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.
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.
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.
Side effects
The most common side effects identified in clinical studies are anemia and thrombocytopenia.
Hematological adverse events: anemia (81.7%), thrombocytopenia (67.4%), neutropenia (15.3%). These reactions are dose-dependent.
The most common non-hematological laboratory abnormalities include increased activity of alanine aminotransferase (ALT) (26.2%) and asparagine aminotransferase (AST) (18.6%), hypercholesterolemia (16.6%).
The most common non-hematological adverse reactions include subcutaneous hematomas (18.6%), dizziness (14%), headache (12.6%).
In phase III clinical trials, discontinuation of Jakavi due to the development of side effects (regardless of the cause-and-effect relationship) was required in 9.6% of patients.
Frequency of side effects: very often - ≥ 1/10, often - from ≥ 1/100 to < 1/10, infrequently - ≥ 1/1000 to < 1/100, rarely - from ≥ 1/10,000 to < 1/ 1000, very rarely - < 1/10,000.
Possible adverse reactions:
- from the hematopoietic system: very often - neutropenia of 1 and 2 degrees of severity, thrombocytopenia of 1 and 2 degrees of severity, anemia, including 3 degrees of severity (> 80–65 g/l), bleeding (including purpura , petechiae, subcutaneous hemorrhages, intracranial hemorrhages and gastrointestinal bleeding); often – thrombocytopenia grade 3 (50–25×109/l) and severity grade 4 (< 25×109/l), neutropenia grade 3 (< 1–0.5×109/l) and severity grade 4 (< 0.5×109/l), grade 4 anemia (<65 g/l);
- from the liver and biliary tract: very often - increased AST activity 1, 2 degrees, increased ALT activity 1 degree; often – an increase in ALT activity 5–20 times higher than normal;
- from the metabolic side: very often – hypercholesterolemia of 3 and 4 degrees; often – weight gain;
- from the digestive system: often – flatulence;
- from the nervous system: very often – headache, dizziness; often – imbalance; infrequently - Meniere's disease;
- infectious and parasitic diseases: very often - urinary tract infections (cystitis, pyuria, urosepsis), kidney infections; often - herpes zoster, tuberculosis.
Classification of severity of side effects:
- 1 – mild degree;
- 2 – moderate degree;
- 3 – severe;
- 4 – extremely severe, life-threatening.
special instructions
Before prescribing Jakavi, it is necessary to conduct a general blood test with counting of blood cells. The absolute number of blood cells should be monitored every 2–4 weeks during the period of drug dose titration and further as clinically indicated.
If anemia develops, it may be necessary to transfuse red blood cells to the patient and adjust the dose of the drug.
At 8–12 weeks of treatment, the hemoglobin level reaches its lowest level (15–20 g/l below the initial value). Subsequently, it gradually increases and remains at a level of 10 g/l below the initial level (before the start of therapy). This trend occurs in patients regardless of whether they receive a blood transfusion during treatment.
Severe neutropenia (stages 3 and 4), if developed, is usually noted by week 12 of taking Jakavi. In general, it is reversible and can be corrected by temporarily stopping the drug.
Before prescribing therapy, it is recommended to conduct an examination for the presence and risk of developing severe fungal, bacterial, viral and mycobacterial infections. There are isolated cases of tuberculosis developing in patients receiving ruxolitinib. Jakavi should not be administered until a severe active infection has resolved. Patients should be closely monitored for symptoms of infection so that appropriate treatment can be provided promptly if necessary.
The drug can cause the development of herpes zoster. The doctor must teach the patient how to identify the early signs of this disease in a timely manner in order to begin treatment on time.
There is a separate case of the development of progressive multifocal leukoencephalopathy (PML) in a patient taking Jakavi. Therefore, clinicians should be alert to the occurrence of neuropsychiatric symptoms that may indicate PML.
After stopping treatment, symptoms of myelofibrosis (fatigue, night sweats, fever, bone pain, itching, weight loss, symptomatic splenomegaly) may return. In clinical studies, the overall myelofibrosis symptom score gradually returned to baseline values within 7 days after discontinuation of the drug.
Women of fertile age are advised to use reliable methods of contraception during the period of use of Jakavi. If pregnancy occurs during treatment, the balance of benefits and risks should be carefully assessed taking into account data on the embryotoxicity of the drug.
Studies have not been conducted on the effect of ruxolitinib on the speed of reactions and the ability to concentrate. However, given the potential for dizziness, patients are advised to exercise caution when driving or performing any work that requires alertness.
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.
Drug interactions
Potent CYP3A4 inhibitors increase ruxolitinib concentrations and prolong its half-life. If they are used concomitantly, the dose of Jakavi should be reduced by approximately 50%, patients should be closely monitored for a decrease in blood cell counts, and the dose should be adjusted if necessary.
With the simultaneous use of mild and moderate inhibitors of the CYP3A4 isoenzyme (for example, erythromycin), the total concentration of ruxolitinib slightly increases, but dose adjustment of Jakavi is not required; only careful monitoring of patients and assessment of the number of blood cells is recommended.
In the case of concomitant use of inducers of the CYP3A4 isoenzyme, no dose adjustment of ruxolitinib is required at the beginning of treatment, however, if the effectiveness of Jakavi decreases, a gradual increase in its dose may be required.
In healthy volunteers who received a powerful inducer of the CYP3A4 isoenzyme rifampicin for 10 days at a daily dose of 600 mg (in 1 dose), the total dose of ruxolitinib when taken once a day was reduced by 71%, and the half-life decreased to 1.7 hours (from 3 ,3 hours). The relative amount of active metabolites increased relative to the parent substance.
When coadministering P-glycoprotein or other transporters, dose adjustment is not recommended.
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.
