BARIJAK Tablets (Baricitinib)

Table of Content

Baricitinib is an orally administered, selective and reversible inhibitor of Janus kinase (JAK)1 and JAK2 with a potential therapeutic against SARS-CoV-2. The proposed mechanism of action of baricitinib in the management of COVID-19 may be two-fold as it has both anti-inflammatory and potential antiviral activity. Baricitinib has received restricted emergency use approval from the CDSCO for use in combination with Remdesivir for treatment of suspected or laboratory confirmed COVID-19 in hospitalized adults requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). BARIZAK (Baricitinib) tablets (4 mg) should be given orally once daily, with or without food for 14 days.

 

 

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Qualitative And Quantitative Composition

Baricitinib Tablets 4 mg

Each film-coated tablet contains:

Baricitinib………………….4 mg

Colours: Red oxide of Iron, Yellow oxide of Iron and Titanium dioxide IP

Dosage Form(S) And Strength(S)

Film-coated tablet containing baricitinib (4 mg strengths).

Clinical Particulars

Therapeutic Indications

Baricitinib, in combination with remdesivir, for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalised adults requiring supplemental oxygen, invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

Posology and Method of Administration

Baricitinib tablets should be given orally once daily, with or without food.

Alternate Administration

For patients who are unable to swallow whole tablets, alternate administration may be considered as follows:

  • Oral administration of dispersed tablets in water
  • Via a gastrostomy feeding tube (G-tube)
  • Via a nasogastric (enteral) feeding tube (NG-tube)

Preparation for Alternate Administration

Oral Administration of Dispersed Tablets in Water

For patients who are unable to swallow whole tablets, 2 mg baricitinib tablet(s), or any combination of tablets necessary to achieve the desired dose up to 4 mg, may be placed in a container with approximately 10 mL (5 mL minimum) of room temperature water, dispersed by gently swirling the tablet(s), and immediately taken orally. The container should be rinsed with an additional 10 mL (5 mL minimum) of room temperature water and the entire contents should be swallowed by the patient (see Table 1).

Administration Via A G-Tube

In patients with a G-tube, 2 mg baricitinib tablet(s), or any combination of tablets necessary to achieve the desired dose up to 4 mg, may be placed in a container with approximately 15 mL (10 mL minimum) of room temperature water and dispersed with gentle swirling. Ensure that the tablet(s) are sufficiently dispersed to allow free passage through the tip of a syringe. Withdraw the entire contents from the container into an appropriate syringe and immediately administer through the G-tube. Rinse the container with approximately 15 mL (10 mL minimum) of room temperature water, withdraw the contents into the syringe, and administer again through the tube (see Table 1).

Administration Via Ng-Tube

For patients with an NG-tube, 2 mg baricitinib tablet(s), or a combination of tablets necessary to achieve the desired dose, may be placed into a container with approximately 30 mL of room temperature water and dispersed with gentle swirling. Ensure that the tablet(s) are sufficiently dispersed to allow free passage through the tip of a syringe. Withdraw the entire contents from the container into an appropriate syringe and immediately administer through the NG-tube. To avoid clogging of small-diameter tubes (smaller than 12 Fr), the syringe can be held horizontally and shaken during administration. Rinse the container with a sufficient amount (minimum of 15 mL) of room temperature water, withdraw the contents into the syringe, and administer again through the tube (see Table 1).

Intact tablets are not hazardous. Tablets may be crushed to facilitate dispersion. It is unknown if powder from the crushed tablets may constitute a reproductive hazard to the preparer. Use proper control measures (e.g. ventilated enclosure) or personal protective equipment (i.e. N95 respirator). Dispersed tablets are stable in water for up to 4 hours.

Table 1: Minimum dispersion and rinse volume for alternate administration

Administration Route

Dispersion Volume

Container Rinse Volume

Oral intake of dispersed tablets

10 mL

10 mL

Via G-tube

15 mL

15 mL

Via NG-tube

30 mL

15 mL

Patient Selection
  • Evaluate baseline estimated glomerular filtration rate (eGFR), liver enzymes, and complete blood count to determine treatment suitability and dose. Monitor closely patients with abnormal baseline and post-baseline laboratory values. See Table 2 for dosage adjustments for adult patients with laboratory abnormalities.
  • Baricitinib is not recommended for the following:
  • Patients who are on dialysis, have end-stage renal disease (, eGFR <15 mL/min/1.73 m2), or have acute kidney injury.
  • Patients with known active tuberculosis.
  • There is currently limited information on the use of baricitinib in combination with systemic corticosteroids for treating patients with COVID-19. Currently, there is no information on the concomitant use of Baricitinib with Tocilizumab.

Adult Patients

  • The recommended dosage in adults with eGFR ≥60 mL/min/1.73 m2 is 4 mg once daily for 14 days of total treatment or until hospital discharge, whichever is first. See Table 2 for dosage adjustments for patients with laboratory abnormalities.
  • Dosage adjustments in patients with renal or hepatic impairment are recommended (see Use in Special Populations – Patients with Renal Impairment, Patients with Hepatic Impairment).
  • Dosage adjustments due to drug interactions are recommended (see Drug Interactions).
  • In hospitalised patients with COVID-19, prophylaxis for venous thromboembolism (VTE) is recommended unless contraindicated.
Table 2: Dosage adjustments for patients with abnormal laboratory values a,b

Laboratory Analyte

Laboratory Analyte Value

Recommendation

eGFR

≥60 mL/min/1.73 m2

Adults: No dosage adjustment

30 to <60 mL/min/1.73 m2

Adults: 2 mg once daily

15 to <30 mL/min/1.73 m2

Adults: 1 mg once daily

<15 mL/min/1.73 m2

Not recommended

ALC

≥200 cells/μL

Maintain dose

<200 cells/μL

Consider interruption until ALC is ≥200 cells/μL

ANC

≥500 cells/μL

Maintain dose

<500 cells/μL

Consider interruption until ANC is ≥500 cells/μL

Aminotransferases

If increases in ALT

or AST are observed

and

DILI is suspected

Interrupt baricitinib until the diagnosis of DILI is excluded

 

a Abbreviations: ALC = absolute lymphocyte count, ALT = alanine transaminase, ANC = absolute neutrophil count, AST = aspartate transaminase, DILI = drug-induced liver injury, eGFR = estimated glomerular filtration rate

b If a laboratory abnormality is likely due to the underlying disease state, consider the risks and benefits of continuing baricitinib at the same or a reduced dose.

Contraindications

There are no known contraindications for baricitinib.

Special Warnings and Precautions for Use

Serious Infections

Serious infections have occurred in patients receiving baricitinib:

  • Avoid the use of baricitinib with known active tuberculosis.
  • Consider if the potential benefits outweigh the potential risks of baricitinib treatment in patients with active serious infections besides COVID-19.

Thrombosis

In hospitalised patients with COVID-19, prophylaxis for VTE is recommended unless contraindicated. If clinical features of deep vein thrombosis/pulmonary embolism occur, patients should be evaluated promptly and treated appropriately.

Abnormal Laboratory Values

Evaluate at baseline and thereafter according to local patient management practice. Monitor closely when treating patients with abnormal baseline and post-baseline laboratory values.

Vaccinations

Avoid use of live vaccines with baricitinib and until four weeks after stopping Baricitinib.

Hypersensitivity

If a serious hypersensitivity occurs, discontinue baricitinib while evaluating the potential causes of the reaction.

Drug Interactions

Strong Organic Anion Transporters (OAT)3 Inhibitors

Baricitinib exposure is increased when baricitinib is co-administered with strong OAT3 inhibitors (such as probenecid). In patients taking strong OAT3 inhibitors, such as probenecid, reduce the recommended dose as follows:

  • If the recommended dose is 4 mg once daily, reduce dose to 2 mg once daily.
  • If the recommended dose is 2 mg once daily, reduce dose to 1 mg once daily.
  • If the recommended dose is 1 mg once daily, consider discontinuing probenecid.

Other Janus kinase (JAK) Inhibitors or Biologic Disease-modifying Anti-Rheumatic Drugs (DMARDs)

Baricitinib has not been studied in combination with other JAK inhibitors or with biologic DMARDs (biologic treatments targeting cytokines, B-cells, or T-cells).

Use in Special Populations

Pregnant Women

Baricitinib should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the foetus. Consistent with the mechanism of action, embryo-foetal toxicities, including skeletal anomalies and reduced fertility, have been observed in animals dosed in excess of the maximum human exposure. The limited human data on use of baricitinib in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage. Currently, there is no information on the use of baricitinib in lactating women.

Patients with Renal Impairment

  • There are limited data for baricitinib in patients with severe renal impairment.
  • Baricitinib is not recommended in patients who are on dialysis, have severe ESRD, or have acute kidney injury.
  • Baricitinib should only be used in adults with eGFR 15 to <30 mL/min/1.73 m2 and if the potential benefit outweighs the potential risk.

Patients with Hepatic Impairment

Baricitinib has not been studied in patients with severe hepatic impairment. Baricitinib should only be used in patients with severe hepatic impairment if the potential benefit outweighs the potential risk. It is not known if dosage adjustment is needed in patients with severe hepatic impairment.

Effects on Ability to Drive and Use Machines

Studies were not conducted.

Serious Side Effects

Serious venous thrombosis, including pulmonary embolism, and serious infections have been observed in COVID-19 patients treated with baricitinib.

Pharmacological Properties

Mechanism of Action

The JAK/STAT pathway mediated the signaling of multiple cytokines and interrupting this pathway is therefore a useful way to modulate the immunopathology seen with SARS-CoV-2 infection.

Pharmacodynamic Properties

ACTT-2 (Adaptive COVID-19 Treatment Trial 2) Study in Hospitalised Adults Diagnosed with COVID-19 Infection

A randomized, double-blind, placebo-controlled clinical trial (ACTT-2, NCT04401579) of hospitalized adults with confirmed SARS-CoV-2 infection compared treatment with Baricitinib, a JAK inhibitor, plus remdesivir, an anti-viral (combination group; n=515) with placebo plus remdesivir (placebo group; n=518). Patients had to have laboratory confirmed SARS-CoV-2 infection as well as at least one of the following to be enrolled in the trial: Radiographic infiltrates by imaging, SpO2 ≤94% on room air, a requirement for supplemental oxygen, or a requirement for mechanical ventilation. Patients treated with the combination received the following regimen:

  • Baricitinib 4 mg once daily (orally) for 14 days or until hospital discharge
  • Remdesivir 200 mg on Day 1 and 100 mg once daily (via intravenous infusion) on subsequent days for a total treatment duration of 10 days or until hospital discharge.

Scientific Evidence Supporting this Emergency use Authorisation:

  • For the overall population, the median time to recovery (defined as discharged from hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care) was 7 days for baricitinib + remdesivir compared to 8 days for placebo + remdesivir .
  • Patients assigned to baricitinib + remdesivir were more likely to have a better clinical status (according to an 8-point ordinal scale) at Day 15 compared to patients assigned to placebo + remdesivir .
  • The proportion of patients who died or progressed to non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation by Day 29 was lower in baricitinib + remdesivir (23%) compared to placebo + remdesivir (28%) .
  • Patients who required noninvasive ventilation/high-flow oxygen or invasive mechanical ventilation (including ECMO) at baseline needed to worsen by at least 1 point on an 8-point ordinal scale to progress.
  • The proportion of patients who died by Day 29 was 4.7% (24/515) for baricitinib + remdesivir vs. 7.1% (37/518) for placebo + remdesivir .
  • Data on deaths, serious adverse events (SAEs), AEs leading to discontinuation, infections and VTEs are summarized in Table 3.
Table 3: Comparisons and confidence intervals for adverse events in the as treated population a,b

Patients with at least 1:

PBO + RDV

(N = 509) n (%)

BARI + RDV

(N = 507) n (%)

Risk Difference

% (95% CI)

AE

242 (48)

210 (41)

-6 (-12, 0)

Grade 3-4 AE

238 (47)

207 (41)

-6 (-12, 0)

SAE

103 (20)

77 (15)

-5 (-10, 0)

SAE with fatal outcome

31 (6)

19 (4)

-2 (-5, 0)

AE leading to discontinuation of

study drug

59 (12)

34 (7)

-5 (-8, 1)

Infections

50 (10)

32 (6)

-4 (-7, 0)

VTE

16 (3)

21 (4)

1 (-1, 3)

Pulmonary Embolism

2 (0.4)

5 (1)

0.6 (-0.4, 1.6)

a Abbreviations: AE = adverse event; BARI + RDV = baricitinib plus remdesivir; NIAID = National Institute of Allergy and Infectious Disease; N = number of patients in the As-Treated Population; n = number of patients reporting at least 1 event; PBO + RDV = placebo plus remdesivir; SAE = serious adverse event; VTE = venous thromboembolic events.

b Patients are counted once for each category regardless of the number of events.

Non-Clinical Properties

Animal Toxicology and/or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of tumorigenicity was observed in male or female rats that received Baricitinib for 91 to 94 weeks at oral doses up to 8 or 25 mg/kg/day, respectively (approximately 12 and 55 times the MRHD on an AUC basis). Baricitinib tested negative in the in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosome aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay. Fertility (achievement of pregnancy) was reduced in male and female rats that received Baricitinib at oral doses of 50 and 100 mg/kg/day respectively (approximately 113 and 169 times the MRHD in males and females, respectively, on an AUC basis).

Description

Baricitinib is a JAK inhibitor. Its chemical name is {1-ethylsulphonyl-3-pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl]acetonitrile. Baricitinib has an empirical formula is C16H17N7O2S and molecular weight is 371.42.

Baricitinib has the following structural formula:

 

 

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf-Life

24 months

Packaging Information

Baricitinib 4 mg Bottle of 14 tablets. One bottle with pack insert and PIL form housed in a carton.

Storage and Handling Instructions

Store below 30°C. Keep out of reach of children.

Patient Counselling Information

Advise patients on the potential benefits and risks of Baricitinib.

Details of the Manufacturer

Manufactured by;

Natco Pharma Ltd.

Pharma division, Kothur (CT) (V), Kothur (M),

Ranga Reddy (D), Telangana, India - 509228.

Marketed by:

M/s Cipla Limited,

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai Lower Parel (India) – 400 013.

Details of Permission or Licence Number with Date

1228387/TS/2021

Date of Revision

24/06/2021