Jakavi (ruxolitinib)

Release form, packaging and composition of the drug Jakavi

Tablets are white or almost white, oblong, biconvex, without chamfer, engraved “L20” on one side and “NVR” on the other.

1 tab.
ruxolitinib phosphate	26.4 mg,
which corresponds to the content of ruxolitinib	20 mg

Excipients: lactose monohydrate – 285.8 mg, microcrystalline cellulose – 273.4 mg, sodium carboxymethyl starch (type A) – 19.2 mg, hyprolose – 12.8 mg, povidone – 12.8 mg, colloidal silicon dioxide – 6.4 mg, magnesium stearate – 3.2 mg.

14 pcs. – blisters (4) – cardboard packs. 60 pcs. – cans (1) – cardboard packs.

Clinical and pharmacological group: Antitumor drug. Protein tyrosine kinase inhibitor

Pharmacotherapeutic group: Antitumor agent, protein tyrosine kinase inhibitor

Release form and composition

Dosage form of the drug – tablets:

5 mg: round, almost white or off-white, engraved with “NVR” on one side and “L5” on the other, without bevel;
15 mg: oval, biconvex, almost white or white in color, engraved “NVR” on one side and “L15” on the other, without chamfer;
20 mg: oblong, biconvex, almost white or off-white, engraved with “NVR” on one side and “L20” on the other, without bevel.

Packing of tablets: 14 pcs. in blisters, 4 blisters in a cardboard pack; 60 pcs. in cans, 1 can in a cardboard pack.

Active substance: ruxolitinib (in phosphate form), 5, 15 or 20 mg in 1 tablet.

Excipients: hydroxypropylcellulose, sodium starch glycolate (type A), microcrystalline cellulose, povidone, magnesium stearate, lactose monohydrate, colloidal silicon dioxide.

pharmachologic effect

Protein tyrosine kinase inhibitor. Ruxolitinib is a selective inhibitor of the JAK kinases (Janus Associated Kinases - JAKs) - JAK 1 and JAK 2. These kinases promote signaling 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 (STATs) (signal transporters and transcription activators), which, as a result of activation, are transported into the nucleus and modulate gene expression. Dysregulation of the JAK-STAT pathway is associated with certain types of malignancies and increased proliferation and survival of malignant cells. Myelofibrosis is a myeloproliferative disease associated with dysregulation of the JAIC1 and JAK2 signaling pathway. The basis of dysregulation is believed to be high circulating levels of cytokines that activate the JAK-STAT pathway, leading to pathological functional mutations, such as JAK2 V 617F, 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 STAT 3 phosphorylation in whole blood in both healthy volunteers and patients with myelofibrosis. Ruxolitinib resulted in maximal inhibition of STAT 3 phosphorylation at 2 hours after administration, which returned to baseline after 8 hours in healthy volunteers and patients with myelofibrosis, indicating a lack of accumulation of both the parent substance and its metabolites.

The initial increase in inflammatory markers such as TNFα, IL-6 and C-reactive protein observed in patients with myelofibrosis is reduced after treatment with ruxolitinib. In patients with myelofibrosis, resistance to the pharmacodynamic effects of ruxolitinib was not observed.

In a clinical study, there was no prolongation of the QT/QTc interval when ruxolitinib was used as a single dose at supratherapeutic doses (200 mg), indicating no effect on cardiac repolarization.

Directions for use and dosage

The drug is indicated for oral use. Eating does not affect effectiveness.

Initial doses for patients based on platelet count:

50–100×109/l – 5 mg 2 times a day;
100–200×109/l – 15 mg 2 times a day;
> 200×109/l – 20 mg 2 times a day.

At the initial dose, treatment is carried out for 4 weeks. The further dose is selected individually, taking into account the tolerability and effectiveness of Jakavi.

If the platelet count decreases to less than 50×109/L or the absolute neutrophil count decreases to less than 0.5×109/L, treatment is suspended. Resume therapy at a dose of 5 mg 2 times a day after an increase in the number of platelets/neutrophils above the specified values. Then, if necessary, the dose is gradually increased, carefully monitoring the number of blood cells.

If the platelet count decreases to less than 100×109/L, it is recommended to reduce the dose of Jakavi to avoid interruption in treatment due to developing thrombocytopenia.

If necessary and provided that the number of platelets and neutrophils is sufficient, the dose of the drug can be increased by a maximum of 5 mg 2 times a day no more than once every 2 weeks.

The maximum permissible daily dose is 50 mg: 25 mg 2 times a day.

If a dose is missed, do not take an additional dose. The patient should take the next dose at the usual time.

Treatment with the drug is continued as long as its therapeutic effect remains.

Special patient groups

In patients with severe renal failure (creatinine clearance <30 ml/minute) and liver failure, it is recommended to reduce the initial dose by 50%. Patients should be closely monitored. To avoid the development of side effects, reduce the dose if necessary.

In patients with end-stage renal disease undergoing hemodialysis, data on the use of ruxolitinib are limited. The initial dose for such patients is 15 or 20 mg 1 time per day, depending on the platelet count. After assessing the benefit-risk ratio, an additional dose may be prescribed after the hemodialysis procedure.

Elderly patients over 65 years of age do not require dose adjustment.

The safety and effectiveness of ruxolitinib in children and adolescents under 18 years of age have not been established.

For patients who simultaneously receive potent inhibitors of the CYP3A4 isoenzyme (nelfinavir, itraconazole, saquinavir, indinavir, voriconazole, ketoconazole, telithromycin, lopinavir, ritonavir, clarithromycin, grapefruit juice), the daily dose of the drug is reduced by approximately 50% (or by proportionally reducing the dose when taking 2 times per day, or reducing the frequency of administration to 1 time per day, if such a regimen is possible). Patients should be closely monitored for hematological parameters as well as clinical signs for the development of side effects of Jakavi.

Pharmacokinetics

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

Apparent Cssmax was 53-65 L in patients with myelofibrosis. At clinically relevant concentrations of ruxolitinib, protein binding in vitro (mainly albumin) was approximately 97%. An animal study showed that ruxolitinib does not cross the BBB.

Ruxolitinib is a CYP3A4 substrate. After oral administration, 60% of ruxolitinib circulates unchanged in the blood. In human blood, 2 main active metabolites of ruxolitinib have been identified, representing 25% and 11% AUC. The pharmacological activity of ruxolitinib consists of 18% of the activity of its metabolites. At clinically relevant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and is not a strong inducer of CYP1A2, CYP2B6, or CYP3A4.

After administering a single dose of radiolabeled ruxolitinib to patients, the majority (74%) of the radioactivity was detected in the urine (excreted by the kidneys), and 22% was excreted through the intestines. Unchanged material accounted for less than 1% of the total excreted drug. The average T1/2 of ruxolitinib is approximately 3 hours.

The pharmacokinetics of ruxolitinib varies in proportion to the administered (single, multiple) doses of the drug.

The AUC of ruxolitinib metabolites increases with increasing severity of renal failure and reaches significant values in patients with end-stage renal failure requiring hemodialysis. Ruxolitinib is not eliminated by dialysis. For patients with severe and end-stage renal failure (creatinine clearance less than 30 ml/min), dose adjustment of ruxolitinib is recommended.

The mean AUC of ruxolitinib increased in patients with mild, moderate, and severe hepatic impairment by 87%, 28%, and 65%, respectively, compared with normal hepatic function, with no apparent relationship with the degree of hepatic impairment based on the Child-Pugh score. Terminal T1/2 is increased in patients with liver failure compared to healthy volunteers (4.1-5.0 hours versus 2.8 hours). In patients with hepatic impairment, a dose reduction of ruxolitinib is recommended.

Description of the drug JAKAVI®

the average Cmax decreased slightly (24%), while AUC remained virtually unchanged (increased by 4%).

The pharmacokinetics of ruxolitinib varies in proportion to the administered (single, multiple) doses of the drug.

Dosage regimen

The method of administration and dosage regimen of a particular drug depend on its release form and other factors. The optimal dosage regimen is determined by the doctor. The compliance of the dosage form of a particular drug with the indications for use and dosage regimen should be strictly observed.

Taken orally.

The recommended initial dose is 15 mg 2 times a day for patients with a platelet count of 100-200×109/l; and 20 mg 2 times/day for patients with platelet count >200×109/L. The maximum recommended initial dose in patients with a platelet count of 50-100×109/l is 5 mg 2 times a day, followed by dose titration.

The dose of ruxolitinib is selected individually, taking into account the safety and effectiveness of the treatment.

The maximum dose is 25 mg 2 times/day.

Absolute blood cell counts should be monitored every 2-4 weeks during ruxolitinib dose titration and thereafter as clinically indicated.

Patients with severe renal failure (creatinine clearance less than 30 ml/min), patients on hemodialysis, patients with severe liver failure, patients simultaneously receiving strong inhibitors of the CYP3A4 isoenzyme (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice) dosage regimen adjustment is required.

Jakavi

Jakavi is taken orally, regardless of food intake.

Initial dose

The recommended starting dose of Jakavi is 15 mg 2 times/day for patients with a platelet count of 100-200×109/L, and 20 mg 2 times/day for patients with a platelet count >200×109/L. The maximum recommended initial dose in patients with a platelet count of 50-100×109/l is 5 mg 2 times a day, followed by dose titration, which is carried out with caution.

Dose selection

The dose of Jakavi is selected taking into account the safety and effectiveness of the treatment. Treatment should be suspended if the platelet count is less than 50×109/L or if the absolute number of neutrophils decreases to less than 0.5×109/L. After the number of platelets and neutrophils is restored above the specified values, the use of Jakavi can be resumed at a dose of 5 mg 2 times a day, then the dose can be gradually increased, while careful monitoring of the number of blood cells is necessary. It is recommended to reduce the dose if the platelet count decreases to less than 100×109/l in order to avoid stopping the use of the drug due to developed thrombocytopenia.

In case of therapeutic need, and if the number of platelets and neutrophils is sufficient, the dose of Jakavi can be increased by a maximum of 5 mg 2 times / day. The initial dose should not be increased during the first 4 weeks of treatment, and then no more than once every 2 weeks.

The maximum dose of Jakavi is 25 mg 2 times a day.

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

Treatment with the drug is continued as long as the positive therapeutic effect remains.

Monitoring Recommendations

Counting blood cells:

Before starting treatment with Jakavi, a blood test should be performed to count blood cells.

Absolute blood cell counts should be monitored every 2-4 weeks during ruxolitinib dose titration and thereafter as clinically indicated.

Dose adjustment during concomitant use of strong CYP3A4 inhibitors

If Jakavi is used concomitantly with strong CYP3A4 inhibitors (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice), the total daily dose of Jakavi should be reduced by approximately 50% , either by correspondingly reducing the dose when taken 2 times a day, or by reducing the frequency of administration accordingly to 1 time per day (in the case where such a regimen is possible). More frequent monitoring of hematological parameters and clinical signs and symptoms associated with adverse reactions to Jakavi is also recommended.

Special patient groups

In patients with severe renal failure (creatinine clearance less than 30 ml/min)

The recommended starting dose based on platelet count should be reduced by approximately 50%. Patients with severe renal impairment receiving Jakavi require careful monitoring; if necessary, the dose of the drug should be reduced to avoid the development of adverse drug reactions.

There are limited data on the use of ruxolitinib in patients with end-stage renal disease on hemodialysis.

. In this category of patients, treatment should be initiated with a single dose of 15 mg or 20 mg (based on platelet count), followed by a single dose only after hemodialysis, and with careful assessment of the benefit/risk ratio.

In patients with liver failure

The recommended starting dose based on platelet count should be reduced by approximately 50%. Patients diagnosed with severe liver failure receiving Jakavi require careful monitoring, and if necessary, the dose of the drug should be reduced to avoid the development of adverse drug reactions.

In patients aged ≤18 years

The safety and effectiveness of Jakavi have not been established.

Patients aged ≥ 65 years

no dose adjustment is required.

Side effect

Infectious and parasitic diseases: very often - urinary tract infections, often - infection caused by Herpes zoster.

From the hematopoietic system: very often - anemia (including 3 degrees of severity (>80-65 g/l), thrombocytopenia (1, 2 degrees of severity), neutropenia (1, 2 degrees of severity); often - anemia 4 severity (<65 g/l), thrombocytopenia 4 (<25×109/l) and 3 (50-25×109/l) severity), neutropenia 4 (<0.5×109/l) and 3 (<1 -0.5×109/l) degree of severity.

From the metabolic side: very often - hypercholesterolemia (grade 3.4), often - weight gain.

From the nervous system: very often – dizziness, headache.

From the digestive system: often – flatulence.

From the liver and biliary tract: very often - increased ALT activity (grade 1), increased AST activity (grades 1, 2), often - increased ALT activity (5-20 times higher than normal).

From the skin and subcutaneous fat: very often - subcutaneous hemorrhages.

Contraindications

age under 18 years;
period of pregnancy and lactation;
hypersensitivity to any of the components included in Jakavi.

Carefully:

severe infectious diseases in the acute phase;
severe renal failure and hemodialysis;
liver failure;
anemia;
thrombocytopenia;
neutropenia;
lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
simultaneous use of powerful CYP3A4 isoenzymes.

special instructions

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

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

Patients with a low platelet count (<200x109/L) at the start of therapy are approximately 2-fold more likely to develop thrombocytopenia during treatment with ruxolitinib. Thrombocytopenia is generally reversible and can usually be corrected by dose reduction or temporary discontinuation of ruxolitinib. However, in some cases, platelet concentrate transfusions may be required.

If patients develop anemia, they may also require red blood cell transfusions. In addition, the need for dose adjustment of ruxolitinib should be assessed.

Neutropenia (absolute neutrophil count <0.5 × 109/L), if it develops, is generally reversible and can be corrected by temporarily stopping ruxolitinib.

Before initiating ruxolitinib therapy, the presence and risk of severe bacterial, mycobacterial, fungal and viral infections should be assessed. Therapy should not be started until severe active infection has resolved. Physicians should closely 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 global myelofibrosis symptom score gradually returned to baseline within 7 days after discontinuation of use.

Impact on the ability to drive vehicles and machinery

Studies of the effect of ruxolitinib on the ability to drive and use machines have not been conducted. Given the possibility of developing some side effects of ruxolitinib (dizziness), patients should be careful when driving or engaging in other potentially hazardous activities that require increased concentration.

Jakavi

Take orally, regardless of food intake.

Initial dose

The recommended starting dose of the drug is 15 mg 2 times a day for patients with a platelet count of 100-200/nl, and 20 mg 2 times a day for patients with a platelet count >200/nl. The maximum recommended initial dose in patients with a platelet count of 50-100/nl is 5 mg 2 times a day, followed by dose titration, which is carried out with caution.

Dose selection

The dose is selected taking into account the safety and effectiveness of the treatment. Treatment should be suspended if the platelet count is less than 50/nl or if the absolute neutrophil count decreases to less than 0.5/nl. After the number of platelets and neutrophils is restored above the specified values, the use of the drug can be resumed at a dose of 5 mg 2 times a day, then the dose can be gradually increased, while careful monitoring of the number of blood cells is necessary. It is recommended to reduce the dose if the platelet count decreases to less than 100/nl in order to avoid stopping the use of the drug due to developed thrombocytopenia.

In case of therapeutic need, and if the number of platelets and neutrophils is sufficient, the dose taken can be increased by a maximum of 5 mg 2 times a day. The initial dose should not be increased during the first 4 weeks of treatment, and then no more than once every 2 weeks.

The maximum dose is 25 mg 2 times a day.

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

Treatment with the drug is continued as long as the positive therapeutic effect remains.

Monitoring Recommendations

Blood cell count: Before starting treatment, a blood test with a blood cell count should be performed.

Absolute blood cell counts should be monitored every 2-4 weeks during ruxolitinib dose titration and thereafter as clinically indicated.

Dose adjustment during concomitant use of strong CYP3A4 inhibitors

If the drug is used simultaneously with potent inhibitors of the CYP3A4 isoenzyme (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice), the total daily dose of the drug should be reduced by approximately 50%, either by correspondingly reducing the dose when taken 2 times a day, or by reducing the frequency of administration accordingly to 1 time per day (in the case where such a regimen is possible). More frequent monitoring of hematological parameters and clinical signs and symptoms associated with adverse reactions to the drug is also recommended.

Special patient groups

In patients with severe renal impairment (creatinine clearance less than 30 mL/min), the recommended starting dose based on platelet count should be reduced by approximately 50%. Patients with severe renal impairment require careful monitoring; if necessary, the dose of the drug should be reduced to avoid the development of adverse drug reactions.

There are limited data on the use of ruxolitinib in patients with end-stage renal disease on hemodialysis. In this category of patients, treatment should be initiated with a single dose of 15 mg or 20 mg (based on platelet count), followed by a single dose only after hemodialysis, and with careful assessment of the benefit/risk ratio.

In patients with hepatic impairment, the recommended starting dose based on platelet count should be reduced by approximately 50%. Patients diagnosed with severe liver failure require careful monitoring; if necessary, the dose of the drug should be reduced to avoid the development of adverse drug reactions.

In patients under the age of 18 years, the safety and effectiveness of use have not been established.

Patients over 65 years of age do not require dose adjustment.

Drug interactions

In healthy volunteers, taking ketoconazole, a potent inhibitor of the CYP3A4 isoenzyme, at a dose of 200 mg 2 times a day for 4 days, led to an increase in the AUC of ruxolitinib by 91% and an extension of T1/2 from 3.7 hours to 6 hours. In the case of use of ruxolitinib with potent CYP3A4 inhibitors, the total daily dose of ruxolitinib should be reduced by approximately 50%.

Administration of erythromycin, a moderate isoenzyme inhibitor, at a dose of 500 mg 2 times a day to healthy volunteers for several days resulted in a 27% increase in ruxolitinib AUC. Dose adjustment is not required when ruxolitinib is used concomitantly with mild or moderate inhibitors of the CYP3A4 isoenzyme (including erythromycin).

In healthy volunteers receiving rifampicin, a powerful inducer of the CYP3A4 isoenzyme, at a dose of 600 mg 1 time / day for 10 days, the AUC of ruxolitinib after taking a single dose decreased by 71%, T1/2 decreased from 3.3 hours to 1.7 hours. Relative amount active metabolites increased relative to the parent substance.

Order a product

Jakavi, 5 mg, tablets, 56 pcs.

Inside,

regardless of food intake.

Initial dose

The recommended starting dose of Jakavi is 15 mg twice daily for patients with a platelet count of 100–200·109/L; and 20 mg 2 times a day for patients with a platelet count >200·109/L. The maximum recommended initial dose in patients with a platelet count of 50–100·109/L is 5 mg 2 times a day orally, followed by dose titration, which is carried out with caution.

Dose selection

The dose of Jakavi is selected based on the safety and effectiveness of the treatment. Treatment should be suspended if the platelet count is detected to be less than 50·109/L or the absolute number of neutrophils decreases to less than 0.5·109/L. After the platelet and neutrophil counts are restored above the specified values, the use of Jakavi can be resumed at a dose of 5 mg 2 times a day, then the dose can be gradually increased, while careful monitoring of the blood cell count is necessary.

It is recommended to reduce the dose when the platelet count decreases to less than 100·109/l, in order to avoid stopping the use of the drug due to developed thrombocytopenia.

In case of therapeutic need and if the platelet and neutrophil count is sufficient, the dose of Jakavi can be increased by a maximum of 5 mg 2 times a day. The initial dose should not be increased during the first 4 weeks of treatment and then no more than once every 2 weeks.

The maximum dose of Jakavi is 25 mg 2 times a day orally.

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

Treatment with the drug is continued as long as the positive therapeutic effect remains.

Monitoring Recommendations

Blood cell count: A blood cell count should be performed before starting treatment with Jakavi.

Absolute blood cell counts should be monitored every 2–4 weeks during ruxolitinib dose titration and thereafter as clinically indicated.

Dose adjustment during concomitant use of strong CYP3A4 inhibitors

If Jakavi is used concomitantly with strong CYP3A4 inhibitors (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice), the total daily dose of Jakavi should be reduced by approximately 50% , either by correspondingly reducing the dose when taken 2 times a day, or by reducing the frequency of administration accordingly to 1 time a day (in the case where such a regimen is possible). More frequent monitoring of hematological parameters and clinical signs and symptoms associated with adverse reactions to Jakavi is also recommended.

Special patient groups

Kidney failure.

In patients with severe renal impairment (Cl creatinine <30 mL/min), the recommended starting dose based on platelet count should be reduced by approximately 50%.

Patients with severe renal impairment receiving Jakavi should be closely monitored and, if necessary, the dose of the drug should be reduced to avoid the development of adverse drug reactions.

There are limited data on the use of ruxolitinib in patients with end-stage renal disease undergoing hemodialysis. In this category of patients, treatment should be initiated with a single dose of 15 or 20 mg (based on platelet count), followed by a single dose given only after the hemodialysis procedure, and with a careful assessment of the benefit/risk ratio.

Liver failure.

In patients with hepatic impairment, the recommended starting dose based on platelet count should be reduced by approximately 50%. Patients with diagnosed severe hepatic impairment receiving Jakavi should be closely monitored and, if necessary, the dose of the drug should be reduced to avoid the development of adverse drug reactions.

Patients aged ≤18 years.

The safety and effectiveness of Jakavi in patients ≤18 years of age have not been established.

Patients aged ≥65 years.

No dose adjustment is required.