RENOPLAN-1000

INSTRUCTIONS FOR MEDICAL USE OF JAKAVI (JAKAVI)

COMPOSITION

The active substance is ruxolitinib; 1 tablet contains 5 mg, 15 mg, or 20 mg of ruxolitinib (in the form of phosphate); excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), hydroxypropylcellulose, povidone, colloidal silicon dioxide anhydrous, magnesium stearate.

PHARMACEUTICAL FORM

Tablets.

MAIN PHYSICOCHEMICAL PROPERTIES

5 mg tablets: round, curved, white to almost white tablets approximately 7.5 mm in diameter with embossing "NVR" on one side and "L5" on the other; 15 mg tablets: oval, curved, white to almost white tablets measuring approximately 15.0 x 7.0 mm with embossing "NVR" on one side and "L15" on the other; 20 mg tablets: elongated, curved, white to almost white tablets measuring approximately 16.5 x 7.4 mm with embossing "NVR" on one side and "L20" on the other.

PHARMACOTHERAPEUTIC GROUP

Antineoplastic agents. Protein kinase inhibitors. Janus kinase (JAK) inhibitors.

ATC CODE

L01E J01.

PHARMACOLOGICAL PROPERTIES

PHARMACODYNAMICS

Ruxolitinib is a selective inhibitor of Janus kinases (JAKs) JAK1 and JAK2 (IC50 values for JAK1 and JAK2 enzymes are 3.3 nM and 2.8 nM, respectively). These enzymes are mediators in the transmission of signals of a number of cytokines and growth factors that are important for hematopoiesis and the immune system. Myelofibrosis (MF) and true polycythemia (TP) are myeloproliferative neoplasms that are known to be accompanied by a violation of regulation in signal transmission involving JAK1 and JAK2. The basis of the violation of regulation is high levels of circulating cytokines that activate the JAK-STAT-mutation pathway, in which the protein product of the mutated gene acquires new and pathological functions, such as the JAK2V617F mutation, as well as lead to the exclusion of negative regulatory mechanisms. In patients with MF, a violation of regulation in signal transmission involving JAK is noted, regardless of the status regarding the JAK2V617F mutation. Activating JAK2 mutations (V617F or exon 12) are observed in more than 95% of patients with TP. Ruxolitinib inhibits signal transmission along the JAK-STAT pathway and cell proliferation in cytokine-dependent cell models of hematological malignancies, as well as cytokine-dependent proliferating Ba/F3 cells by expressing a modified JAK2V617F protein with an IC50 in the range of 80-320 nM.

PHARMACODYNAMIC EFFECTS

Ruxolitinib inhibits cytokine-induced phosphorylation of STAT3 in the target blood of healthy volunteers and patients with MF and TP. The use of ruxolitinib leads to maximum suppression of STAT3 phosphorylation 2 hours after administration of the drug, with a return of phosphorylation levels to values close to the initial level after 8 hours, both in healthy volunteers and patients with MF, indicating the absence of accumulation of the initial drug or active metabolites. Elevated baseline levels of inflammation markers associated with the appearance of systemic symptoms, such as tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP), in patients with MF decreased after treatment with ruxolitinib. Over time, in patients with MF, signs of refractoriness to the pharmacodynamic effects of ruxolitinib treatment did not develop. Similarly, in patients with TP, an increase in baseline levels of inflammation markers was observed, and these values decreased after treatment with ruxolitinib. In a thorough study of the QT interval in healthy volunteers, no signs of QT/QTc prolongation were found when ruxolitinib was used once at doses exceeding therapeutic ones (up to 200 mg), indicating that ruxolitinib does not affect cardiac repolarization.

PHARMACOKINETICS

ABSORPTION

Ruxolitinib belongs to compounds of class 1 according to the Biopharmaceutical Classification System (BCS) with high permeability, high solubility, and rapid dissolution. During clinical trials, it was found that ruxolitinib is rapidly absorbed after oral administration, with a maximum plasma concentration (Cmax) achieved approximately 1 hour after administration of the dose. Taking into account the data from the study of the balance of body weight in humans, the absorption of ruxolitinib after oral administration of the drug in the form of ruxolitinib or metabolites formed during the first pass is 95% or more. The mean Cmax and total exposure (AUC) of ruxolitinib increased proportionally with an increase in the single dose in the range from 5 to 200 mg. Clinically significant changes in the pharmacokinetics of ruxolitinib after administration of the drug with a high-fat meal were not observed. During administration of the drug with a high-fat meal, the mean Cmax was moderately decreased (by 24%), while the mean AUC remained almost unchanged (increased by 4%).

DISTRIBUTION

In patients with MF and TP, the mean volume of distribution at steady state is approximately 75 liters. Clinically significant concentrations of ruxolitinib in plasma are approximately 97% bound to plasma proteins (mainly to albumin) under in vitro conditions. An autoradiographic study of the whole body in rats showed that ruxolitinib does not penetrate the blood-brain barrier.

BIOTRANSFORMATION

Ruxolitinib is primarily metabolized by CYP3A4 (>50%) with additional participation of the CYP2C9 enzyme. The original compound is the dominant form in human plasma, accounting for about 60% of the drug-related material in the circulation. Two main active metabolites were detected in plasma, accounting for 25% and 11% of the AUC of the original compound. These metabolites have from 1/2 to 1/5 of the JAK-related pharmacological activity of the original compound. In total, the sum of all active metabolites provides up to 18% of the total pharmacodynamics of ruxolitinib. At clinically significant concentrations, ruxolitinib does not inhibit the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6, or CYP3A4, based on the results of in vitro studies. Data obtained in vitro indicate that ruxolitinib may inhibit the activity of P-glycoprotein and the breast cancer resistance protein (BCRP).

ELIMINATION

Ruxolitinib is primarily eliminated by metabolism. The mean half-life of ruxolitinib is approximately 3 hours. After a single oral dose of [14C]-labeled ruxolitinib in healthy adults, elimination occurred mainly through metabolism, with 74% of the radioactively labeled compound excreted in the urine and 22% in the feces. The unchanged original compound accounted for less than 1% of the total radioactively labeled compound excreted.

LINEARITY/NONLINEARITY

Dose proportionality was demonstrated in studies of single and multiple doses of the drug.

SPECIAL GROUPS OF PATIENTS

INFLUENCE OF BODY SURFACE AREA, AGE, GENDER, OR RACE

In studies involving healthy volunteers of different genders and races, no significant differences in the pharmacokinetics of ruxolitinib were observed. During a population pharmacokinetic evaluation in patients with MF, no obvious dependence of oral clearance on the patient's age or race was found. The predicted oral clearance in patients with MF was 17.7 L/h in women and 22.1 L/h in men, with a variability of 39%. In patients with TP, clearance was 12.7 L/h, with a variability of 42%. During a population pharmacokinetic evaluation in patients with TP, no dependence of oral clearance on the patient's gender, age, or race was found. Clearance was 10.4 L/h in patients with acute GVHD and 7.8 L/h in patients with chronic GVHD, with an interindividual variability of 49%. During a population pharmacokinetic evaluation in patients with GVHD, no dependence of oral clearance on the patient's gender, age, or race was found. Exposure increased in patients with GVHD and low body surface area (BSA). In patients with a BSA of 1 m2, 1.25 m2, and 1.5 m2, the predicted mean exposure (AUC) was 31%, 22%, and 12% higher, respectively, than in a typical adult (1.79 m2).

PEDIATRIC POPULATION

The pharmacokinetics of the Jakavi drug in children (under 18 years old) with MF and TP has not been established. The pharmacokinetic profile observed in children with acute or chronic GVHD was comparable to that in the general population of patients.

Ruxolitinib has not been studied in children under 12 years of age with acute or chronic GVHD.

RENAL IMPAIRMENT

Renal function was assessed using the modified diet in renal disease (MDRD) and creatinine clearance. After administration of a single dose of ruxolitinib 25 mg, its exposure was similar in patients with different degrees of renal impairment and in individuals with normal renal function. However, the values of AUC of ruxolitinib metabolites in plasma, as a rule, increased with the severity of renal impairment and were most significantly increased in patients with severe renal impairment. It is unknown whether the increase in exposure to metabolites is relevant to safety issues. A change in the dose of the drug is recommended for patients with severe renal impairment and terminal stage renal failure (see the "Method of administration and dosage" section). The use of the drug only on dialysis days reduces the exposure to metabolites and the pharmacodynamic effect, especially on days between dialysis procedures.

HEPATIC IMPAIRMENT

After administration of a single dose of ruxolitinib 25 mg, the mean AUC of ruxolitinib increased in patients with mild, moderate, and severe hepatic impairment by 87%, 28%, and 65%, respectively, compared to patients with normal hepatic function. No clear correlation was found between AUC of the drug and the degree of hepatic impairment according to the Child-Pugh score. The terminal half-life was prolonged in patients with hepatic impairment compared to the control group of healthy volunteers (4.1-5 hours versus 2.8 hours). A reduction in the dose of the drug by approximately 50% is recommended for patients with MF and TP with hepatic impairment (see the "Method of administration and dosage" section).

For patients with GVHD and hepatic impairment not related to GVHD, the initial dose of ruxolitinib should be reduced by 50%.

PRECLINICAL SAFETY DATA

Ruxolitinib has been evaluated in pharmacological safety studies, repeated dose toxicity studies, genotoxicity studies, and reproductive toxicity studies, as well as in carcinogenicity studies. The target organs related to the pharmacological action of ruxolitinib in repeated dose studies include the bone marrow, peripheral blood, and lymphoid tissues. Infections, usually associated with immunosuppression, were noted in dogs. Adverse decreases in blood pressure and increases in heart rate were noted in a study on dogs using telemetry measurements; adverse decreases in minute ventilation were noted in a study of respiratory tract function in rats. The acceptable dose limits (based on the levels of unbound drug) in studies on dogs and rats were 15.7 and 10.4 times higher, respectively, than the maximum recommended human dose of 25 mg twice a day. No consequences of exposure were found in the evaluation of neuropharmacological effects of ruxolitinib. In animal studies, the use of ruxolitinib led to a decrease in fetal body weight and an increase in post-implantation loss. No evidence of teratogenicity was found in studies on rats and rabbits. However, the exposure limits and the highest clinical dose were low, so the interpretation of the results in terms of human safety is limited. No consequences of exposure were found in terms of fertility. In studies of prenatal and postnatal development in animals, a slightly prolonged gestation period, decreased implantation sites, and a lower number of live births were observed. In the offspring, decreased initial body weight and a short period of decreased body weight gain were observed. In lactating rats, ruxolitinib and/or its metabolites were excreted in breast milk at a concentration 13 times higher than in the plasma of lactating females. Ruxolitinib did not exhibit mutagenic or clastogenic properties. Ruxolitinib did not exhibit carcinogenic properties in a transgenic model (Tg.rasH2 mice).

CLINICAL CHARACTERISTICS

INDICATIONS

Myelofibrosis. Treatment of diseases associated with splenomegaly or symptoms of primary myelofibrosis (also known as chronic idiopathic myelofibrosis) in adult patients, myelofibrosis due to true polycythemia or myelofibrosis due to essential thrombocythemia.

True polycythemia. Treatment of true polycythemia in adult patients with resistance or intolerance to hydroxyurea.

Graft-versus-host disease (GVHD). Treatment of patients aged 12 years and older with acute GVHD or chronic GVHD who have an inadequate response to corticosteroid therapy or other systemic therapies.

CONTRAINDICATIONS

Increased sensitivity to the active substance or to any of the excipients of the drug. Pregnancy and breastfeeding.

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER TYPES OF INTERACTIONS

Interaction studies were conducted only in adults.

Ruxolitinib is eliminated from the body by metabolism, which is catalyzed by CYP3A4 and CYP2C9. Therefore, the use of drugs that inhibit the activity of these enzymes may lead to an increase in exposure to ruxolitinib.

INTERACTIONS REQUIRING A REDUCTION IN THE DOSE OF RUXOLITINIB

CYP3A4 inhibitors

Potent CYP3A4 inhibitors (boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, etc.)

In healthy volunteers, the simultaneous administration of ruxolitinib (single dose of 10 mg) with the potent CYP3A4 inhibitor ketoconazole led to an increase in the values of Cmax and AUC of ruxolitinib by 33% and 91%, respectively, compared to the values of Cmax and AUC when ruxolitinib was used alone. The half-life was prolonged from 3.7 to 6 hours when ruxolitinib was used simultaneously with ketoconazole.

When ruxolitinib is used with potent CYP3A4 inhibitors, the standard dose of ruxolitinib should be reduced by approximately 50% and administered twice a day. Patients should be closely monitored (e.g., twice a week) for the development of cytopenia, and dose titration of the drug should be performed based on safety and efficacy (see the "Method of administration and dosage" section).

Dual inhibitors of CYP2C9 and CYP3A4

In healthy volunteers, the simultaneous administration of ruxolitinib (single dose of 10 mg) with the dual inhibitor of CYP2C9 and CYP3A4, fluconazole, led to an increase in the values of Cmax and AUC of ruxolitinib by 47% and 232%, respectively, compared to the values of Cmax and AUC when ruxolitinib was used alone.

It is recommended to consider reducing the dose of the drug by 50% when using drugs that are dual inhibitors of CYP2C9 and CYP3A4 (e.g., fluconazole). The use of ruxolitinib with fluconazole at doses exceeding 200 mg per day should be avoided.

OTHER INTERACTIONS AFFECTING RUXOLITINIB

Mild or moderate CYP3A4 inhibitors (ciprofloxacin, erythromycin, amprenavir, atazanavir, diltiazem, cimetidine, etc.)

In healthy volunteers, the simultaneous administration of ruxolitinib (single dose of 10 mg) with erythromycin at a dose of 500 mg twice a day for four days led to an increase in the values of Cmax and AUC of ruxolitinib by 8% and 27%, respectively, compared to the values of Cmax and AUC when ruxolitinib was used alone.

When ruxolitinib is used simultaneously with mild or moderate CYP3A4 inhibitors (e.g., erythromycin), a correction of the dose of ruxolitinib is not recommended. However, at the beginning of treatment with ruxolitinib in combination with a moderate CYP3A4 inhibitor, patients should be closely monitored for the appearance of cytopenia.

INFLUENCE OF RUXOLITINIB ON OTHER MEDICINAL PRODUCTS

Substances transported by P-glycoprotein or other transporters

Ruxolitinib may inhibit the activity of P-glycoprotein and the breast cancer resistance protein (BCRP) in the intestine. This may lead to an increase in systemic exposure to substrates of these transporters, such as dabigatran etexilate, cyclosporine, rosuvastatin, and possibly digoxin. Therapeutic drug monitoring or clinical monitoring of the affected substrates is recommended.

It is possible that the expected inhibition in the intestine of P-glycoprotein and BCRP may be minimized if the interval between taking the drugs is as long as possible.

A study in healthy volunteers showed that ruxolitinib did not inhibit the metabolism of midazolam, which is administered orally and is a substrate of CYP3A4. Therefore, an increase in exposure to CYP3A4 substrates when used simultaneously with ruxolitinib is not expected. In another study in healthy volunteers, it was found that ruxolitinib did not affect the pharmacokinetics of oral contraceptives containing ethinyl estradiol and levonorgestrel. Therefore, it is not expected that ruxolitinib will affect the effectiveness of oral contraceptives when used simultaneously.

SPECIAL FEATURES OF USE

MYELOSUPPRESSION

Treatment with the Jakavi drug may lead to the development of hematological adverse reactions to the drug, including thrombocytopenia, anemia, and neutropenia. Before starting treatment with the Jakavi drug, a complete blood count, including a differential count of blood leukocytes, must be performed. Treatment should be discontinued in patients with a platelet count of less than 50,000/μL (50 × 10^9/L) or an absolute neutrophil count of less than 500/μL (0.5 × 10^9/L) (see the "Method of administration and dosage" section).

It has been determined that patients with MF and a low platelet count (<200,000/μL (<200 × 10^9/L)) at the start of treatment are more likely to develop thrombocytopenia during treatment.

Thrombocytopenia, in general, is reversible and usually corrected by reducing the dose of the drug or temporarily discontinuing the use of the Jakavi drug (see the "Method of administration and dosage" and "Adverse reactions" sections). However, according to clinical indications, platelet transfusions may be required.

Patients with anemia may require blood transfusions. For patients who develop anemia, a change in the dose of the drug or interruption of treatment may be possible.

Patients with a hemoglobin level below 10.0 g/dL (100 g/L) at the start of treatment have a higher risk of reducing the hemoglobin level to below 8 g/dL (80 g/L) during treatment compared to patients with a higher hemoglobin level at the start of treatment (79.3% compared to 30.1%). For patients with a hemoglobin level below 10.0 g/dL (100 g/L) at the start of treatment, more frequent monitoring of hematological parameters and clinical symptoms of adverse reactions associated with the use of the Jakavi drug is recommended. Neutropenia (absolute neutrophil count <500 (<0.5 × 10^9/L)), in general, was reversible and usually corrected by temporarily discontinuing the use of the Jakavi drug (see the "Method of administration and dosage" and "Adverse reactions" sections). According to clinical indications, a complete blood count should be performed, and the dose of the drug should be adjusted as necessary (see the "Method of administration and dosage" and "Adverse reactions" sections).

INFECTIONS

In patients who took the Jakavi drug, severe bacterial, mycobacterial, fungal, viral, and other opportunistic infections were observed. The condition of patients should be assessed for the risk of developing severe infections. Doctors should carefully monitor the condition of patients taking Jakavi for symptoms of infectious diseases and quickly start appropriate treatment if necessary. Treatment with the Jakavi drug should not be started until active serious infectious diseases have been eliminated.

Tuberculosis has been reported in patients taking Jakavi. According to local recommendations, patients should be examined for the presence of active and inactive ("hidden") tuberculosis before starting treatment. This may include studying the history of the disease, determining the possibility of previous contact with patients with tuberculosis, and/or conducting appropriate screening, such as chest X-rays, tuberculin tests, and/or gamma-interferon analysis, depending on the circumstances. There is a risk of false-negative results of the skin tuberculin test, especially in patients with severe diseases or weakened immunity.

In patients with chronic viral hepatitis B who took Jakavi, an increase in viral load (HBV DNA titer) with an increase in alanine aminotransferase and aspartate aminotransferase levels or without such was observed. Before starting treatment with the Jakavi drug, it is recommended to examine patients for the presence of HBV. Patients with chronic HBV infection should undergo treatment and monitoring in accordance with clinical recommendations.

HERPES ZOSTER

Doctors should inform patients about the appearance of early symptoms of herpes zoster, informing patients that treatment should be started as soon as possible.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Progressive multifocal leukoencephalopathy (PML) has been reported in patients taking Jakavi. Doctors should be particularly attentive to symptoms that may indicate PML, which patients may not notice (e.g., cognitive, neurological, or psychiatric symptoms). Patients should be monitored for the occurrence of new or worsening existing symptoms, and if such symptoms occur, the need to consult a neurologist and conduct appropriate diagnostic measures to detect PML should be considered. If PML is suspected, further administration of the drug should be discontinued until the suspicion of PML is excluded.

LIPID DISORDERS

Treatment with the Jakavi drug has been associated with an increase in lipid metabolism parameters, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. Monitoring of lipid levels and treatment of dyslipidemia are recommended in accordance with clinical recommendations.

MAJOR ADVERSE CARDIAC EVENTS (MACE)

In a large randomized study of tofacitinib (another JAK inhibitor) with active control in patients aged 50 years and older with rheumatoid arthritis and at least one additional risk factor for cardiovascular diseases, a higher frequency of MACE, defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, was observed when using tofacitinib compared to the use of tumor necrosis factor (TNF) inhibitors.

Cases of MACE have been reported in patients receiving the Jakavi drug. Before starting or continuing therapy with the Jakavi drug, the benefit and risk should be weighed for each individual patient, especially for patients aged 65 years and older, patients who smoke or have smoked for a long time, and patients with a history of atherosclerotic cardiovascular diseases or other risk factors for cardiovascular diseases.

THROMBOSIS

In a large randomized study of tofacitinib (another JAK inhibitor) with active control in patients aged 50 years and older with rheumatoid arthritis and at least one additional risk factor for cardiovascular diseases, a dose-dependent higher frequency of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), was observed when using tofacitinib compared to the use of TNF inhibitors.

Cases of thrombosis of the deep veins (DVT) and pulmonary embolism (PE) have been reported in patients taking the Jakavi drug. In clinical trials involving patients with myelofibrosis and true polycythemia, the frequency of thromboembolism was comparable in the Jakavi group and the control group.

Before starting or continuing therapy with the Jakavi drug, the benefit and risk should be weighed for each individual patient, especially for patients with risk factors for cardiovascular diseases (also see above "Major adverse cardiac events (MACE)").

Patients with symptoms of thrombosis should be examined immediately and receive appropriate treatment.

SECONDARY, FIRST-DETECTED MALIGNANT TUMORS

In a large randomized study of tofacitinib (another JAK inhibitor) with active control in patients aged 50 years and older with rheumatoid arthritis and at least one additional risk factor for cardiovascular diseases, a higher frequency of malignant tumors, including lung cancer, lymphomas, and non-melanoma skin cancer (NMSC), was observed when using tofacitinib compared to the use of TNF inhibitors.

Cases of lymphomas and other malignant tumors have been reported in patients taking JAK inhibitors, including the Jakavi drug.

NMSC, including basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma, has been observed in patients taking ruxolitinib. Most of these patients with MF and TP had a history of long-term treatment with hydroxyurea and previous cases of NMSC or precancerous skin lesions. Patients with an increased risk of skin cancer are recommended to undergo periodic skin examinations.

SPECIAL GROUPS OF PATIENTS

PATIENTS WITH RENAL IMPAIRMENT

The initial dose of the Jakavi drug should be reduced for patients with severe renal impairment. For patients with MF and terminal stage renal failure undergoing hemodialysis, the initial dose of the drug should be determined based on the platelet count, while the recommended initial dose for patients with TP is 10 mg once daily (see the "Method of administration and dosage" section). Subsequent doses of the drug (single dose of 20 mg or two doses of 10 mg, taken 12 hours apart, separately for patients with MF; single dose of 10 mg or two doses of 5 mg, taken 12 hours apart, for patients with TP) should be taken only on dialysis days after completion of each hemodialysis procedure. Additional changes in the dosing regimen of the drug should be made with careful monitoring of safety and efficacy (see the "Method of administration and dosage" and "Pharmacokinetics" sections).

PATIENTS WITH HEPATIC IMPAIRMENT

The initial dose of the Jakavi drug should be reduced by approximately 50% for patients with MF or TP and hepatic impairment. Further changes in the dose of the drug should be made based on safety and efficacy. For patients with GVHD and hepatic impairment not related to GVHD, the initial dose of the Jakavi drug should be reduced by approximately 50% (see the "Method of administration and dosage" and "Pharmacokinetics" sections).

INTERACTIONS

If the Jakavi drug is used simultaneously with potent CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 (e.g., fluconazole), the standard dose of the Jakavi drug should be reduced by approximately 50% and administered twice a day (information on the frequency of monitoring is provided in the "Method of administration and dosage" and "Interactions with other medicinal products and other types of interactions" sections).

Concomitant use of cytoreductive therapy with the Jakavi drug has been associated with treatable cytopenia (see the "Method of administration and dosage" section).

WITHDRAWAL SYNDROME

Symptoms of MF may return within approximately one week after temporary discontinuation or cessation of the Jakavi drug. Cases of withdrawal of the Jakavi drug have been observed among patients who have undergone more severe serious adverse reactions, including acute concomitant disease. It is not established whether the sudden cessation of the Jakavi drug contributes to the development of these phenomena. Except in cases where sudden cessation of the drug is necessary, it is recommended to consider the possibility of gradual reduction of the dose of the Jakavi drug, although the benefit of such a gradual reduction in dose has not been proven.

EXCIPIENTS

Jakavi contains lactose. Patients with established intolerance to some sugars should consult a doctor before taking this medicinal product. Patients with rare hereditary diseases such as galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, which means it is considered sodium-free.

USE DURING PREGNANCY OR BREASTFEEDING

PREGNANCY

Data on the use of the Jakavi drug in pregnant women are not available. Animal studies have shown that ruxolitinib is an embryotoxic and fetotoxic drug. Teratogenicity was not observed in rats or rabbits. However, the exposure limits and the highest clinical dose were low, so the interpretation of the results in terms of human safety is limited. The potential risk to humans is unknown. As a precautionary measure, the use of the Jakavi drug during pregnancy is contraindicated (see the "Contraindications" section).

WOMEN OF CHILDBEARING AGE/CONTRACEPTION

Women of childbearing age should use effective contraceptive methods during treatment with the Jakavi drug. In the event of pregnancy during treatment with the Jakavi drug, an assessment of the risk/benefit ratio should be made on an individual basis, taking into account the potential risks to the fetus.

BREASTFEEDING

The Jakavi drug should not be used during breastfeeding, and breastfeeding should be discontinued if treatment is started. It is not known whether ruxolitinib and/or its metabolites are excreted in human breast milk. The risk to the child cannot be excluded. Available pharmacodynamic/toxicological data from animal studies show that ruxolitinib and its metabolites are excreted in the breast milk of animals.

FERTILITY

Data on the impact of ruxolitinib on human fertility are not available. No effect on fertility was observed in animal studies.

ABILITY TO INFLUENCE THE RATE OF REACTION WHEN DRIVING VEHICLES OR OPERATING OTHER MECHANISMS

Jakavi does not have a sedative effect or has a minimal sedative effect. However, patients who experience dizziness after taking Jakavi should refrain from driving vehicles or operating other mechanisms.

METHOD OF ADMINISTRATION AND DOSAGE

The Jakavi drug should be taken orally, regardless of food intake.

If a dose of the drug is missed, the patient should not take an additional dose of the drug, and the next dose should be taken at the usual time.

Treatment with the Jakavi drug should be started by a doctor who has experience in the use of anticancer drugs.

Before starting treatment with the Jakavi drug, a complete blood count, including a differential count of blood leukocytes, must be performed.

The parameters of the complete blood count, including the differential count of blood leukocytes, should be monitored every 2-4 weeks, and then as clinically indicated, until the dose of the Jakavi drug is stabilized (see the "Special features of use" section).

DOSAGE

Initial dose

The recommended initial dose of the Jakavi drug for myelofibrosis (MF) is determined based on the platelet count (see the "Initial doses for myelofibrosis" table).

The recommended initial dose of the Jakavi drug for patients with true polycythemia (TP) is 10 mg orally twice a day.

The recommended initial dose of the Jakavi drug for acute and chronic graft-versus-host disease (GVHD) is 10 mg orally twice a day. Jakavi can be used as an add-on to long-term corticosteroid therapy and/or calcineurin inhibitors (CNIs).

DOSE ADJUSTMENT

Doses can be titrated based on safety and efficacy.

Myelofibrosis and true polycythemia

If the efficacy of the drug is considered insufficient, but the quantitative indicators of blood are at the corresponding level, the dose of the drug can be increased from 5 mg twice a day to a maximum dose of 25 mg twice a day.

The initial dose of the drug should not be increased during the first four weeks of treatment, and then it can be increased no more than every two weeks.

Treatment should be discontinued if the platelet count is less than 50,000/μL (50 × 10^9/L) or the absolute neutrophil count is less than 500/μL (0.5 × 10^9/L). In the case of TP, treatment should also be interrupted if the hemoglobin level is less than 8 g/dL (80 g/L). After the blood parameters are restored above these levels, the use of the drug can be resumed at a dose of 5 mg twice a day, with a gradual increase in the dose based on careful monitoring of the complete blood count, including the differential count of blood leukocytes.

The dose should be reduced if the platelet count decreases during treatment, as indicated in the "Dose adjustment recommendations for patients with MF and thrombocytopenia" table, in order to avoid discontinuation of treatment due to thrombocytopenia.

Graft-versus-host disease

A reduction in dose and discontinuation of treatment should be considered in patients with GVHD and thrombocytopenia, neutropenia, or elevated total bilirubin after standard supportive therapy, including growth factors, anti-infective agents, and blood transfusions. It is recommended to reduce the dose by one level (from 10 mg twice a day to 5 mg twice a day or from 5 mg twice a day to 5 mg once a day). Patients who do not tolerate Jakavi at a dose of 5 mg once a day should discontinue treatment. Detailed dosing recommendations are provided in the "Dose adjustment recommendations for patients with GVHD and thrombocytopenia, neutropenia, or elevated total bilirubin" table.

CORRECTION OF DOSE WHEN USED SIMULTANEOUSLY WITH POTENT CYP3A4 INHIBITORS OR DUAL CYP2C9/3A4 INHIBITORS

When ruxolitinib is used with potent CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 (e.g., fluconazole), the standard dose of ruxolitinib should be reduced by approximately 50% and administered twice a day (see the "Interactions with other medicinal products and other types of interactions" section). The use of ruxolitinib with fluconazole at doses exceeding 200 mg per day should be avoided.

During concomitant use of the drug with potent CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4, more frequent (e.g., twice a week) monitoring of hematological parameters and clinical symptoms of adverse reactions associated with the use of the Jakavi drug is recommended.

SPECIAL GROUPS OF PATIENTS

Renal impairment

Patients with mild or moderate renal impairment do not require a dose adjustment.

For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended initial dose based on the platelet count for MF should be reduced by approximately 50% and administered twice a day. The recommended initial dose for patients with TP and severe renal impairment is 5 mg twice a day. In terms of safety and efficacy, patients should be closely monitored during treatment with the Jakavi drug.

There are only limited data on dosing for patients with terminal stage renal failure undergoing hemodialysis.

Pharmacokinetic/pharmacodynamic modeling based on available data suggests that the initial dose of the drug for patients with MF and terminal stage renal failure undergoing hemodialysis is a single dose of 15-20 mg or two doses of 10 mg, taken 12 hours apart; the initial dose is administered after hemodialysis and only on the day of hemodialysis. For patients with MF and a platelet count between 100,000/μL (100 × 10^9/L) and 200,000/μL (200 × 10^9/L), a single dose of 15 mg is administered. For patients with MF and a platelet count greater than 200,000/μL (>200 × 10^9/L), a single dose of 20 mg or two doses of 10 mg, taken 12 hours apart, is administered. Subsequent doses of the drug should be administered only on hemodialysis days, after completion of each hemodialysis procedure (single dose or two doses of 10 mg, taken 12 hours apart).

The recommended initial dose for patients with TP and terminal stage renal failure undergoing hemodialysis is 10 mg once daily or 5 mg twice a day, administered after dialysis, only on the day of the hemodialysis procedure. These dosing recommendations are based on modeling, and any modifications to the dose for patients with terminal stage renal failure should be made with careful monitoring of safety and efficacy (see the "Method of administration and dosage" and "Pharmacokinetics" sections).

There are no data on patients with GVHD and terminal stage renal failure.

Hepatic impairment

For patients with MF and any degree of hepatic impairment, the recommended initial dose based on the platelet count should be reduced by approximately 50% and administered twice a day. Subsequent doses of the drug should be adjusted based on careful monitoring of safety and efficacy. The recommended initial dose for patients with TP is 5 mg twice a day. Patients with hepatic impairment should undergo a complete blood count, including a differential count of blood leukocytes, at least every one to two weeks during the first six weeks after starting treatment with the Jakavi drug, and then as clinically indicated, until liver function and blood parameters stabilize. The dose of the Jakavi drug can be titrated to reduce the risk of cytopenia.

For patients with mild, moderate, or severe hepatic impairment not related to GVHD, the initial dose of ruxolitinib should be reduced by 50% (see the "Pharmacokinetics" section).

Patients with GVHD and hepatic impairment associated with GVHD and elevated total bilirubin >3 × ULN should undergo more frequent blood tests for toxicity. It is recommended to reduce the dose by one level.

ELDERLY PATIENTS (≥65 YEARS)

No additional dose adjustment is required for elderly patients.

DISCONTINUATION OF TREATMENT

Treatment of MF and TP with the Jakavi drug may be continued as long as the benefit/risk ratio remains positive. However, treatment should be discontinued after 6 months if there is no reduction in spleen size or improvement in symptoms after starting therapy.

Patients who have demonstrated some degree of clinical improvement should discontinue treatment with ruxolitinib if they experience a further increase in spleen size by 40% compared to the baseline size (which is approximately equivalent to an increase in spleen volume by 25%) and lack further relief of disease-related symptoms.

For GVHD, consideration should be given to gradually reducing the dose of the Jakavi drug in patients who respond to treatment and after discontinuation of corticosteroids. It is recommended to reduce the dose of the Jakavi drug by 50% every two months. Consideration should be given to re-escalating the dose if signs or symptoms of GVHD recur during or after dose reduction of the Jakavi drug.

CHILDREN

The safety and efficacy of the Jakavi drug in children (under 18 years old) with MF and TP have not been studied. Data are not available (see the "Pharmacodynamics" section).

The safety and efficacy of the Jakavi drug in children aged 12 years and older with GVHD are supported by data from randomized phase 3 studies REACH2 and REACH3. The dose of the Jakavi drug for children with GVHD is the same as for adults. The safety and efficacy of the Jakavi drug in children under 12 years old have not been established.

OVERDOSAGE

The antidote for overdose with the Jakavi drug is unknown. The use of single doses of the drug up to 200 mg was accompanied by acceptable tolerability of the drug. The use of higher doses of the drug than the recommended repeated doses was accompanied by increased levels of myelosuppression, including leukopenia, anemia, and thrombocytopenia. In such cases, appropriate supportive therapy should be used. It is not expected that hemodialysis will lead to accelerated elimination of ruxolitinib from the body.

Adverse Reactions

Summary of Safety Profile

Myelofibrosis

The most frequently reported adverse reactions were thrombocytopenia and anemia.

Hematologic adverse reactions (any grade by Common Terminology Criteria for Adverse Events [CTCAE]) included anemia (83.8%), thrombocytopenia (80.5%), and neutropenia (20.8%).

Anemia, thrombocytopenia, and neutropenia are dose-dependent effects.

The three most common non-hematologic adverse reactions were bruising (33.3%), other bleeding (including nosebleeds, bleeding after procedures, and hematuria) (24.3%), and dizziness (21.9%).

The three most common non-hematologic laboratory abnormalities were elevated levels of alanine aminotransferase (40.7%), elevated levels of aspartate aminotransferase (31.5%), and hypertriglyceridemia (25.2%). In phase 3 clinical trials in patients with myelofibrosis, hypertriglyceridemia or elevated aspartate aminotransferase levels of grade 3 or 4 severity by CTCAE were not observed, and elevated alanine aminotransferase or hypercholesterolemia of grade 4 severity by CTCAE were not observed.

Discontinuation of therapy due to adverse reactions, regardless of causality, occurred in 30.0% of patients.

Polycythemia Vera

The most common adverse reactions reported were anemia and elevated levels of alanine aminotransferase.

Hematologic adverse reactions (any grade by CTCAE) included anemia (61.8%), thrombocytopenia (25.0%), and neutropenia (5.3%). Anemia and thrombocytopenia of grade 3 or 4 by CTCAE occurred in 2.9% or 2.6% of patients, respectively.

The three most common non-hematologic adverse reactions were weight increase (20.3%), dizziness (19.4%), and headache (17.9%).

The three most common non-hematologic laboratory abnormalities identified as adverse reactions were elevated levels of alanine aminotransferase (45.3%), elevated levels of aspartate aminotransferase (42.6%), and hypercholesterolemia (34.7%). Elevated levels of alanine aminotransferase or hypercholesterolemia of grade 4 by CTCAE were not observed; one case of elevated aspartate aminotransferase of grade 4 by CTCAE was reported.

Discontinuation of therapy due to adverse reactions, regardless of causality, occurred in 19.4% of patients.

Acute Radiation Syndrome

The most common adverse reactions were thrombocytopenia, anemia, and neutropenia.

Hematologic laboratory abnormalities defined as adverse reactions included thrombocytopenia (85.2%), anemia (75.0%), and neutropenia (65.1%). Anemia of grade 3 was reported in 47.7% of patients (grade 4 not applicable according to CTCAE version 4.03). Thrombocytopenia of grade 3 and 4 occurred in 31.3% and 47.7% of patients, respectively.

The three most common non-hematologic adverse reactions included cytomegalovirus (CMV) infection (32.3%), sepsis (25.4%), and urinary tract infections (17.9%).

The three most common non-hematologic laboratory abnormalities defined as adverse reactions included elevated levels of alanine aminotransferase (54.9%), elevated levels of aspartate aminotransferase (52.3%), and hypercholesterolemia (49.2%). Most were grade 1 and 2 in severity.

Discontinuation of therapy due to adverse reactions, regardless of causality, occurred in 29.4% of patients.

Chronic Radiation Syndrome

The most common adverse reactions were anemia, hypercholesterolemia, and elevated levels of aspartate aminotransferase.

Hematologic laboratory abnormalities defined as adverse reactions included anemia (68.6%), thrombocytopenia (34.4%), and neutropenia (36.2%). Anemia of grade 3 was reported in 14.8% of patients (grade 4 not applicable according to CTCAE version 4.03). Neutropenia of grade 3 and 4 occurred in 9.5% and 6.7% of patients, respectively.

The three most common non-hematologic adverse reactions included arterial hypertension (15.0%), headache (10.2%), and urinary tract infections (9.3%).

The three most common non-hematologic laboratory abnormalities defined as adverse reactions included hypercholesterolemia (52.3%), elevated levels of aspartate aminotransferase (52.2%), and elevated levels of alanine aminotransferase (43.1%). Most were grade 1 and 2 in severity.

Discontinuation of therapy due to adverse reactions, regardless of causality, occurred in 18.1% of patients.

Summary of Adverse Reactions in Clinical Trials

The safety of Jakavi was evaluated in patients with myelofibrosis based on long-term follow-up data from two phase 3 studies (COMFORT I and COMFORT II), including data from patients who were initially randomized to the Jakavi group (n = 301) and patients who crossed over from the control group to receive Jakavi (n = 156). The median exposure, on which the frequency of adverse reactions is based, in patients with myelofibrosis is 30.5 months (range 0.3 to 68.1 months).

The safety of Jakavi was evaluated in patients with polycythemia vera based on long-term follow-up data from two phase 3 studies (RESPONSE, RESPONSE 2), including data from patients who were initially randomized to the Jakavi group (n = 184) and patients who crossed over from the control group to receive Jakavi (n = 156). The median exposure, on which the frequency of adverse reactions is based, in patients with polycythemia vera is 41.7 months (range 0.03 to 59.7 months).

The safety of Jakavi in patients with acute radiation syndrome was studied in a phase 3 study (REACH2), including data from patients who were initially randomized to the Jakavi group (n = 152) and patients who crossed over from the best available therapy group to receive Jakavi (n = 49). The median exposure, on which the frequency of adverse reactions is based, was 8.9 weeks (range 0.3 to 66.1 weeks).

The safety of Jakavi in patients with chronic radiation syndrome was studied in a phase 3 study (REACH3), including data from patients who were initially randomized to the Jakavi group (n = 165) and patients who crossed over from the best available therapy group to receive Jakavi (n = 61). The median exposure, on which the frequency of adverse reactions is based, was 41.4 weeks (range 0.7 to 127.3 weeks).

In the clinical trial program, the severity of adverse reactions was assessed using the CTCAE, which defines Grade 1 as mild, Grade 2 as moderate, Grade 3 as severe, Grade 4 as life-threatening or disabling, and Grade 5 as fatal.

Frequency of Adverse Reactions in Phase 3 Studies in Patients with Myelofibrosis and Polycythemia Vera

Frequency of Adverse Reactions in Phase 3 Studies in Patients with Acute Radiation Syndrome

Description of Selected Adverse Reactions

Anemia

In phase 3 clinical trials in patients with myelofibrosis, the median time to first onset of anemia with a grade 2 or higher by CTCAE was 1.5 months. One patient (0.3%) discontinued treatment due to anemia.

In patients receiving Jakavi, the mean maximum decrease in hemoglobin from baseline was 10 g/L after 8-12 weeks of therapy, after which the hemoglobin level gradually recovered to a new steady-state level, which was approximately 5 g/L lower than baseline. This pattern was observed in patients regardless of whether they received transfusions during treatment.

In the randomized, placebo-controlled study COMFORT I, 60.6% of patients with myelofibrosis receiving Jakavi and 37.7% of patients with myelofibrosis receiving placebo underwent red blood cell transfusions during the randomized treatment period. In the study COMFORT II, the frequency of red blood cell transfusions was 53.4% in the Jakavi group and 41.1% in the best available care group.

In the randomized period of the base studies, anemia was reported less frequently in patients with polycythemia vera (40.8%) compared to patients with myelofibrosis (82.4%). In the polycythemia vera population, events of grade 3 and 4 by CTCAE were reported in 2.7%, whereas in the myelofibrosis population, the frequency was 42.56%.

Anemia of grade 3 by CTCAE was reported in 47.7% and 14.8% of patients in the acute and chronic radiation syndrome studies, respectively.

Thrombocytopenia

In phase 3 clinical trials in patients with myelofibrosis, in patients who developed thrombocytopenia with a grade 3 or 4 by CTCAE, the median time to first onset was approximately 8 weeks. Thrombocytopenia was generally reversible after dose reduction or interruption of treatment. The median time to recovery of platelet count above 50,000/μL was 14 days. During the randomized period, platelet transfusions were administered to 4.7% of patients receiving Jakavi and 4.0% of patients receiving control therapy. Treatment was discontinued due to thrombocytopenia in 0.7% of patients receiving Jakavi and 0.9% of patients receiving control therapy. In patients with a baseline platelet count of 100,000-200,000/μL, the frequency of grade 3 or 4 thrombocytopenia was higher compared to patients with a baseline platelet count > 200,000/μL (64.2% versus 38.5%).

In the randomized period of the base studies, thrombocytopenia occurred less frequently in patients with polycythemia vera (16.8%) compared to patients with myelofibrosis (69.8%). The frequency of severe thrombocytopenia (i.e., grade 3 or 4 by CTCAE) in patients with polycythemia vera (2.7%) was lower than in patients with myelofibrosis (11.6%).

In the acute radiation syndrome study, thrombocytopenia of grade 3 and 4 by CTCAE occurred in 31.3% and 47.7% of patients, respectively. In the chronic radiation syndrome study, the frequency of thrombocytopenia of grade 3 and 4 by CTCAE was lower (5.9% and 10.7%, respectively) than in patients with acute radiation syndrome.

Neutropenia

In phase 3 clinical trials in patients with myelofibrosis, in patients who developed neutropenia with a grade 3 or 4 by CTCAE, the median time to first onset was approximately 12 weeks. During the randomized period, treatment was interrupted or dose reduced due to neutropenia in 1.0% of patients, and treatment was discontinued due to neutropenia in 0.3% of patients.

In the randomized period of the base studies, neutropenia was reported in 1.6% of patients receiving Jakavi compared to 7% of patients in the control group. One patient in the Jakavi group developed grade 4 neutropenia by CTCAE. During long-term follow-up in the clinical trials, grade 4 neutropenia by CTCAE was reported in two patients.

In the acute radiation syndrome study, neutropenia of grade 3 and 4 by CTCAE occurred in 17.9% and 20.6% of patients, respectively. In the chronic radiation syndrome study, the frequency of neutropenia of grade 3 and 4 by CTCAE was lower (9.5% and 6.7%, respectively) than in patients with acute radiation syndrome.

Bleeding

In the base studies in patients with myelofibrosis, bleeding events (including intracranial hemorrhage, gastrointestinal bleeding, bruising, and other bleeding) were reported in 32.6% of patients receiving Jakavi and 23.2% of patients receiving control therapy. The frequency of grade 3-4 events was similar in patients receiving Jakavi or control therapy (4.7% versus 3.1%). Most patients with bleeding reported bruising (65.3%). Bruising was reported more frequently in patients receiving Jakavi compared to those receiving control therapy (21.3% versus 11.6%). Intracranial hemorrhage was reported in 1% of patients receiving Jakavi and 0.9% of patients receiving control therapy. Gastrointestinal bleeding was reported in 5.0% of patients receiving Jakavi compared to 3.1% of patients receiving control therapy. Other bleeding (including nosebleeds, bleeding after procedures, and hematuria) was reported in 13.3% of patients receiving Jakavi and 10.3% of patients receiving control therapy.

During long-term follow-up in the clinical trials in patients with myelofibrosis, the cumulative frequency of bleeding events increased proportionally with increasing exposure time. Bruising was the most frequently reported bleeding event (33.3%). Intracranial hemorrhage and gastrointestinal bleeding occurred in 1.3% and 10.1% of patients, respectively.

In the comparative period of the base studies in patients with polycythemia vera, bleeding events (including intracranial hemorrhage, gastrointestinal bleeding, bruising, and other bleeding) were reported in 16.8% of patients receiving Jakavi, 15.3% of patients receiving best available therapy in the RESPONSE study, and 12.0% of patients receiving best available therapy in the RESPONSE 2 study. Bruising was reported in 10.3% of patients receiving Jakavi, 8.1% of patients receiving best available therapy in the RESPONSE study, and 2.7% of patients receiving best available therapy in the RESPONSE 2 study. Intracranial hemorrhage or gastrointestinal bleeding was not reported in patients receiving Jakavi. One patient receiving Jakavi experienced a grade 3 bleeding event (post-procedural bleeding); no grade 4 bleeding events were reported. Other bleeding (including nosebleeds, post-procedural bleeding, and bleeding gums) was reported in 8.7% of patients receiving Jakavi, 6.3% of patients receiving best available therapy in the RESPONSE study, and 6.7% of patients receiving best available therapy in the RESPONSE 2 study.

During long-term follow-up in the clinical trials in patients with polycythemia vera, the cumulative frequency of bleeding events increased proportionally with increasing exposure time. Bruising was the most frequently reported bleeding event (17.4%). Intracranial hemorrhage and gastrointestinal bleeding occurred in 0.3% and 3.5% of patients, respectively.

In the comparative period of the acute radiation syndrome study, bleeding events were reported in 25.0% and 22.0% of patients in the Jakavi and best available therapy groups, respectively. Bleeding events were generally similar between the two treatment groups: bruising (5.9% in the Jakavi group versus 6.7% in the best available therapy group), gastrointestinal bleeding (9.2% versus 6.7%), and other bleeding (13.2% versus 10.7%). Intracranial hemorrhage was reported in 0.7% of patients in the best available therapy group and not in any patient in the Jakavi group.

In the comparative period of the chronic radiation syndrome study, bleeding events were reported in 11.5% and 14.6% of patients in the Jakavi and best available therapy groups, respectively. Bleeding events were generally similar between the two treatment groups: bruising (4.2% in the Jakavi group versus 2.5% in the best available therapy group), gastrointestinal bleeding (1.2% versus 3.2%), and other bleeding (6.7% versus 10.1%). No intracranial hemorrhage was reported in either treatment group.

Infections

In the base studies in patients with myelofibrosis, urinary tract infection of grade 3 or 4 by CTCAE was reported in 1.0% of patients, herpes zoster in 4.3%, and tuberculosis in 1.0%. Sepsis was reported in 3.0% of patients. Results from extended follow-up of patients receiving Jakavi showed no trend towards an increase in the frequency of sepsis over time.

In the randomized period of the base studies in patients with polycythemia vera, urinary tract infection of grade 3 by CTCAE was reported in one case (0.5%), and no grade 4 events were reported. The frequency of herpes zoster was similar in patients with polycythemia vera (4.3%) and patients with myelofibrosis (4.0%). One case of post-herpetic neuralgia of grade 3 by CTCAE was reported in a patient with polycythemia vera. Pneumonia was reported in 0.5% of patients receiving Jakavi compared to 1.6% of patients receiving control therapy. No patient in the Jakavi group reported sepsis or tuberculosis.

During long-term follow-up in the clinical trials in patients with polycythemia vera, urinary tract infections (11.8%), herpes zoster (14.7%), and pneumonia (7.1%) were commonly reported. Sepsis was reported in 0.6% of patients. During extended follow-up, no patient reported tuberculosis.

In the comparative period of the acute radiation syndrome study, urinary tract infections were reported in 9.9% (grade ≥ 3, 3.3%) of patients in the Jakavi group compared to 10.7% (grade ≥ 3, 6.0%) in the best available therapy group. CMV infections were reported in 28.3% (grade ≥ 3, 9.3%) of patients in the Jakavi group compared to 24.0% (grade ≥ 3, 10.0%) in the best available therapy group. Sepsis was reported in 12.5% (grade ≥ 3, 11.1%) of patients in the Jakavi group compared to 8.7% (grade ≥ 3, 6.0%) in the best available therapy group. BK virus infection was reported in three patients in the Jakavi group, with one grade 3 event. During extended follow-up of patients receiving Jakavi, urinary tract infections were reported in 17.9% (grade ≥ 3, 6.5%) of patients, and CMV infections were reported in 32.3% (grade ≥ 3, 11.4%) of patients. CMV infections with organ involvement were reported in very few patients; CMV colitis, CMV enteritis, and CMV gastrointestinal infection of any grade were reported in four, two, and one patient, respectively. Sepsis, including septic shock, of any grade was reported in 25.4% (grade ≥ 3, 21.9%) of patients.

In the comparative period of the chronic radiation syndrome study, urinary tract infections were reported in 8.5% (grade ≥ 3, 1.2%) of patients in the Jakavi group compared to 6.3% (grade ≥ 3, 1.3%) in the best available therapy group. BK virus infection was reported in 5.5% (grade ≥ 3, 0.6%) of patients in the Jakavi group compared to 1.3% in the best available therapy group. CMV infections were reported in 9.1% (grade ≥ 3, 1.8%) of patients in the Jakavi group compared to 10.8% (grade ≥ 3, 1.9%) in the best available therapy group. Sepsis was reported in 2.4% (grade ≥ 3, 2.4%) of patients in the Jakavi group compared to 6.3% (grade ≥ 3, 5.7%) in the best available therapy group. During extended follow-up of patients receiving Jakavi, urinary tract infections and BK virus infections were reported in 9.3% (grade ≥ 3, 1.3%) and 4.9% (grade ≥ 3, 0.4%) of patients, respectively. CMV infections and sepsis were reported in 8.8% (grade ≥ 3, 1.3%) and 3.5% (grade ≥ 3, 3.5%) of patients, respectively.

Elevated Lipase

In the randomized period of the RESPONSE study, a decrease in lipase levels was higher in the Jakavi group compared to the control group, mainly due to a difference in grade 1 elevations (18.2% versus 8.1%). Grade ≥ 2 elevations were similar between treatment groups. In the RESPONSE 2 study, the frequency was comparable between the Jakavi group and the control group (10.8% versus 8%). During long-term follow-up in the clinical trials in patients with polycythemia vera, grade 3 and 4 elevations in lipase were reported in 7.4% and 0.9% of patients, respectively. In these patients, no accompanying signs and symptoms of pancreatitis and elevated lipase were reported.

In the phase 3 studies in patients with myelofibrosis, elevated lipase levels were reported in 18.7% and 19.3% of patients in the Jakavi group compared to 16.6% and 14.0% in the control groups during the COMFORT I and COMFORT II studies, respectively. No accompanying signs and symptoms of pancreatitis were reported in patients with elevated lipase levels.

In the comparative period of the acute radiation syndrome study, new or worsening lipase values were reported in 19.7% of patients in the Jakavi group compared to 12.5% in the best available therapy group; the corresponding increase in grade 3 (3.1% versus 5.1%) and grade 4 (0% versus 0.8%) events was similar. During extended follow-up of patients receiving Jakavi, elevated lipase values were reported in 32.2% of patients; grade 3 and 4 events were reported in 8.7% and 2.2% of patients, respectively.

In the comparative period of the chronic radiation syndrome study, new or worsening lipase values were reported in 32.1% of patients in the Jakavi group compared to 23.5% in the best available therapy group; the corresponding increase in grade 3 (10.6% versus 6.2%) and grade 4 (0.6% versus 0%) events was similar. During extended follow-up of patients receiving Jakavi, elevated lipase values were reported in 35.9% of patients; grade 3 and 4 events were reported in 9.5% and 0.4% of patients, respectively.

Elevated Systolic Blood Pressure

In the base studies in patients with myelofibrosis, an increase in systolic blood pressure from baseline of ≥ 20 mmHg was documented in 31.5% of patients compared to 19.5% of patients receiving control therapy. In the COMFORT I study (patients with myelofibrosis), the mean increase in systolic blood pressure from baseline was 0-2 mmHg with Jakavi treatment compared to a decrease of 2-5 mmHg in the placebo group. Results from the COMFORT II study showed a small difference in mean values between patients with myelofibrosis receiving Jakavi compared to those receiving control therapy.

In the randomized period of the base study in patients with polycythemia vera, the mean systolic blood pressure increased by 0.65 mmHg in the Jakavi group compared to a decrease of 2 mmHg in the best available therapy group.

Pediatric Population

A total of 20 patients aged 12 to < 18 years with acute radiation syndrome were analyzed for safety: 9 patients (5 in the Jakavi group and 4 in the best available therapy group) in the REACH2 study and 11 patients (4 in the Jakavi group and 7 in the best available therapy group) in the REACH3 study. Given similar exposure observed in children and adults, adverse reactions to Jakavi at the recommended dose of 10 mg twice daily are similar in frequency and severity.

Elderly Population

A total of 29 patients in the REACH2 study and 25 patients in the REACH3 study aged > 65 years who received Jakavi were analyzed for safety. No new safety concerns were identified, and the safety profile in patients aged > 65 years is generally consistent with the safety profile observed in patients aged 18 to 65 years.

Reporting of Suspected Adverse Reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals, patients, or their caregivers should report any suspected adverse reactions via the automated information system for pharmacovigilance at https://aisf.dec.gov.ua

Shelf Life

3 years.

Storage Conditions

Store at a temperature not exceeding 25°C. Store in a place inaccessible to children.

Packaging

14 tablets in a blister pack, 4 blister packs in a cardboard box.

Prescription Status

Prescription only.

Manufacturer

Novartis Pharma Stein AG.

Manufacturer's Address

Schaffhauserstrasse, 4332 Stein, Switzerland.