Baritrona^® (Tablets) Instructions for Use

Marketing Authorization Holder

R-Pharm JSC (Russia)

Manufactured By

Ortat, JSC (Russia)

ATC Code

L04AF02 (Baricitinib)

Active Substance

Baricitinib (Rec.INN WHO registered)

Dosage Form

Baritrona®

Film-coated tablets 4 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
14 pcs. – jars – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – By prescription
28 pcs. – jars – cardboard packs (28 pcs.) – By prescription

Clinical-Pharmacological Group

Selective immunosuppressant

Pharmacotherapeutic Group

Immunosuppressants; Janus kinase (JAK) inhibitors

Pharmacological Action

Baricitinib is a selective and reversible inhibitor of Janus kinase 1 and 2 (JAK1 and JAK2). Baricitinib inhibits the activity of JAK1, JAK2, tyrosine kinase 2, and JAK3 with IC₅₀ (half-maximal inhibitory concentration) values of 5.9, 5.7, 53, and >400 nM, respectively.

Within the intracellular signaling pathway, Janus kinases phosphorylate and activate STATs (signal transducers and activators of transcription), which in turn activate gene expression in the cell.

Baricitinib modulates these signaling cascades by partially inhibiting the enzymatic activity of JAK1 and JAK2, thereby reducing the phosphorylation and activation of STAT.

Pharmacokinetics

After oral administration, Baricitinib is rapidly absorbed, with the time to reach C_max being approximately 1 hour (range 0.5-3 hours); the absolute bioavailability is about 79% (CV = 3.94%). The pharmacokinetics of baricitinib are linear over time.

The mean V_d after intravenous administration is 76 L, indicating distribution of baricitinib into tissues. Approximately 50% of baricitinib is bound to plasma proteins.

The metabolism of baricitinib is mediated by the CYP3A4 isoenzyme, with less than 10% of the dose undergoing biotransformation. Baricitinib metabolites are not detected in plasma. In vitro, Baricitinib is a substrate for the CYP3A4 isoenzyme, organic anion transporter 3 (OAT3), P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug and toxin extrusion proteins 2-K (MATE 2-K). Baricitinib may be an inhibitor of organic cation transporters (OCT) 1.

Renal excretion via glomerular filtration and active secretion through OAT3, Pgp, BCRP, and MATE2-K is the main mechanism of baricitinib clearance. Approximately 75% of the administered dose is excreted by the kidneys, and about 20% via the intestine. In patients with rheumatoid arthritis, the mean clearance and T_1/2 were 9.42 L/h (CV= 34.3%) and 12.5 hours (CV= 27.4%), respectively. The C_max and AUC of baricitinib at steady-state pharmacokinetics in patients with rheumatoid arthritis were 1.4 and 2 times higher, respectively, than in healthy volunteers.

Renal function significantly affects baricitinib exposure. The mean AUC ratios in patients with mild and moderate renal impairment compared to patients with normal renal function were 1.41 (90% CI: 1.15-1.74) and 2.22 (90% CI: 1.81-2.73), respectively. The mean C_max ratios in patients with mild and moderate renal impairment compared to patients with normal renal function were 1.16 (90% CI: 0.92-1.45) and 1.46 (90% CI: 1.17-1.83), respectively.

Indications

Treatment of moderate to severe active rheumatoid arthritis in adult patients with intolerance or inadequate response to one or more disease-modifying antirheumatic drugs.

ICD codes

Dosage Regimen

Take Baritrona^®orally.

The recommended dose for adult patients with rheumatoid arthritis is 4 mg once daily.

For patients with moderate renal impairment (creatinine clearance 30-59 mL/min), reduce the dose to 2 mg once daily.

For patients taking strong OAT3 inhibitors (e.g., probenecid), reduce the dose to 2 mg once daily.

Do not use in patients with severe renal impairment (creatinine clearance less than 30 mL/min).

Use with caution in patients over 75 years of age.

Perform routine laboratory monitoring before and during treatment.

Assess neutrophil count, lymphocyte count, and hemoglobin levels before initiating therapy.

Do not initiate therapy if absolute neutrophil count is less than 1 x 10⁹/L, lymphocyte count is less than 0.5 x 10⁹/L, or hemoglobin is less than 8 g/dL.

Interrupt treatment if a patient develops a serious infection until the infection is controlled.

Screen for latent tuberculosis before starting treatment.

Do not use live vaccines during or immediately prior to therapy.

Evaluate lipid parameters approximately 12 weeks after initiating therapy.

Adverse Reactions

Infections and infestations Very common – upper respiratory tract infection; Common – herpes zoster, herpes simplex, gastroenteritis, urinary tract infection.

Blood and lymphatic system disorders Common – thrombocytosis >600×10⁹ cells/L; Uncommon – neutropenia <1×10⁹ cells/L.

Metabolism and nutrition disorders Very common – hypercholesterolemia; Uncommon – hypertriglyceridemia.

Gastrointestinal disorders Common – nausea.

Skin and subcutaneous tissue disorders Uncommon – acne.

Other Common – increased ALT, AST activity; Uncommon – weight gain, increased CPK concentration.

Contraindications

Hypersensitivity to baricitinib; pregnancy; breastfeeding period; age under 18 years (due to lack of data on efficacy and safety).

Use in Pregnancy and Lactation

The use of baricitinib during pregnancy is contraindicated.

Baricitinib should not be used during breastfeeding.

Use in Hepatic Impairment

Baricitinib should be used with caution in severe hepatic impairment.

Use in Renal Impairment

Baricitinib should be used with caution in renal impairment (creatinine clearance less than 30 ml/min).

Pediatric Use

The use of baricitinib is contraindicated in patients under 18 years of age.

Geriatric Use

Baricitinib should be used with caution in patients over 75 years of age.

Special Precautions

Baricitinib should be used with caution in renal impairment (creatinine clearance less than 30 ml/min); severe hepatic impairment; active, chronic, or recurrent infections (including tuberculosis); active viral hepatitis B and C; decreased neutrophil count (<1×10⁹/L), decreased leukocyte count (<0.5×10⁹/L), decreased hemoglobin (<8 g/dL); in combination with biological disease-modifying antirheumatic drugs or other Janus kinase inhibitors; in combination with potent immunosuppressants (e.g., azathioprine, tacrolimus, cyclosporine); concurrent use of live vaccines; patients with risk factors for DVT/PE; patients over 75 years of age.

In patients with active, chronic, or recurrent infections, the benefit/risk ratio of using baricitinib should be carefully assessed before starting therapy.

Before starting baricitinib, patients should be screened for tuberculosis. Baricitinib is not recommended for use in patients with active tuberculosis. In patients with latent tuberculosis who have not been previously treated, the possibility of anti-tuberculosis therapy should be considered before starting baricitinib therapy.

It is not recommended to start therapy or baricitinib should be temporarily discontinued in case of a decrease in neutrophil count <1×10⁹/L, a decrease in leukocyte count <0.5×10⁹/L, or a decrease in hemoglobin <8 g/dL.

In elderly patients with rheumatoid arthritis, the risk of lymphocytosis increases. There are reports of rare cases of lymphoproliferative diseases.

If a patient develops herpes zoster, baricitinib should be temporarily discontinued until the disease resolves.

Before starting baricitinib therapy, patients should be screened for viral hepatitis. If hepatitis B virus DNA is detected, the patient should be referred to a hepatologist to determine the possibility of continuing or discontinuing therapy.

The use of live attenuated vaccines during or immediately before baricitinib use is not recommended. When considering varicella vaccination before starting baricitinib, international guidelines for vaccination in patients with rheumatoid arthritis should be followed.

Approximately 12 weeks after starting baricitinib, the lipid profile should be assessed, after which patients should be managed according to international clinical guidelines for the management of patients with hyperlipidemia.

If an increase in ALT or AST activity is detected during patient examination and drug-induced liver injury is suspected, baricitinib should be temporarily discontinued until this diagnosis is ruled out.

Patients with rheumatoid arthritis have an increased risk of malignancies, including the risk of lymphoma. The use of immunomodulatory drugs may increase the risk of malignancies, including the risk of lymphoma.

If clinical signs of DVT/PE are detected, baricitinib should be temporarily discontinued, the patient’s condition should be immediately assessed, and appropriate treatment should be provided.

Drug Interactions

When baricitinib is used in combination with potent immunosuppressants such as azathioprine, tacrolimus, or cyclosporine, the risk of additive immunosuppression cannot be excluded.

The use of probenecid led to an approximately two-fold increase in AUC_(0-∞) without changing the T_max or C_max of baricitinib. Therefore, in patients taking OAT3 inhibitors with strong inhibitory activity, such as probenecid, the recommended dose of baricitinib is 2 mg once daily.

Caution should be exercised when co-administering leflunomide or teriflunomide and baricitinib.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.