Ruxolitinib - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Antineoplastic agents - inhibitors of protein kinases

Included in the formulation

Jakavi®

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Novartis Pharma AG Switzerland

Jakavi®

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Novartis Pharma AG Switzerland

АТХ:

L.01.X.E Protein kinase inhibitors

L.01.X.E.18 Русосолитиниб

Pharmacodynamics:

An antineoplastic agent, a protein kinase inhibitor. Русосолитиниб is a selective inhibitor of JAK-kinases (JAKs) - JAK1 and JAK2, which promote the transmission of signals from numerous cytokines and growth factors that play an important role in hematopoiesis and immune system function. Activated JAK kinases, acting on cytokine receptors, activate STAT proteins (signal transducers and transcription activators) that, 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 malignant neoplasms and increased proliferation and survival of malignant cells.

Pharmacokinetics:

In clinical trials rosolitinib was rapidly absorbed after oral administration with a time to reach a maximum concentration of about 1 hour. The absorption of rutzolitinib is 95% or more. Average maximum concentration and the area under the concentration-time curve (AUC) increases proportionally in the dose range of 5 to 200 mg.

In clinically significant concentrations of rutzolitinib, the association with proteins in vitro (mainly with albumin) was approximately 97%. In an animal study, it was shown that rosolitinib does not penetrate the blood-brain barrier.

Ruxolitinib is a substrate of the isoenzyme CYP3A4. After taking the drug, 60% of rutzolitinib circulates in the blood in an unchanged form. The pharmacological activity of rutzolitinib is 18% of the activity of its metabolites. In clinically significant concentrations rosolitinib does not inhibit the isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and is not a potent inducer of the isoenzymes CYP1A2, CYP2B6 or CYP3A4.

After the administration of a single dose of radiolabeled radiolabeled ratsolitinib to patients, most (74%) of radioactivity was detected in the urine (excreted by the kidneys), and 22% was excreted through the intestine. The average half-life of rutzolitinib is approximately 3 hours.

Indications:

Treatment of patients with myelofibrosis, including primary myelofibrosis and secondary myelofibrosis, developed due to true polycythemia and essential thrombocythemia.

ICD-10

II.D37-D48.D47.1 Chronic myeloproliferative disease

Contraindications:

Pregnancy.
Lactation period (breastfeeding).
The age is under 18 years.
Hypersensitivity to ratsolitinib or any other component of the drug.

Carefully:

Caution should be used in patients with severe renal insufficiency and in hemodialysis patients, in patients with hepatic insufficiency, in patients with severe infectious diseases in the acute phase, also in patients with thrombocytopenia, anemia and neutropenia, in patients with lactase deficiency, intolerance to lactose and glucose-galactase malabsorption, simultaneously with potent inhibitors of the isoenzyme CYP3A4.

Pregnancy and lactation:

Contraindicated use of the drug during pregnancy and lactation (breastfeeding).

Recommendations for FDA - category X.

Dosing and Administration:

The recommended initial dose of the drug rosolitinib is 15 mg twice a day for patients with a platelet count of 100-200 × 10⁹/ l, and 20 mg twice a 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 titrating the dose, which is carried out with caution.

Side effects:

Infectious and parasitic diseases: very often - urinary tract infections, particularly cystitis, urosepsis, pyuria, kidney infections; often - herpes zoster, tuberculosis.

From the side hematopoiesis 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), bleeding, including gastrointestinal bleeding, intracranial hemorrhage, subcutaneous hemorrhages, petechiae, purpura; often - anemia 4 degrees of severity (<65 g / l), thrombocytopenia 4 degrees of severity (<25 × 10⁹/ l) and 3 degrees of gravity (50-25 × 10⁹/ l), neutropenia 4 degrees of severity (<0.5 × 10⁹/ l) and 3 degrees of gravity (<1-0.5 × 10⁹/ l).

From the side metabolism: very often - hypercholesterolemia (3-4 degrees); often - weight gain.

From the side nervous system: very often - dizziness, headache; often - imbalance; infrequently Meniere's disease.

From the side digestive system: often - flatulence.

From the side liver and bile ducts: very often - increased ALT activity (1 degree), increased ACT activity (1-2 degrees); often - increased ALT activity (5-20 times higher than normal).

Overdose:

Symptoms: the use of rutzolitinib once in a dose up to 200 mg was tolerated satisfactorily. Exceeding the recommended doses was associated with increased myelosuppression, which was manifested by leukopenia, anemia and thrombocytopenia.

Treatment: with the development of adverse reactions associated with overdose of the drug, it is necessary to apply appropriate supportive treatment. Hemodialysis is ineffective. Antidote to ratsolitinibu is unknown.

Interaction:

Powerful inhibitors of the isoenzyme CYP3A4: in healthy volunteers, the administration of ketoconazole, a potent inhibitor of the isoenzyme CYP3A4, at a dose of 200 mg twice daily for 4 days, resulted in an increase in the AUC of the preparation by 91% and elongation of the half-lifefrom 3.7 hours to 6 hours.

In the case of using rutzolitinib with potent inhibitors of the isoenzyme CYP3A4, the total daily dose of rutzolitinib should be reduced by approximately 50%.

Patients should be carefully monitored to reduce the number of blood cells, if necessary, further correction of the dose is recommended based on efficacy and safety data.

Light and moderate inhibitors of the isoenzyme CYP3A4: reception of erythromycin,a moderate isozyme inhibitor, at a dose of 500 mg twice a day in healthy volunteers for 4 days, resulted in an increase in the AUC of rutisolithinib by 27%.

Dose correction is not required when the drug is administered simultaneously with light or moderate inhibitors of the CYP3A4 isoenzyme (including erythromycin). At the beginning of therapy with ratsolitinib simultaneously with moderate inhibitors of the CYP3A4 isoenzyme, careful monitoring of patients and evaluation of the number of blood elements are required.

P-glycoprotein and other transporters: dose adjustment is not recommended when the drug is used concomitantly with drugs interacting with P-glycoprotein and other transports.

Special instructions:

Reduction of the number of blood elements

Treatment with ratsolitinib can lead to the development of hematological adverse reactions, including thrombocytopenia, anemia and neutropenia. Before the start of treatment with rutzolitinib, a general blood test should be performed.

Thrombocytopenia

In patients with a reduced number of platelets (<200 × 109 / L) at the beginning of therapy, the probability of thrombocytopenia increases during treatment with ratsolitinib approximately 2-fold.In clinical studies, thrombocytopenia of grade 3 or 4 developed around the 8th week of therapy. Thrombocytopenia, as a whole, is reversible and is usually corrected by a decrease in the dose or a temporary discontinuation of rusesolithinib. The platelet count was restored to more than 50x10⁹/ l for 14 days. However, in some cases, transfusions of platelet concentrates may be required.

With the development of anemia, patients may also need a transfusion of erythrocyte mass. In addition, it is necessary to assess the need for dose adjustment with rutisolithinib. Approximately 50% of patients who participated in clinical trials and received rosolitinib, and in 37% of patients in the control group, a red blood cell transfusion was required during the study.

In patients who received rosolitinib, the hemoglobin index reached the lowest possible level (by 15-20 g / L below the initial value) at the 8-12th week of therapy. In the future, the hemoglobin index gradually increased and remained at a level of 10 g / l below the baseline (before treatment). This trend was observed in patients, regardless of whether they received blood transfusion during therapy.

Neutropenia

Neutropenia 3 and 4 stages developed around the 12th week of therapy.In general, neutropenia (absolute number of neutrophils <0.5x10⁹/ l), in the case of its development, was reversible and corrected by the temporary abolition of rusesolitinib.

Bleeding

Bleeding (including intracranial hemorrhage, gastrointestinal hemorrhage, subcutaneous hemorrhage, petechiae, purpura and other bleeding) were reported in 32.6% of patients who received rosolitinib. 65.3% of all bleeding were cases of development of subcutaneous hematomas, which were noted in 21.3% of patients. The incidence of bleeding of grade 3 and 4 was 4.7%. Cases of intracranial hemorrhage were noted in 1% of patients, gastrointestinal bleeding - in 5% of patients, bleeding due to other causes (including nasal bleeding, postoperative hemorrhages and hematuria) in 13.3% of patients who received rosolitinib.

Infections

Before prescribing rusovolitinib, the presence and risk of developing severe bacterial, mycobacterial, fungal and viral infections should be assessed. In patients who received rosolitinib, reported cases of tuberculosis. It should be remembered about the possibility of developing an active or latent form of tuberculosis.Therapy with ratsolitinib should not begin before the resolution of a severe active infection process. The physician should carefully monitor patients receiving rosolitinib for the development of symptoms of infection and, if necessary, begin promptly appropriate treatment.

Shingles Herpes (Herpes Zoster)

Before prescribing rusesolitinib, a physician should train patients in the timely detection of early symptoms of herpes zoster, reporting the need for early initiation of treatment.

Progressive multifocal leukoencephalopathy

With the use of rutzolitinib, a report was received on the case of the development of progressive multifocal leukoencephalopathy. The physician should be wary of neuropsychiatric symptoms, suggesting the development progressive multifocal leukoencephalopathy

The withdrawal syndrome

After the termination of therapy with rutzolitinib, myelofibrosis symptoms (such as fatigue, bone pain, fever, pruritus, night sweats, symptomatic splenomegaly and weight loss) may return.In clinical trials, the overall scale of symptoms of myelofibrosis gradually returned to baseline values within 7 days after discontinuation of use.

Influence on the ability to drive and / or work with machinery

Studies of the effect of the drug on the ability to drive vehicles and work with mechanisms have not been carried out. Given the possibility of developing some side effects with russolithinib (dizziness), patients should be careful when driving vehicles and engaging in other potentially hazardous activities that require increased concentration.

Instructions

Русосолитиниб (Русосолитиниб)