Composition, form of production and packaging
Tablets are white or almost white, round, without a bevel, with engraving "L5" on one side and "NVR" on the other.
rutzolitinib phosphate 6.6 mg,
which corresponds to the content of rutzolitinib 5 mg
Excipients: lactose monohydrate 71.45 mg, microcrystalline cellulose 68.35 mg, sodium starch glycolate (type A) 4.8 mg, hydroxypropylcellulose 3.2 mg, povidone 3.2 mg, colloidal silicon dioxide 1.6 mg, magnesium stearate 0.8 mg.
14 pcs. - blisters (4) - packs of cardboard.
60 pcs. - cans (1) - packs cardboard.
Tablets are white or almost white, oval, biconcave, without chamfer, with engraving "L15" on one side and "NVR" on the other.
rutzolitinib phosphate 19.8 mg,
which corresponds to the content of rutzolitinib 15 mg
Excipients: lactose monohydrate 214.35 mg, microcrystalline cellulose 205.05 mg, sodium starch glycolate (type A) 14.4 mg, hydroxypropyl cellulose 9.6 mg, povidone 9.6 mg, silicon colloidal 4.8 mg, magnesium stearate 2.4 mg.
14 pcs. - blisters (4) - packs of cardboard.
60 pcs. - cans (1) - packs cardboard.
Tablets are white or almost white, oblong, biconvex, without chamfer, with engraved "L20" on one side and "NVR" on the other.
rutzolitinib phosphate 26.4 mg,
which corresponds to the content of rutzolitinib 20 mg
Excipients: lactose monohydrate 285.8 mg, microcrystalline cellulose 273.4 mg, sodium starch glycolate (type A) 19.2 mg, hydroxypropyl cellulose 12.8 mg, povidone 12.8 mg, colloidal colloidal silicon 6.4 mg, magnesium stearate 3.2 mg.
14 pcs. - blisters (4) - packs of cardboard.
60 pcs. - cans (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
An antineoplastic agent, a protein kinase inhibitor. Ruxolitinib is a selective inhibitor of JAK-kinases (JAKs) -JAK 1 and JAK 2. These kinases 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), 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 malignant neoplasms and increased proliferation and survival of malignant cells. Myelofibrosis is a myeloproliferative disorder associated with the dysregulation of the JAIC 1 and JAK 2 signaling pathway. It is believed that the basis for dysregulation is a high circulating level of cytokines that activate the JAK-STAT pathway, leading to pathological functional mutations such as JAK 2 V 617 F and to suppression of negative regulatory mechanisms. In patients with myelofibrosis, dysregulation of the JAK signaling pathway is detected, regardless of the presence of the JAK2V617F mutation.
Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood, both in healthy volunteers and in patients with myelofibrosis. Р СѓСЃРѕСЃРѕР»РёС‚РёРЅРёР± leads to the maximum inhibition of phosphorylation of STAT3 2 h after the administration, which returned to baseline in 8 hours in healthy volunteers and in patients with myelofibrosis, which indicates the absence of cumulation of both the starting material and its metabolites.
The initial increase in inflammatory markers such as TNFО±, interleukin-6 (IL-6) and C-reactive protein (CRP) observed in patients with myelofibrosis decreases after treatment with rutzolithinib. In patients with myelofibrosis, there was no evidence of resistance to the pharmacodynamic effects of rutzolitinib.
In the clinical study, there was no QT / QT prolongation of the interval with the use of rutzolitinib once in supra-therapeutic doses (200 mg), which indicates a lack of influence on repolarization of the heart.
Р СѓСЃРѕСЃРѕР»РёС‚РёРЅРёР± concerns to I class of molecules on biopharmaceutical classification system (Biopharmaceutical Classification System), with high permeability, high solubility and fast decay. In clinical trials, rutzolithinib was rapidly absorbed after oral administration with a time to reach a maximum concentration ( Cmax ) of about 1 hour. The absorption of rutzolitinib is 95% or more. The mean C max and the area under the concentration-time curve (AUC) increase proportionally in the dose range of 5 to 200 mg. With the use of rutzolitinib simultaneously with high-fat food, clinically insignificant changes in the pharmacokinetics of rutzolitinib were observed: the mean C max decreased slightly (24%), while the AUC remained practically unchanged (increased by 4%).
The apparent volume of distribution in the equilibrium state was 53-65 l in patients with myelofibrosis. In clinically significant concentrations of rutzolitinib, in vitro binding to proteins (mainly with albumin) was approximately 97%. In an animal study, it was shown that ratsolitinib does not penetrate the blood-brain barrier.
Biotransformation / metabolism
Ruxolitinib is a substrate of the CYP 3A4 isoenzyme. After taking the drug, 60% of rutzolitinib circulates in the blood in an unchanged form. In the human blood, 2 main active metabolites of rutisolithinib are identified, representing 25% and 11% of AUC. The pharmacological activity of rutzolitinib is 18% of the activity of its metabolites. In clinically significant concentrations, rutzolithinib does not inhibit the isoenzymes CYP 1A2, CYP 2B6, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4 and is not a potent inducer of CYP 1A2, CYP 2B6 or CYP 3A4 isoenzymes.
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 unchanged substance was less than 1% of the total withdrawn drug. The average half-life of rutzolitinib is approximately 3 hours.
Linearity / Nonlinearity of Pharmacokinetics
The pharmacokinetics of ratsolitinib varies in proportion to the doses administered (once, repeatedly).
Pharmacokinetics in selected groups of patients
The influence of age, sex or race
There were no significant differences in the pharmacokinetics of ratsolitinib, depending on sex and race. The clearance of rutzolitinib is 17.7 l / h in women and 22.1 l / h in men, with 39% interindividual variability.
Patients aged 18 years
The efficacy and safety of the Giacavi drug in patients younger than 18 years of age is not established.
Impaired renal function
The index value of the area under the concentration-time curve (AUC) of the metabolites of rutzolitinib increases with increasing severity of renal insufficiency reaches significant values вЂ‹вЂ‹in patients with terminal stage of renal failure who need hemodialysis. Ruxolitinib is not excreted by dialysis. For patients with severe and terminal stages of renal failure (QC less than 30 ml / min), dose correction of rutzolitinib is recommended.
Impaired liver function
The mean AUC of ratsolitinib increased in patients with mild, moderate and severe hepatic impairment by 87%, 28%, and 65%, respectively, compared with normal liver function, with no apparent relationship to the degree of liver failure based on the Child-Pugh scale. The final half-life is prolonged in patients with hepatic impairment compared with healthy volunteers (4.1-5.0 h vs. 2.8 h). In patients with hepatic insufficiency, a dose reduction of rutzolitinib is recommended.
- treatment of patients with myelofibrosis, including primary myelofibrosis and secondary myelofibrosis, developed due to true polycythemia and essential thrombocythemia.
The drug Giacavi is taken orally, regardless of food intake.
The recommended initial dose of the Giacavi preparation is 15 mg 2 times / day for patients with a platelet count of 100-200 Г— 10 9 / L, and 20 mg 2 times / day for patients with platelet count> 200 Г— 10 9 / L. The maximum recommended initial dose in patients with a platelet count of 50-100 Г— 10 9 / L is 5 mg 2 times / day, followed by a titration dose, which is carried out with caution.
The dose of the drug Giacavi is selected taking into account the safety and effectiveness of the treatment. Treatment should be suspended if the number of platelets is less than 50 Г— 10 9 / l or when the absolute number of neutrophils is less than 0.5 Г— 10 9 / l. After the recovery of platelets and neutrophils is higher than the indices, the use of the Giacavi preparation can be resumed at a dose of 5 mg 2 times / day, then the dose may gradually increase, and careful monitoring of the number of blood elements is necessary. It is recommended to reduce the dose, with a decrease in the number of platelets less than 100? 10 9 / l to avoid suspension of the drug due to developed thrombocytopenia.
In case of therapeutic necessity, and if the amount of platelets and neutrophils is sufficient, the dose of Giacavi preparation taken can be increased by max. 5 mg 2 times / day. The initial dose should not be increased during the first 4 weeks of treatment, and then no more often than once in 2 weeks.
The maximum dose of the drug Giacavi is 25 mg 2 times / day.
In case of missed intake of the next dose of the drug, 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 until a positive therapeutic effect is maintained.
Counting the blood elements: before the beginning of treatment with Giacavi, a blood test should be performed with the counting of blood cells.
Absolute number of blood elements should be monitored every 2-4 weeks during the selection of a dose of rutzolitinib and further on the clinical indications.
Correction of the dose while using powerful inhibitors of CYP3A4
If the Giacavi preparation is used simultaneously with the potent inhibitors of the isoenzyme CYP3A4 (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir / ritonavir, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice), the total daily dose of Giacavi should be reduced by approximately 50 %, or by a corresponding reduction in dose when taken 2 times / day, or by reducing the frequency of administration, respectively, to 1 time per day (in the case when such a mode of reception is possible). Also, more frequent monitoring of hematological parameters and clinical signs and symptoms associated with adverse reactions to the Giacavi preparation is recommended.
Special patient groups
In patients with renal insufficiency (QC less than 30 mL / min) of severe severity, the recommended initial dose based on the platelet count should be reduced by approximately 50%. Patients with severe renal insufficiency who receive the preparation of Giacavi require careful monitoring; if necessary, the dose of the drug should be reduced to avoid the development of unwanted drug reactions.
There are limited data on the use of rutzolithinib in patients with terminal stage of renal failure on hemodialysis . In this category of patients, treatment should begin with a single dose of 15 mg or 20 mg (based on the number of platelets) followed by a single dose, which is administered only after the hemodialysis procedure, and with a careful assessment of the benefit / risk ratio.
In patients with hepatic insufficiency, the recommended initial dose, based on the number of platelets, should be reduced by approximately 50%. Patients with diagnosed severe hepatic insufficiency receiving the preparation of Giacavi require careful observation, if necessary, the dose of the drug should be reduced in order to avoid the development of unwanted drug reactions.
In patients aged в‰Ґ 18 years, the safety and efficacy of the drug Gakavi has not been established.
Patients aged? 65 years dose adjustment is not required.
A study of the safety of the drug was carried out in clinical trials in 617 patients. The most frequently reported adverse drug reactions were thrombocytopenia and anemia.
Hematologic adverse reactions (of any severity *) included anemia (81.7%), thrombocytopenia (67.4%) and neutropenia (15.3%). The development of anemia, thrombocytopenia and neutropenia was dose-dependent.
The most frequent non-hematological adverse reactions: subcutaneous hematomas (18.6%), dizziness (14.0%) and headache (12.6%).
The most frequent nonhematological laboratory disorders: increased ALT activity (26.2%), ACT (18.6%) and hypercholesterolemia (16.6%).
In III In the phase of clinical trials, discontinuation of treatment due to the development of adverse reactions, regardless of their cause-effect relationship, was observed in 9.6% of patients.
Determination of the frequency of adverse reactions: very often (? 1/10), often (? 1/100; <1/10), infrequently (? 1/1000; <1/100), rarely (? 1/10 000; <1 / 1000), very rarely (<1/10 000).
Infectious and parasitic diseases: very often - urinary tract infections, in particular cystitis, urosepsis, pyuria, kidney infections; often - herpes zoster, tuberculosis.
On the part of the 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 hemorrhages, subcutaneous hemorrhages, petechiae, purpura, often anemia of 4 degrees of severity (<65 g / l), thrombocytopenia (4 degrees of severity (<25 Г— 10 9 / L) and 3 degrees of severity (50-25 Г— 10 9 / l)), neutropenia (4 degrees of severity (<0.5 Г— 10 9 / l) and 3 degrees of severity (<1-0.5 Г— 10 9 / L)).
From the side of metabolism: very often - hypercholesterolemia (3,4 degrees); often - weight gain.
From the nervous system: very often - dizziness, headache; often - imbalance; infrequently Meniere's disease.
From the digestive system: often - flatulence.
From the liver and biliary tract: very often - increased ALT activity (1 degree), increased activity of ACT (1, 2 degrees); often - increased ALT activity (5-20 times higher than normal).
* - a classification of the severity of unwanted reactions:
1 - mild degree
2- moderate degree
3- Heavy degree
4- extremely heavy (life-threatening) degree
If any of the above adverse reactions are aggravated, or if the patient has noticed any other adverse reactions, he should inform the doctor about it.
- the period of lactation (breastfeeding);
- the age is under 18 years;
- Hypersensitivity to ratsolitinib or any other component of the drug.
Caution should be used in patients with severe renal insufficiency and hemodialysis patients, in patients with hepatic insufficiency, in patients with severe infectious diseases in the acute phase, as well as in patients with thrombocytopenia, anemia and neutropenia, in patients with lactase defecitium intolerance to lactose and glucose-galactase malabsorption, simultaneously with potent inhibitors of the isoenzyme CYP3A4.
PREGNANCY AND LACTATION
The drug Giacavi is contraindicated in pregnancy and lactation (breastfeeding).
Patients of fertile age during the therapy with Giacavi are recommended to use methods of contraception. In the case of pregnancy during therapy with Giacavi, the benefit / risk ratio should be carefully assessed for each individual patient, taking into account the latest known data on the embryotoxicity of the drug.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with severe renal failure (QC less than 30 ml / min), the recommended initial dose based on the platelet count should be reduced by approximately 50%.
Patients with severe renal insufficiency who receive Giacavi should be carefully observed, and if necessary, the dose of the drug should be reduced to avoid the development of unwanted drug reactions.
There are limited data on the use of rutzolithinib in patients with terminal stage of renal failure on hemodialysis. In this category of patients, treatment should be initiated with a single dose of 15 mg or 20 mg (based on the number of platelets), followed by a single dose, which is administered only after the hemodialysis procedure, and with a careful assessment of the benefit / risk ratio.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with hepatic insufficiency, the recommended initial dose, based on the number of platelets, should be reduced by approximately 50%. Patients with diagnosed severe hepatic insufficiency who receive Giacavi should be carefully observed and, if necessary, the dose of the drug should be reduced to avoid the development of unwanted drug reactions
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under 18 years of age
APPLICATION IN ELDERLY PATIENTS
Patients aged> 65 years are not required to adjust the dose of the drug.
Reduction of the number of blood elements
Treatment with Giacavi can lead to the development of hematological adverse reactions, including thrombocytopenia, anemia and neutropenia. Before starting treatment with Giacavi, a general blood test should be performed.
In patients with a reduced number of platelets (<200 Г— 10 9 / L) at the beginning of therapy, the probability of thrombocytopenia during treatment with ratsolitinib is approximately 2-fold increased. In clinical studies, 3 or 4 thrombocytopenia severity evolved to about 8 weeks of therapy. Thrombocytopenia is generally reversible and is usually adjusted dose reduction or a temporary discontinuation of drug Dzhakavi. Platelet count was restored to values more 50h10 9 / l for 14 days. However, in some cases, may require transfusion of platelet concentrates.
With the development of anemia in patients may also need transfusions of red cells. Furthermore, it is necessary to evaluate the need for correction Dzhakavi dose preparation. Approximately 50% of patients participating in clinical trials and receiving the drug Dzhakavi, and in 37% of patients in the control group during the study required red blood cell transfusions.
In patients receiving the drug Dzhakavi, hemoglobin index reaches the lowest level (15-20 g / l lower baseline) at 8-12 weeks of therapy. Subsequently hemoglobin index gradually rose and was maintained at 10 g / l lower than baseline (prior to treatment). This trend was observed in patients regardless of whether they received a blood transfusion during therapy.
Neutropenia 3 and step 4 was developed to about 12 weeks of therapy. In general, neutropenia (absolute neutrophil count (ANC) <0,5h10 9 / l) in the case of development was reversible and corrected temporary cancellation Dzhakavi receiving drug.
Bleeding (including intracranial hemorrhage, gastrointestinal bleeding, bruising, petechiae, purpura and other bleeding) were reported in 32.6% of patients receiving the drug Dzhakavi. 65.3% of all cases of bleeding were subcutaneous haematomas that were observed in 21.3% of patients. The rate of bleeding 3 and 4 severity was 4.7% cases of intracranial hemorrhages were observed in 1% of patients with gastrointestinal bleeding - in 5.0% of patients, bleeding due to other reasons (including, nosebleeds, post-operative bleeding and hematuria) - in 13.3% of patients receiving drug Dzhakavi.
Before the appointment of the drug should be Dzhakavi assess the presence and the risk of serious bacterial, mycobacterial, fungal and viral infections. Patients treated with the drug Dzhakavi, reported cases of tuberculosis. Should be aware of the possibility of active or latent TB infection. Dzhakavi drug therapy should not begin until the resolution of severe active infection. The physician should be closely monitored for patients receiving the drug Dzhakavi for the development of symptoms of the infection, and, if necessary, to immediately begin appropriate treatment.
Shingles (Herpes Zoster)
Before the appointment of the drug Dzhakavi physician should educate patients timely detection of early symptoms of herpes zoster, reporting need early treatment.
Progressive multifocal leukoencephalopathy
In applying the drug Dzhakavi message was received on the case of progressive multifocal leykoeitsefalopatii (PML). The physician should be wary of neuropsychiatric symptoms that suggest the development of PML.
After discontinuation of therapy Dzhakavi myelofibrosis symptoms (such as fatigue, bone pain, fever, itching, night sweats, symptomatic splenomegaly and weight loss) can be returned. In clinical studies, the common scale myelofibrosis symptoms gradually returned to the initial performance for 7 days after discontinuation.
Effects on ability to drive vehicles and / or use machines
Studies of the effect of the drug on the ability to drive vehicles and work with the mechanisms have not been conducted. Given the possibility of some side effects in patients receiving the drug Dzhakavi (dizziness) patients should use caution when driving and busy with other potentially hazardous activities that require high concentration.
Symptoms application ruksolitiniba single dose of 200 mg satisfactorily tolerated. Exceeding the recommended dose was associated with increased myelosuppression, manifested by leukopenia, anemia and thrombocytopenia.
Treatment: the development of adverse reactions associated with overdose of the drug, it is necessary to apply appropriate supportive treatment. Hemodialysis is ineffective. Antidote to ruksolitinibu unknown.
Drugs that may increase the concentration ruksolitiniba blood
powerful inhibitors isoenzyme CYP3A4: in healthy volunteers receiving ketoconazole, a potent inhibitor of isozyme CYP3A4, at a dose of 200 mg of 2 times / day for 4 days resulted in an increase in AUC Dzhakavi preparation by 91% and elongation T 1.2 to 3.7 hours to 6 hours.
In the case of Dzhakavi drug with potent inhibitors isoenzyme CYP3A4, ruksolitiniba total daily dose should be reduced by approximately 50%.
Patients should be carefully monitored for reduction in the number of blood cells, it is recommended further dose adjustment on the basis of efficacy and safety as needed.
Other interaction, which should be taken into account
mild to moderate inhibitors isoenzyme CYP3A4: receiving erythromycin moderate isoenzyme inhibitor at a dose of 500 mg of 2 times / day in healthy volunteers for 4 days resulted in an increase in AUC ruksolitiniba 27%.
No dose adjustment is required while applying Dzhakavi drug with mild or moderate inhibitors isoenzyme CYP3A4 (including erythromycin). At the beginning of therapy ruksolitinibom simultaneously with moderate inhibitors of CYP3A4 isozyme requires careful monitoring of the patient and to estimate the number of blood cells.
Inducers of CYP3A4 isoenzyme:at the beginning of the treatment together with inducers of CYP3A4 dose adjustment is recommended. If the efficiency of therapy with Dzhakavi reduced by concurrent therapy isoenzyme CYP3A inducers is necessary to consider a gradual increase in the dose Dzhakavi preparation.
In healthy volunteers, treated with rifampicin, a potent inducer isoenzyme CYP3A4, 600 mg 1 time / day for 10 days, AUC ruksolitiniba Dzhakavi after receiving the drug in a single dose was decreased by 71% and T 1/2 decreased from 3.3 to 1.7 h h. The relative amount of active metabolites was increased respect to the starting material.
P-glycoprotein and other transporters: not recommended dose correction at application Dzhakavi drug simultaneously with drugs that interact with P-glycoprotein and other conveyors.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in reach of children at a temperature not higher than 30 В° C. Shelf-life of the drug in blister packs - 1 year; banks - 2 years.