Arcevia^® (Tablets) Instructions for Use

Marketing Authorization Holder

R-Pharm JSC (Russia)

Manufactured By

Ortat, JSC (Russia)

ATC Code

L01EJ01 (Ruxolitinib)

Active Substance

Ruxolitinib (Rec.INN registered by WHO)

Dosage Forms

	Arcevia®	Tablets 5 mg
		Tablets 15 mg
		Tablets 20 mg

Dosage Form, Packaging, and Composition

Tablets

56 pcs. – bottles – cardboard packs (56 pcs.) – By prescription
60 pcs. – bottles – cardboard packs (60 pcs.) – By prescription

Tablets

56 pcs. – bottles – cardboard packs (56 pcs.) – By prescription
60 pcs. – bottles – cardboard packs (60 pcs.) – By prescription

Tablets

56 pcs. – bottles – cardboard packs (56 pcs.) – By prescription
60 pcs. – bottles – cardboard packs (60 pcs.) – By prescription

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; Janus kinase (JAK) inhibitors

Pharmacological Action

Protein tyrosine kinase inhibitor. Ruxolitinib is a selective inhibitor of JAK kinases (Janus Associated Kinases – JAKs) – JAK 1 and JAK 2. These kinases facilitate signal transduction from numerous cytokines and growth factors that play an important role in hematopoiesis and immune system function.

Activated JAK kinases, acting on cytokine receptors, activate STAT proteins (Signal Transducers and Activators of Transcription), which upon activation are transported into the nucleus and modulate gene expression. Dysregulation of the JAK-STAT pathway is associated with some types of malignancies and increased proliferation and survival of malignant cells. Myelofibrosis is a myeloproliferative disorder associated with dysregulation of the JAK1 and JAK2 signaling pathway. The basis of this dysregulation is believed to be high circulating levels of cytokines that activate the JAK-STAT pathway, leading to pathological functional mutations, such as JAK2 V617F, and suppression of negative regulatory mechanisms. Patients with myelofibrosis exhibit dysregulation of the JAK signaling pathway, regardless of the presence of the JAK2V617F mutation.

Ruxolitinib inhibits cytokine-induced phosphorylation of STAT 3 in whole blood, both in healthy volunteers and in patients with myelofibrosis. Ruxolitinib leads to maximum inhibition of STAT 3 phosphorylation 2 hours after administration, which returned to baseline within 8 hours in healthy volunteers and patients with myelofibrosis, indicating no accumulation of the parent substance or its metabolites.

Baseline elevation of inflammatory markers, such as TNFα, IL-6, and C-reactive protein, observed in patients with myelofibrosis, decreases after treatment with ruxolitinib. No development of resistance to the pharmacodynamic effects of ruxolitinib was noted in patients with myelofibrosis.

A clinical study showed no prolongation of the QT/QT_c interval with single-dose administration of ruxolitinib at supratherapeutic doses (200 mg), indicating no effect on cardiac repolarization.

Pharmacokinetics

Ruxolitinib is classified as a Class I molecule according to the Biopharmaceutical Classification System, with high permeability, high solubility, and rapid dissolution. In clinical studies, ruxolitinib was rapidly absorbed after oral administration with a time to reach C_max of approximately 1 hour. The absorption of ruxolitinib is 95% or more. Mean C_max and total exposure (AUC) increase proportionally over the dose range of 5 to 200 mg. When ruxolitinib was administered with a high-fat meal, clinically insignificant changes in the pharmacokinetics of ruxolitinib were observed: mean C_max slightly decreased (24%), while AUC remained virtually unchanged (increased by 4%).

The apparent volume of distribution at steady state (V_ss) was 53-65 L in patients with myelofibrosis. At clinically significant concentrations, the in vitro protein binding of ruxolitinib (primarily to albumin) was approximately 97%. Animal studies have shown that ruxolitinib does not cross the blood-brain barrier.

Ruxolitinib is a substrate of the CYP3A4 isoenzyme. After oral administration, 60% of circulating ruxolitinib in the blood is unchanged. Two main active metabolites of ruxolitinib, representing 25% and 11% of the AUC, have been identified in human blood. The pharmacological activity of ruxolitinib is composed of 18% from the activity of its metabolites. At clinically significant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6, or CYP3A4.

After administration of a single dose of radiolabeled ruxolitinib to patients, the majority (74%) of radioactivity was detected in the urine (excreted by the kidneys), and 22% was excreted via the intestine. The unchanged substance accounted for less than 1% of the total excreted drug. The mean elimination half-life (T_1/2) of ruxolitinib is approximately 3 hours.

The pharmacokinetics of ruxolitinib change proportionally with the administered (single, multiple) doses of the drug.

The AUC of ruxolitinib metabolites increases with the severity of renal impairment, reaching significant values in patients with end-stage renal disease requiring hemodialysis. Ruxolitinib is not removed by dialysis. Dose adjustment of ruxolitinib is recommended for patients with severe and end-stage renal impairment (creatinine clearance less than 30 ml/min).

The mean AUC of ruxolitinib increased in patients with mild, moderate, and severe hepatic impairment by 87%, 28%, and 65%, respectively, compared to normal liver function, with no clear correlation with the degree of hepatic impairment based on the Child-Pugh score. The terminal T_1/2 was prolonged in patients with hepatic impairment compared to healthy volunteers (4.1-5.0 hours vs. 2.8 hours). Dose reduction of ruxolitinib is recommended in patients with hepatic impairment.

Indications

Treatment of patients with myelofibrosis, including primary myelofibrosis and secondary myelofibrosis developing after polycythemia vera and essential thrombocythemia.

ICD codes

Dosage Regimen

For oral administration.

The recommended starting dose is 15 mg twice daily for patients with a platelet count of 100-200×10⁹/L; and 20 mg twice daily for patients with a platelet count >200×10⁹/L. The maximum recommended starting dose for patients with a platelet count of 50-100×10⁹/L is 5 mg twice daily with subsequent dose titration.

The dose of ruxolitinib should be individualized based on the safety and efficacy of the treatment.

The maximum dose is 25 mg twice daily.

The absolute blood cell count must be monitored every 2-4 weeks during ruxolitinib dose titration and thereafter as clinically indicated.

Patients with severe renal impairment (creatinine clearance less than 30 ml/min), patients on hemodialysis, patients with severe hepatic impairment, and patients concurrently receiving strong CYP3A4 isoenzyme inhibitors (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice) require dosage regimen adjustment.

Adverse Reactions

Infections and infestations: Very common – urinary tract infections; Common – herpes zoster infection.

Blood and lymphatic system disorders: Very common – anemia (including grade 3 (>80-65 g/L)), thrombocytopenia (grade 1, 2), neutropenia (grade 1, 2); Common – anemia grade 4 (<65 g/L), thrombocytopenia grade 4 (<25×10⁹/L) and grade 3 (50-25×10⁹/L)), neutropenia grade 4 (<0.5×10⁹/L) and grade 3 (<1-0.5×10⁹/L)).

Metabolism and nutrition disorders: Very common – hypercholesterolemia (grade 3,4); Common – weight increased.

Nervous system disorders: Very common – dizziness, headache.

Gastrointestinal disorders: Common – flatulence.

Hepatobiliary disorders: Very common – increased ALT (grade 1), increased AST (grade 1, 2); Common – increased ALT (5-20 times above normal).

Skin and subcutaneous tissue disorders: Very common – subcutaneous hemorrhages.

Contraindications

Pregnancy, lactation (breastfeeding), children and adolescents under 18 years of age, hypersensitivity to ruxolitinib.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Women of childbearing potential must use reliable methods of contraception during treatment.

In case of pregnancy during therapy, the benefit/risk ratio must be carefully assessed individually for each patient, taking into account known data on the embryotoxicity of ruxolitinib.

Use in Hepatic Impairment

Dose reduction of ruxolitinib is recommended in patients with hepatic impairment.

Use in Renal Impairment

Dose adjustment of ruxolitinib is recommended for patients with severe and end-stage renal impairment (creatinine clearance less than 30 ml/min).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Special Precautions

Ruxolitinib should be used with caution in patients with severe renal impairment, patients on hemodialysis, patients with hepatic impairment, patients with severe infectious diseases in the acute phase, as well as in patients with thrombocytopenia, anemia, and neutropenia, concurrently with strong potent inhibitors of the CYP3A4 isoenzyme.

A complete blood count should be performed before starting treatment with ruxolitinib.

In patients with a reduced platelet count (<200×10⁹/L) at the start of therapy, the likelihood of developing thrombocytopenia during treatment with ruxolitinib increases approximately 2-fold. Thrombocytopenia is generally reversible and usually managed by dose reduction or temporary discontinuation of ruxolitinib. However, in some cases, platelet transfusions may be required.

If anemia develops, patients may also require red blood cell transfusions. Furthermore, the need for ruxolitinib dose adjustment should be assessed.

Neutropenia (absolute neutrophil count <0.5×10⁹/L), if it occurs, is generally reversible and managed by temporary discontinuation of ruxolitinib.

Before starting therapy with ruxolitinib, the presence and risk of developing severe bacterial, mycobacterial, fungal, and viral infections should be assessed. Therapy should not be initiated until a severe active infectious process has resolved. The physician should carefully monitor patients receiving ruxolitinib therapy for the development of symptoms of infection and, if necessary, promptly initiate appropriate treatment.

After discontinuation of ruxolitinib therapy, symptoms of myelofibrosis (such as fatigue, bone pain, fever, itching, night sweats, symptomatic splenomegaly, and weight loss) may return. In clinical studies, the total symptom score of myelofibrosis gradually returned to baseline within 7 days after discontinuation.

Effect on ability to drive and operate machinery

Studies on the effect of ruxolitinib on the ability to drive and operate machinery have not been conducted. Given the possibility of some adverse effects of ruxolitinib (dizziness), patients should exercise caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration.

Drug Interactions

In healthy volunteers, administration of ketoconazole, a potent CYP3A4 isoenzyme inhibitor, at a dose of 200 mg twice daily for 4 days, led to a 91% increase in the AUC of ruxolitinib and an extension of the T_1/2 from 3.7 hours to 6 hours. When ruxolitinib is used with potent CYP3A4 isoenzyme inhibitors, the total daily dose of ruxolitinib should be reduced by approximately 50%.

Administration of erythromycin, a moderate inhibitor of the isoenzyme, at a dose of 500 mg twice daily in healthy volunteers for several days, led to a 27% increase in the AUC of ruxolitinib. No dose adjustment is required when ruxolitinib is used concomitantly with mild or moderate inhibitors of the CYP3A4 isoenzyme (including erythromycin).

In healthy volunteers receiving rifampicin, a potent inducer of the CYP3A4 isoenzyme, at a dose of 600 mg once daily for 10 days, the AUC of ruxolitinib after a single dose decreased by 71%, and the T_1/2 decreased from 3.3 hours to 1.7 hours. The relative amount of active metabolites increased relative to the parent substance.

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.