transporter 3 (OAT3) inhibitors

• The recommended dose is 2mg, dly in patients taking OAT3 inhibitors with a strong inhibition potential, such as probenecid

Alternate administration routes for patients with COVID-19

• For patients who are unable to swallow whole tablets, alternate administration may be considered:
  - Oral dispersion
  - Gastrostomy tube (G tube)
  - Nasogastric tube (NG tube) or orogastric tube (OG)
• Tablets may be dispersed whole or may be crushed for dispersion. If tablets are crushed, use proper control measures or personal protective equipment:
  - Place tablets in a container with at least the minimum  dispersion volume (see table below) of room temperature water and gently swirl to disperse
  - Administer immediately
  - Rinse the container with at least the minimum volume of room temperature water (see table below) and administer immediately

Administration via	Dispersion volume	Container rinse volume
Oral dispersion	10ml (5ml minimum)	10ml (5ml minimum)
G tube	15ml (10ml minimum)	15ml (10ml minimum)
NG tube	30ml	15ml

Hepatitis B and C

• Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with baricitinib for rheumatoid arthritis
• Patients with evidence of active hepatitis B or C infection were excluded from clinical trials
• Patients, who were positive for hepatitis C antibody but negative for hepatitis C virus RNA, were allowed to participate
• Patients with hepatitis B surface antibody and hepatitis B core antibody, without hepatitis B surface antigen, were also allowed to participate; such patients should be monitored for expression of hepatitis B virus (HBV) DNA. If HBV DNA is detected, a liver specialist should be consulted to determine if treatment interruption is warranted

Diverticulitis

• Events of diverticulitis and gastrointestinal perforation have been reported in clinical trials and from postmarketing sources 
• Baricitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medications associated with an increased risk of diverticulitis: nonsteroidal anti-inflammatory drugs, corticosteroids, and opioids
• Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation

Baricitinib is a selective and reversible inhibitor of Janus kinase (JAK)1 and JAK2. In isolated enzyme assays, baricitinib inhibited the activities of JAK1, JAK2, Tyrosine Kinase 2 and JAK3 with IC50 values of 5.9, 5.7, 53 and >400 nM, respectively. Janus kinases (JAKs) are enzymes that transduce intracellular signals from cell surface receptors for a number of cytokines and growth factors involved in haematopoiesis, inflammation and immune function. Within the intracellular signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which activate gene expression within the cell. Baricitinib modulates these signalling pathways by partially inhibiting JAK1 and JAK2 enzymatic activity, thereby reducing the phosphorylation and activation of STATs.

Baricitinib has been identified as a numb-associated kinase (NAK) inhibitor with high-affinity for AP2-associated protein kinase 1 (AAK1)-8.2nM, BIKE-20nM and GAK-120nM. Specific NAK’s AAK1 and GAK are linked to SARS-CoV-2 (COVID-19) entry in human cells.

Film coated tablet 2mg

• Unamity 2mg (Eli Lilly) originator

Film coated tablet 4mg

• Unamity 4mg (Eli Lilly) originator