Kiskali (Kisqali)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRibocyclobRibocyclob
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  • Kiskali
    pills inwards 
    Novartis Pharma AG     Switzerland
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet, film-coated, contains:

    active ingredients: ribocyclob (in the form of ribocylic succinate) - 200.00 mg (254.40 mg);

    Excipients: microcrystalline cellulose - 67.44 mg, low-substituted giprolose 48.12 mg, crospovidone (type A) 42.04 mg, magnesium stearate 14.82 mg, silicon colloidal dioxide 3.18 mg;

    shell: Premix shell white - 16,804 mg, premix coat black - 0,249 mg, premix shell red - 0,146 mg;

    premix sheath white: polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E 171), talc, soy lecithin, xanthan gum;

    premix sheath black: polyvinyl alcohol (partially hydrolyzed), iron dye oxide black (E172), talc, soy lecithin, xanthan gum;

    premix shell red: polyvinyl alcohol (partially hydrolysed), iron dye red oxide (E172), talc, soy lecithin, xanthan gum.

    Description:

    Round biconvex tablets covered with a film membrane, light grayish-violet, with bevelled edges. On one side is engraved "RIC", another - "NVR".

    Pharmacotherapeutic group:Antitumor agent, protein kinase inhibitor
    ATX: & nbsp

    L.01   Antineoplastic agents

    Pharmacodynamics:

    Mechanism of action

    Ribocyclib is a selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6. These kinases are activated under binding conditions with D-cyclins and play a major role in the signaling pathways that regulate the cell cycle and cell proliferation. Cyclin complex D-CDK4/6 regulates the progression of the cell cycle by phosphorylation of the protein retinoblastoma (pRb).

    In vitro ribocyclob decreased phosphorylation pRb, which caused the cell cycle to stop in the phase G1 and a decrease in cell proliferation in the breast cancer cell lines. In vivo monotherapy with ribocyclob in well-tolerated doses caused tumor regression, this correlated with inhibition of phosphorylation pRb.

    In studies in vivo using models with a patient's received xenotransplant of breast cancer positive for estrogen receptors, a combination of ribo-cyclemb and anti-estrogenic agents (for example, letrozole) led to more pronounced inhibition of tumor growth compared to each drug alone. After discontinuation of the drug, the tumor growth was resumed after 33 days.

    Pharmacodynamics

    According to biochemical analysis ribocyclob inhibits the enzymatic complexes C0K4 / cyclin-01 and C0K6 / cyclin-03 at a concentration of 0.01 (4.3 ng / ml) and 0.039 μmol (16.9 ng / ml), which provides 50% inhibition (1C50) respectively.

    In studies on cells ribocyclob inhibits COK4 / 6-dependent proliferation pRb at an average 1C50, which is 0.06 μmol (26 ng / ml). Ribocyclob causes the cell to stop from G1-phases in S-phase of the cell cycle, which is determined by flow cytometry at an average IC50, which is 0.11 μmol (47.8 ng / ml). Ribocyclob also inhibits cell proliferation measured by capture of bromodeoxyuridine (BrdU) with the value IC50, which is 0.8 μmol (34.8 ng / ml). Similar values 1C50 obtained in the analysis of target modulation, cell cycle and proliferation confirm that phosphorylation blockade pRb Ribocyclob directly results in stopping the transition of the cell cycle from G1-phases in Sphase with subsequent inhibition of cell proliferation. When analyzed on a panel of cell lines of breast cancer with a known status of estrogen receptors (ER), Ribocyclob demonstrated higher efficacy for cell lines with ER-positive status than with ER-negative.

    Electrophysiology of the heart

    To assess the effect of ribo-cyclib on the interval QTc in patients with advanced cancer, a series of electrocardiograms (ECG) were performed three times after applying a single dose when the equilibrium state was reached. Interrelation analysis pharmacokinetics and pharmacodynamics were performed in a total of 267 patients treated with ribocyclob in a dose range of 50 to 1200 mg, including 193 patients treated with 600 mg ribo-cyclib. This analysis suggested that ribocyclob caused a concentration-dependent increase in the interval QTc.

    After taking in the recommended dose of 600 mg, the calculated mean change QTcF relative to the initial value was 22.87 msec [90% Confidence Interval (CI): 21.6, 24.1] with an average value of the maximum concentration in the blood plasma (Cma) in an equilibrium state of 2237 ng / ml (see section "Carefully").
    Pharmacokinetics:

    Pharmacokinetic parameters of ribocyclob have been studied in patients with common solid tumors or lymphomas after ingestion of daily doses from 50 mg to 1200 mg. Healthy volunteers received orally single doses ranging from 400 mg to 600 mg or repeated doses of 400 mg daily (8 days).

    Suction

    After ingestion of ribocyclob in patients with common solid tumors and lymphomas CmOh Ribocyclob in plasma was achieved after 1-4 hours (time to reach the maximum concentration, TmOh). There was a slight over-proportional increase in exposure (Cmax and the area under the "concentration-time" curve (AUC)) ribocyclob in the studied range of doses (from 50 mg to 1200 mg). After repeated administration of 1 time / day, the equilibrium state was usually achieved after 8 days, ribocyclob accumulated with an average geometric ratio of 2.51 (range: from 0.972 to 6.40).

    Effect of food

    Compared to fasting, the intake of ribocyclob in film-coated tablets in a single dose of 600 mg with a high-fat high-calorie food does not affect the rate and extent of absorption of the ribo-cyclic (CmOh geometric mean deviation (SGA): 1.00; 90% CI: 0.889, 1.11; AUCinf CDF: 1.06; 90% CI: 1.01, 1.12) (see section "Interaction with other drugs").

    Distribution

    Binding of Ribocyclob to Human Blood Plasma in vitro was approximately 70% and did not depend on the concentration (from 10 ng / ml to 10,000 ng / ml). Ribocyclob was evenly distributed between erythrocytes and blood plasma with an average blood / plasma ratio in vivo 1.04. According to the analysis of population pharmacokinetics, the apparent volume of distribution in the equilibrium state (Vss/F) was 1090 liters.

    Metabolism

    In studies in vitro and in vivo it is shown that in humans ribocyclob is extensively metabolized in the liver mainly with the participation of isoenzyme CYP3A4. After receiving ribomyclobin in a single dose of 600 mg [14C] in humans, the pathways of the primary metabolism of ribo-cyclib included oxidation (dealkylation, C and / or N- Oxygenation, oxidation (-2H)) and their combinations. The primary metabolites of ribocyclob were conjugated by N-acetylation, sulfation, cysteine ​​binding, glycosylation and glucuronization. Ribocyclob was the main pharmacologically active compound present in the blood plasma (43.5%). The main circulating metabolites: metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation) and M1 (secondary glucuronization), 9.39%, 8.60% and 7.78% of the total radioactivity and 21.6%, 19.8% and 17.9% of the exposure of the ribocyclob, respectively, were present for each compound represented.Clinical activity (pharmacological properties and safety) of ribo-cyclib was mainly due to unchanged substance, while circulating metabolites were not of significant significance.

    Ribocyclob was extensively metabolized, the amount of unchanged substance was 17.3% and 12.1% in feces and urine, respectively. Metabolite LEQ803 in a significant amount was determined in the stool, its number was 13.9% and 3.74% of the accepted dose in feces and urine, respectively. Other metabolites were detected in both feces and urine in small amounts (≤2.78% of the dose taken).

    Excretion

    In the equilibrium state, when a dose of 600 mg was used in patients with advanced cancer, the geometric mean of the effective plasma half-life (based on the accumulation ratio) was 32.0 hours (63% CV) and the geometric mean of the apparent apparent clearance (CL/F) when taken orally was 25.5 l / h (66% CV). The geometric mean of the apparent final half-life of the ribo-cyclab from the blood plasma (T1 / 2) is in the range from 29.7 to 54.7 hours and the geometric mean CL/F Ribocyclob in the range from 39.9 to 77.5 l / h at a dose of 600 mg in all studies in healthy volunteers.

    Ribocyclob is excreted mainly through the intestine and to a small extent by the kidneys. In 6 healthy male volunteers after taking a single dose [14C] ribocyclob, 91.7% of the total administered radioactive dose was detected within 22 days;

    the excretion mainly occurred through the intestine (69.1%), 22.6% of the dose was excreted by the kidneys.

    Linearity / nonlinearity

    A super-proportional increase in exposure (CmOh and AUC) ribocyclob was observed both after a single dose and after taking repeated doses in the range from 50 mg to 1200 mg. Data analysis is limited to a small sample size in most cohorts receiving specific doses, with the largest amount of data coming from a cohort receiving a dose of 600 mg.

    Pharmacokinetics in specific patient groups

    Patients with impaired renal function

    In patients with impaired renal function of mild and moderate severity, dose adjustment is not required, in patients with impaired renal function of a serious degree, no studies have been performed. According to population pharmacokinetic analysis included 77 patients with normal renal function (calculated GFR≥90 ml / min / 1.73 m2), 76 patients with renal dysfunction of mild degree (rSCF from 60 to <90 ml / min / 1.73 m2) and 35 patients with impaired renal function of medium degree (rSFF from 30 to <60 ml / min / 1.73 m2), mild to moderate renal dysfunction does not affect the exposure of the ribciclib.

    Patients with impaired hepatic function

    In patients with mild liver function disorder (class A Child-Pugh classification), dose adjustment is not required; dose adjustment is needed in patients with moderate and severe liver dysfunction (Child-Pugh class B and C), an initial dose of 400 mg is recommended. According to the pharmacokinetic study in patients with impaired liver function, a mild liver function disorder does not affect the exposure of the ribo-cyclbra. The average exposure of the ribo-cyclib increased less than 2-fold in patients with impaired hepatic function (MS: 1.50 for CmOh; 1.32 for AUCinf) and severe severity (GHS: 1.34 for CmOh; 1.29 for AUCinf). According to the population pharmacokinetic analysis, which included 160 patients with normal liver function and 47 patients with mild liver function disorder, mild liver function disorders did not affect the exposure of ribocycloba,which confirms the data of special studies in patients with impaired liver function.

    The influence of age, sex and race

    Population pharmacokinetic analysis showed that age, body weight, sex, and race did not have a clinically significant effect on the systemic exposure of ribo-cyclbra, which might require dose adjustment.

    Patients aged ≥65 years

    Of the 334 patients who received ribocyclob in the Phase III study (in the group receiving ribocyclob a plus letrozole), 150 (44.9%) patients were aged ≥65 years and 35 (10.5%) patients were ≥75 years of age. There were no significant differences in the safety and efficacy of ribo-cyclib between these patients and younger patients.

    Indications:

    The drug Kiskali is indicated for the treatment of postmenopausal women with a positive hormone receptor (HR+) and negative for the epidermal growth factor receptor of type 2 human (HER2-) common or metastatic breast cancer:

    - in combination with an aromatase inhibitor in the first line of endocrine therapy.
    Contraindications:

    Hypersensitivity to the ribocyclobus or any of the auxiliary components of the drug.

    Children under 18 years of age (efficacy and safety not proven).

    Pregnancy and the period of breastfeeding.

    Carefully:

    Caution should be used when using Kiskali in patients with grade 3-4 neutropenia, with severe renal dysfunction, in patients with hepatobiliary toxicity, in patients with a significant risk of lengthening the interval QT (lengthening interval syndrome QT, uncontrolled or clinically significant heart diseases, including recent myocardial infarction, chronic heart failure, unstable angina and bradyarrhythmia, disturbances of water-electrolyte balance), while simultaneous use with drugs that extend the interval QTc, with potent inhibitors of isoenzyme CYP3A, when used with isoenzyme substrates CYP3A with a narrow therapeutic index (see section "Method of administration and dose").

    Pregnancy and lactation:

    Research on animals

    In studies of embryo-fetal development in rats and rabbits, pregnant animals receivedorally ribocyclob in doses up to 1000 mg / kg / day and 60 mg / kg / day, respectively, during the period of organogenesis.

    For the body of pregnant rats, the dose of 1000 mg / kg / day was lethal. At a dose of 300 mg / kg / day, there was a slight, not negative, tendency to decrease the weight gain of such animals and fetotoxicity, as evidenced by a decrease in body weight of the fetuses combined with skeletal changes that were considered temporary and / or associated with a lower body weight of the fruit. At doses of 50 or 300 mg / kg / day, there was no effect on embryo-fetal mortality or undesired effects on fetal morphology. When studying the effect on pregnant rats, it was considered that the dose at which no adverse effects were observed (NOAEL), was 300 mg / kg / day. When studying the effect on embryo-fetal development, it was considered that the dose at which no effects were observed (NOEL), was 50 mg / kg / day.

    In rabbits at doses ≥30 mg / kg / day, an undesirable effect on embryo-fetal development was noted, which was manifested by an increase in the number of fetal anomalies (malformations, external anomalies, changes in the internal organs and skeleton) and fetal growth (decrease in fetal body weight).These data included a decrease in lobes of the lungs, development of additional vessels on the aortic arch, diaphragmatic hernia, absence of an additional fraction or (partial) fusion of lobes, a decrease in the additional lobe fraction (30 and 60 mg / kg), extra / rudimentary 13th rib, deformation hyoid bone, a decrease in the number of phalanges of the thumb. There were no data on embryo-fetal mortality. NOEL for a pregnant animal was not less than 30 mg / kg / day, for embryo-fetal development - was 10 mg / kg / day.

    At a dose of 300 mg / kg / day in rats and 30 mg / kg / day in rabbits, systemic exposure in the body of a pregnant animal (AUC) was 13,800 ng h / ml and 36,700 ng h / ml, which was 1.5 times lower than that achieved in patients with the maximum recommended dose of 600 mg / day.

    Women with preserved reproductive potential

    Women with preserved reproductive potential should be recommended to use effective methods of contraception (probability of pregnancy <1%) during therapy with Kiskali and not less than 21 days after the end of the drug. Before starting treatment with Kiskaly, a pregnancy test should be performed.

    Fertility

    Fertility studies in rats have not been conducted, however, toxicological studies have reported atrophic changes in the testes in rats and dogs at exposure that was less or equivalent to that in humans at the maximum recommended daily dose of 600 mg / day, based on AUC. There is insufficient clinical data on the effect of Kiskali's drug on fertility. The potential impact of Kiskali's drug on male and female fertility is unknown. According to animal studies, the Kiskali drug may impair fertility in men with a preserved reproductive potential.

    Dosing and Administration:

    Treatment with Kiskaly should be done only under the supervision of a doctor who has experience with antitumor drugs.

    Dosing regimen

    Total target population

    The recommended dose of Kiskali for oral administration is 600 mg (3 tablets coated with a film coating of 200 mg) once a day, consistently for 21 days, followed by a break in taking the drug for 7 days. The full cycle is 28 days.

    Simultaneously with the preparation Kiskali should be taken letrozole in a dose of 2.5 mg or another aromatase inhibitor 1 time / day during the entire 28-day cycle. Read the instructions for the medical use of the aromatase inhibitor. It is necessary to take prescribed doses of drugs every day at the same time, preferably in the morning.

    The use of Kiskali does not depend on food intake. If there is vomiting in the patient after using the Kiskali drug or when missing the next dose, do not take an additional dose of the drug on this day. The next dose should be taken at the usual time. Tablets of the preparation Kiskali should be swallowed whole (do not chew, do not break and do not divide before swallowing). Do not take damaged tablets (broken, cracked, or otherwise damaged).

    Correction of dose

    For the correction of severe or intolerable adverse drug reactions (NLR), temporary cancellation, dose reduction or complete withdrawal of the drug may be required Kiskaly.

    Guidance on reducing (if necessary) the recommended dose for NRH is listed in Table 1.

    Table 1 Guidelines for changing the recommended dose for NLP

    Preparation Kiskali

    Dose

    Number of tablets

    Initial dose

    600 mg / day

    Tablets 200 mg x 3

    First dose reduction

    400 mg / day

    Tablets 200 mg x 2

    Second dose reduction

    200 mg / day *

    Tablets 200 mg x 1

    * If further lowering of the dose is required below 200 mg / day, the drug should be discontinued

    Tables 2, 3, 4 and 5 provide recommendations for temporary withdrawal, dose reduction or complete elimination of Kiskali's preparation for the correction of individual NLRs. When deciding in accordance with the clinical situation, the attending physician should be guided by the management plan for each patient, taking into account the benefit / risk ratio in each individual case.

    Table 2 Dose variation and use in hematological toxicity

    Neutropenia

    1 or 2 degree

    (Absolute number of neutrophils (ACH) 1000 / mm3 - <lower bound of the norm (NGN))

    3 degree

    (АЧН 500 - <1000 / mm3)

    Febrile neutropenia of the 3rd degree *

    4 degree

    (ACN <500/ mm3)

    Correction of dose is not required

    Temporary cancellation until recovery to ≤2 degree. Renewal of intake in the same dose. With the repeated development of grade 3 neutropenia, discontinue therapy until the indicator recovers, then resume taking the dose at a dose reduced to the next level.

    Temporary cancellation until recovery of neutropenia to ≤2 degree. Resume the intake in a dose reduced to the next level.

    Temporary cancellation until the recovery of the indicator to ≤2 degree. Resume the intake in a dose reduced to the next level.

    Before starting treatment with the drug, perform a general blood test (KLA).

    After the beginning of treatment with the drug, control the OAB every 2 weeks for the first 2 cycles, at the beginning of each of the next 4 cycles, then according to clinical indications.

    * Neutropenia of grade 3 with a single episode of fever > 38.3 C (or) above 38'C for more than an hour and / or accompanied by an infection

    Gradation of the degree of toxicity according to STACEA 4.03 version of STACEA = General terminology of criteria for assessing adverse events.

    Table 3 Dose change and use for hepatobiliary toxicity

    Increased activity ACT and / or ALT as compared to baseline * without increasing the concentration of total bilirubin above 2 x upper limit of norm (VGN)

    1 degree (> VGN - 3 X VGN)

    2 degree (> 3 to 5 x VGN)

    3 degree (> 5 to 20 x VGN)

    4th degree (> 20 x VGN)

    Correction of the dose is not required

    Initially <2 degree: Temporary cancellation to decrease ≤ of initial degree, then resumption of reception in the same dose. When repeated development of toxicity 2 degrees, resume reception at a dose reduced to the next level.

    Initial - grade 2: Do not discontinue taking the drug.

    Temporary cancellation of the drug before reduction to ≤ original degree, then resume reception at a dose reduced to the next level. When repeated development of toxicity of 3 degrees, reception should be canceled.

    Cancel preparation.

    Combined increase in activity ACT and / or ALT together with increase in the total bilirubin for absence of cholestasis

    If ALT activity and / or ACT increases to> 3 x HNG, along with an increase in the concentration of total bilirubin> 2 x VGN, the drug should be discontinued, regardless of the initial degree.

    Before the start of therapy, liver function should be assessed using functional liver tests (FTS).

    After starting treatment with Kiskaly, the control is every 2 weeks for the first 2 cycles, at the beginning of each of the next 4 cycles, then according to clinical indications.

    If violations of ≥2 degree are observed, more frequent monitoring is recommended.

    * Baseline = before the start of treatment.

    Gradation of the degree of toxicity according to STACEA 4.03 version of STACEA = General terminology of criteria for assessing adverse events.

    Table 4 Dose variation and application for lengthening the interval QT

    On the ECG QTcF > 480 msec

    Temporary cancellation of Kiskaly preparation.

    If the interval QTcF decreased to <481 msec, the reception should be resumed at the same dose;

    If the interval QTcF again increased to> 481 msec, the administration of Kiskali should be temporarily suspended until the interval QTcF up to <481 msec; then you should resume taking the dose at the dose reduced to the next level

    On the ECG QTcF > 500 msec

    If the interval QTcF exceeds 500 msec, at least when 2 repeated ECGs are performed: temporary withdrawal of the Kiskali preparation until the interval is shortened QTcF <481 msec, then resume reception in a dose reduced to the next level. If the duration of the interval QTcF greater than 500 msec, or an elongation of more than 60 msec compared to the baseline value in combination with ventricular pirouette tachycardia or polymorphic ventricular arrhythmia or symptoms / signs of severe arrhythmia, Kiskali should be discontinued.

    An ECG should be performed before starting treatment.

    After the beginning of treatment with Kiskaly preparation, the repeated ECG should be performed approximately on day 14 of the first cycle and at the beginning of the second cycle, then - according to the clinical indications.

    In the case of an extension of the interval QTcF during treatment, more frequent ECG monitoring is recommended.

    Table 5 Dose variation and use in other manifestations of toxicity *

    Other manifestations of toxicity

    1 or 2 degree

    3 degree

    4 degree

    Correction of the dose is not required. Initiate appropriate drug therapy and monitor in accordance with clinical indications.

    Temporarily stop taking Kiskali before recovery to ≤1 degree, then resume taking the same dose. If the toxicity of grade 3 develops again, resume the dose at a dose reduced to the next level.

    Abolition of the drug.

    * Except for hematologic toxicity, hepatobiliary toxicity and lengthening of the interval QT.

    Gradation of the degree of toxicity according to the STACEA 4.03 version of the STACEA-General terminology of criteria for assessing adverse events.

    Change in the dose of Kiskaly preparation when used with potent inhibitors of isoenzyme CYP3A

    It is necessary to avoid simultaneous application of Kiskaly preparation with powerful inhibitors of isoenzyme CYP3A, it is necessary to consider the possibility of alternative therapy in combination with less potent inhibitors of the isoenzyme CYP3A. If it is necessary to simultaneously use a potent inhibitor of isoenzyme CYP3A The dose of Kiskaly should be reduced to 200 mg 1 time / day. With the cancellation of a potent inhibitor of isoenzyme CYP3A, the dose of Kiskaly should be changed (after at least a 5-fold half-life of a potent inhibitor of isoenzyme CYP3A) to the dose that was used before the use of a potent inhibitor of isoenzyme CYP3A.

    Special patient groups

    Use in patients with impaired renal function

    No dosage adjustment is necessary for the use of the drug in patients with impaired renal function of mild or moderate severity.

    Due to the lack of experience in the use of the drug in patients with severe renal dysfunction, caution should be exercised when using Kiskali in patients in this category.

    Use in patients with impaired liver function

    Based on studies of liver function abnormalities involving healthy volunteers and patients without malignant disease with impaired liver function, it has been established that dose adjustment in patients with mild liver function disorder (class A Child-Pugh classification) is not required.Dose correction is necessary in patients with violations of the liver function of medium and severe degree (classes B and C according to the Child-Pugh classification, respectively), the recommended initial dose is 400 mg. The use of Kiskaly in patients with breast cancer with a violation of liver function of medium and severe degree has not been studied.

    Use in patients aged 18 years and under

    Data on the use of Kiskali in patients aged 18 years and younger are limited, safety and efficacy in this category of patients is not established.

    Use in patients aged 65 years and over

    Correction of dose in patients aged 65 years and older is not required.

    Side effects:

    Security Profile Summary

    The overall safety profile of the Kiskaly drug is based on data from 898 patients: 568 of them received a Kiskali preparation at the recommended dose of 600 mg according to the treatment regimen (1-21 days of the 28-day cycle), including 381 patients who received the drug Kiskali in combination with letrozol in a dose of 2.5 mg per day.

    The safety data presented below was obtained in a Phase III clinical trial involving 668 postmenopausal women randomized in a 1: 1 ratio for treatment with Kiskali in combination with letrozole or placebo in combination with letrozole.

    The median duration of therapy with the combination of Kiskaly and letrozole was 13 months, with 58.1% of patients receiving this treatment> 12 months. A reduction in the dose due to adverse events (AEs), regardless of the cause, occurred in 44.6% of patients who received the Kiskali preparation in combination with letrozole and 3% of patients receiving placebo in combination with letrozole. The final early discontinuation of treatment due to AEs was reported in 7.5% of patients receiving Kiskaly in combination with letrozole, and 2.1% of patients receiving placebo in combination with letrozole. The most frequent AEs that led to an early cessation of treatment with a combination of Kiskali and letrozole were an increase in ALT activity (2.7%), an increase in ACT activity (2.4%), and vomiting (1.5%).

    Fatal outcomes were reported in 3 cases (0.9%) in patients treated with Kiskali in combination with letrozole compared to 1 case (0.3%) in patients treated with placebo in combination with letrozole. The causes of death in the treatment with the Kiskaly preparation in combination with letrozole included one case in each group: according to the testimony of the study,death (for unknown reason) and sudden death (with the development of hypokalemia of grade III and lengthening of the QTII interval). In one case, the lethal outcome was associated with the indications of the study in the placebo group in combination with letrozole. The most frequent NLR (reported with a frequency> 20% and whose frequency in the group of patients treated with Kiskaly plus letrozole exceeded the frequency in the placebo group in combination with letrozole) were neutropenia, leukopenia, headache, pain in the back, nausea, fatigue, diarrhea, vomiting, constipation, alopecia and skin rash.

    The most frequent 3/4 grade NLR (reported with a frequency> 2% and whose frequency in the group of patients treated with Kiskali plus letrozole exceeded the frequency in the placebo group in combination with letrozole) were neutropenia, leukopenia , abnormalities in functional liver tests, lymphopenia, hypophosphatemia, vomiting, nausea, fatigue and back pain.

    The summary table of NLR from the data of clinical research of the III phase

    The NLRs in the Phase III clinical trial (Table 6) are grouped according to the classification of organs and systems of MedDRA organs, listed in order of decreasing incidence.

    Frequency of occurrence was estimated as follows: "very often" - ≥10%, "often" -> 1 - <10%, "infrequently" - ≥0.1% - <1%, "rarely" - ≥0.01 - < 0.1%, "very rarely" - <0.01%, including individual messages, the frequency is unknown (can not be determined from available data). Within each frequency category, NLRs are distributed in order of decreasing frequency of occurrence.

    Table 6 NLR observed in the Phase III clinical trial

    NLR

    Frequency Categories

    All degrees

    Infectious and parasitic diseases

    Urinary tract infection

    Often

    Violations of the blood and lymphatic system

    Neutropenia

    Often

    Leukopenia

    Often

    Anemia

    Often

    Lymphopenia

    Often

    Thrombocytopenia

    Often

    Febrile neutropenia

    Often

    Disturbances on the part of the organ of sight

    Lachrymation

    Often

    Dry eyes

    Often

    Disorders from the metabolism and nutrition

    Decreased appetite

    Often

    Hypocalcemia

    Often

    Hypokalemia

    Often

    Hypophosphatemia

    Often

    Disturbances from the nervous system

    Headache

    Often

    Insomnia

    Often

    Heart Disease

    Fainting

    Often

    Disturbances from the respiratory system, chest and mediastinal organs

    Dyspnea

    Often

    Nose bleed

    Often

    Disturbances from the musculoskeletal system and connective tissue

    Backache

    Often

    Disorders from the gastrointestinal tract

    Nausea

    Often

    Diarrhea

    Often

    Vomiting

    Often

    Constipation

    Often

    Stomatitis

    Often

    Stomach ache

    Often

    Dysgeusia

    Often

    Dyspepsia

    Often

    Disturbances from the liver and bile ducts

    Hepatotoxicity1

    Often

    Disturbances from the skin and subcutaneous tissues

    Alopecia

    Often

    Skin rash2

    Often

    Itching

    Often

    Erythema

    Often

    General disorders and disorders at the site of administration

    Fatigability

    Often

    Peripheral edema

    Often

    Asthenia

    Often

    Increased body temperature

    Often

    Laboratory and instrumental data

    Deviations of the FTGC

    Often

    Increase in serum creatinine concentration

    Often

    Decreased body weight

    Often

    Extension of the QT interval on the ECG

    Often

    1Hepatotoxicity: damage to liver cells, liver damage, hepatotoxicity. hepatic insufficiency "1 nonfatal case", autoimmune hepatitis (the only case).

    2Skin rash: rash, maculopapular rash

    3Abnormalities in FPT: increased ALT activity; increased activity of ACT, increased serum bilirubin concentration.





    Description of selected NLRs

    Neutropenia

    In the Phase III study, neutropenia was the most frequently reported abnormality according to laboratory data. Depending on the severity of neutropenia, monitoring was performed by monitoring laboratory indicators, temporary withdrawal of the drug and / or changing the dose. The frequency of early discontinuation of the drug due to neutropenia was low (0.9%).

    Hepatobiliary toxicity

    In a Phase III clinical study, the manifestations of hepatobiliary toxicity were more common in patients treated with Kiskaly in combination with letrozole than in the placebo group in combination with letrozole (24.0% vs. 13.6%, respectively), while about AE of 3/4 degree was more often reported in patients treated with Kiskaly in combination with letrozole (11.4% vs. 3.6% respectively).8.4% of patients treated with Kiskali in combination with letrozole reported a temporary withdrawal and / or dose adjustment due to hepatobiliary toxicity, mainly due to an increase in ALT activity (5.7%) and / or an increase ACT activity (4.5%). Early termination of treatment in the group of patients treated with Kiskali in combination with letrozole, due to impaired FPP, hepatotoxicity was observed in 3.0% and 0.6% of cases, respectively.

    QT interval extension

    In a phase III clinical study, at least one case of prolongation of the QT interval was observed in 7.5% of patients in the group treated with Kiskali plus letrozole and 2.4% of patients in the placebo group in combination with letrozole (including the extended interval QT on the ECG, syncope). There was reported a temporary withdrawal in combination with a dose adjustment due to the prolongation of the QT interval on ECG and syncope (syncope) in 0.9% of patients treated with Kiskali in combination with letrozole.

    Centralized analysis of ECG data (mean value from data of 3 ECGs) showed that in 11 patients (3.3%) and 1 patient (0.3%), there was at least 1 prolongation of QTcF> 480 ms after treatment in group ,treated with Kiskali in combination with letrozole, and in the placebo-treated group in combination with letrozole, respectively. Among patients with QTcF interval prolongation> 480 msec, the median time to onset of the symptom was 15 days and these changes were reversible with a temporary cancellation and / or a decrease in dose.

    If any of the side effects listed in the manual are aggravated, you will notice any other side effects. not specified in the manual, inform the doctor about it.

    Overdose:

    No cases of an overdose of Kiskaly with a human were reported. In case of an overdose, supportive and symptomatic therapy is indicated.

    Interaction:

    The metabolism of ribo-cyclib is mainly through isoenzyme CYP3A. In vivo Ribocyclob is a time-dependent inhibitor of isoenzyme CYP3A. Therefore, drugs that affect the enzymatic activity of the isoenzyme CYP3A, are able to change the pharmacokinetics of ribo-cyclib.

    Medicinal products, which can increase the concentration of ribo-cyclemb in the blood plasma

    With the simultaneous use in healthy volunteers of a potent inhibitor of isoenzyme CYP3A4 ritonavir and ribocyclob increased the exposure of the latter by 3.21 times. Simultaneous use of potent inhibitors of isoenzyme should be avoided CYP3A, including (but not limited to) the following medicines: clarithromycin. indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir. telithromycin, verapamil and voriconazole. Alternative drugs with less pronounced inhibition of isoenzyme should be considered CYP3A, it is also necessary to monitor NLR in patients.

    If it is impossible to avoid simultaneous administration of Kiskaly with a potent inhibitor of isoenzyme CYP3A, should reduce the dose of Kiskali to 200 mg. Clinical data on correction of this dose are absent. With the cancellation of a potent inhibitor, the administration of Kiskaly should be resumed (after at least a 5-fold half-life of a potent inhibitor of isoenzyme CYP3A) in a dose used before the onset of a potent inhibitor of the isoenzyme CYP3A. The recommended dose adjustment may not be optimal for all patients due to interindividual variability, therefore careful monitoring of NLR is recommended.In case of manifestations related to the toxicity of the Kiskaly preparation, the dose should be changed, or the treatment should be temporarily discontinued until the signs of toxicity of the drug are resolved.

    The patient should be informed about the need to avoid eating pomegranates or pomegranate juice, grapefruit or grapefruit juice and all products known as isoenzyme inhibitors CYP3A and capable of increasing the effect of ribo-cyclib.

    Drugs that can lower the concentration of ribo-cyclib in the blood plasma

    With the simultaneous use in healthy volunteers of a powerful isoenzyme inductor CYP3A4 rifampin and ribocyclob exposure of the latter in blood plasma was reduced by 89%. Simultaneous use of powerful isoenzyme inducers should be avoided CYP3A. including, but not limited to, the following medicines: phenytoin, rifampicin, carbamazepine and St. John's wort (Hypericum perforatum). It is necessary to consider the possibility of simultaneous application of alternative medicines, with an absent or expressed minimal ability to induce isoenzyme induction CYP3A.

    Medicines whose plasma concentration may alter the ribocyblyb

    With the simultaneous use in healthy volunteers substrate isoenzyme CYP3A4 midazolam with multiple doses of the Kiskali preparation (400 mg), midazolam exposure is increased by 280% (3.80 times) compared with only midazolam. The use of a physiologically based pharmacokinetic model (RVRK) suggests that the use of Kiskaly in a clinical dose of 600 mg is expected to increase AUC midazolam in 5.2 times. Caution is advised when using Kiskali and isoenzyme substrates CYP3A with a narrow therapeutic index. It may be necessary to reduce the dose of a sensitive isoenzyme substrate CYP3A with a narrow therapeutic index, including (but not limited to) the following drugs: alfentanil, ciclosporin, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus, as ribocyclob has the ability to increase their exposure.

    With the simultaneous use in healthy volunteers substrate isoenzyme CYP1A2 caffeine with multiple doses of Kiskaly preparation (400 mg) caffeine exposure increased by 20% (by 1.20 times), compared with taking only caffeine. In a clinically significant dose of 600 mg, modeling using PBMC models allowed predicting only a weak inhibitory effect of ribocyclob on the isoenzyme substrates CYP1A2 (increase AUC <2 times).

    Medicinal products, which are carrier substrates

    Research in vitro showed that ribocyclob in clinically significant concentrations has a low potential for inhibiting the activity of the drug carriers P-glycoprotein, OAT1 / 3, OATP1B1 / B3, and OST1. In clinical concentrations ribocyclob is able to inhibit breast cancer resistance protein (BCRP), OST2, MATE1 and human BSEP.

    Nutritional interactions

    The drug Kiskali can be taken with food or on an empty stomach.

    Compared to fasting, the use of ribocyclob in the form of film-coated tablets in a single dose of 600 mg with high-fat high-fat food does not affect the rate and extent of absorption of the ribo-cyclic (CmOh CEO: 1.00; 90% CI: 0.898, 1.11; AUCinf SGS: 1.06; 90% CI: 1.01, 1.12).

    Medicinal products. affecting the pH of gastric juice

    Ribocyclib is highly soluble at pH 4.5 or lower and in a biological environment (at pH 5.0 and 6.5). Simultaneous use of the Kiskali preparation with drugs that raise the pH of the stomach has not been evaluated in clinical studies; However, neither in the population pharmacokinetic analysis nor in the modeling using PBMC models did the abnormality of ribosyclibe absorption occur.

    Predicted Drug Interactions

    Antiarrhythmic drugs and other medicines, who are able to lengthen the interests QT

    It should avoid the simultaneous use of Kiskaly drug with drugs with a known ability to lengthen the interval QT, such as antiarrhythmics. Avoid simultaneous use of the following antiarrhythmic drugs (including but not limited to): amiodarone, disopyramide, procainamide, quinidine and sotalol; other drugs that extend the interval QT (including but not limited to): chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozid and ondansetron intravenously administered.

    Special instructions:

    Neutropenia

    In patients receiving Kiskaly in combination with letrozole in a Phase III clinical study, the most frequent HLP was neutropenia (74.3%), a decrease in grade 3 or 4 neutrophils (based on laboratory data) was observed in 59.6% of patients.

    Among patients who experienced grade 2, 3 or 4 neutropenia, the median time to development of grade 2, 3 or 4 neutropenia was 16 days. The median time before resolution of neutropenia ≥3 degree (before normalization or reduction to <3 degrees) was 15 days in the treatment group with Kiskali in combination with letrozole. The severity of neutropenia depended on concentration. In patients receiving Kiskaly in combination with letrozole in a Phase III clinical study, development of febrile neutropenia was noted in 1.5% of patients. The patient must necessarily be informed by the doctor about the need to urgently report any cases of fever.

    Before starting therapy with Kiskali, the OAK should be performed. Control of UAC every 2 weeks is necessary for the first 2 cycles, at the beginning of each of the next 4 cycles and then according to clinical indications.

    In severe neutropenia, it may be necessary to temporarily stop taking Kiskali, to reduce the dose, or to completely discontinue the drug. table 2 See section "Dosing and Administration"). In patients with development of neutropenia 1 or 2 degrees, correction of the dose of Kiskaly is not required. In patients with development of grade 3 neutropenia without fever, the use of Kiskali preparation should be temporarily canceled before recovery to ≤2 degree, and then resumed at the same dose. If re-development of grade 3 neutropenia without fever, the use of the Kiskali preparation should be temporarily canceled before the recovery of the indicator, then resumed at a dose reduced to the next level. In patients with febrile neutropenia, grade 3 (ACH from 500 to <1000 / mm3 with a single episode of fever> 38.3 ° C (or) above 38 ° C for> 1 hour and / or concomitant with infection) or in patients with development of grade 4 neutropenia, the use of Kiskali should be temporarily discontinued until neutropenia is restored ≤ 2 degrees, then it should be resumed in a dose reduced to the next level.

    Hepatobiliary toxicity

    In the Phase III clinical study, an increase in the activity of transaminases was observed.ALT activity was reported to increase (10.2% vs. 1.2%) and activity ACT (6.9% vs. 1.5%) grade 3 or 4 in the groups receiving the Kiskaly preparation in combination with letrozole plus placebo plus letrozole respectively.

    In the Phase III clinical trial and study lb phase with Kiskaly preparation in combination with letrozole increase in ALT activity or activity ACT 3 or 4 degrees was observed in 83.8% (31/37) of cases during the first 6 months of treatment. As reported, in most cases, an increase in ALT activity and ACT was observed without an increase in bilirubin concentration. Among patients with an increase in ALT / AST activity of grade 3 or 4, the median time to development of this reaction was 57 days in the Kiskaly preparation group in combination with letrozole. The median time before resolution of this reaction (prior to normalization or ≤2 degrees) was 24 days in the Kiskaly preparation group in combination with letrozole. Simultaneous increase in ALT activity or activity ACT more than three times higher than IGN and the total bilirubin concentration is more than twice as high as IGN. with a normal concentration of alkaline phosphatase and in the absence of cholestasis was observed in 4 (1.2%) patients; all patients normalized within 154 days after drug withdrawal.

    FTC should be performed prior to the initiation of Kiskaly therapy. Control of FTC is performed every 2 weeks for the first 2 cycles, at the beginning of each of the next 4 cycles, and then according to clinical indications.

    If there is a marked increase in the activity of transaminases, it may be necessary to temporarily stop taking, reduce the dose, or completely discontinue the Kiskali preparation (cf. Table 3 of the "Application and dose" section). Recommendations for patients with an initial increase in ACT / ALT activity ≥3 degrees are not established.

    For patients with increased activity ACT and / or ALT in comparison with the baseline (before the start of treatment) without increasing the concentration of total bilirubin (OB) more than 2хVNN, the following dose changes and directions for use are presented:

    At 1 degree (increased activity ACT and / or ALT from> VGN to 3 xVGN) correction of the dose of Kiskaly is not required.

    In patients with baseline values ​​corresponding to <2 degrees (increased activity ACT and / or ALT from <VGN to 3xVGN) - if the 2nd degree develops (increased activity ACT and / or ALT from> 3 to 5xVGN), the Kiskaly preparation should be temporarily withdrawn to ≤ of the initial degree, then the application should be resumed at the same dose.If the 2 degree develops repeatedly, the use of Kiskaly preparation in a dose reduced to the next level should be resumed.

    In patients with baseline values ​​corresponding to grade 2 (increased activity ACT and / or ALT from> 3 to 5xVGN) - if the 2nd degree is maintained, a temporary withdrawal of the Kiskali preparation is not required.

    In patients with development of grade 3 (increased activity of ALT and / or ACT from> 5 to 20xVGN) - the use of the Kiskaly preparation should be temporarily canceled to the values ​​of ≤ of the initial degree, then the application should be resumed at a dose reduced to the next level. If the 3 degree develops repeatedly, then the drug should be canceled.

    In patients with development of the 4th degree (increased activity of ALT and / or ACT > 20хВНН) the preparation of Kiskaly should be canceled.

    For patients with a combination of increased activity ACT and / or ALT together with an increase in the concentration of total bilirubin in the absence of cholestasis, the following dose changes and directions for use:

    In patients with a concentration of total bilirubin> 2 × WGH on the foyer of ALT activity and / or ACT > 3хВГН, regardless of the initial degree of toxicity, the preparation of Kiskali should be canceled.

    Elongation is interesting QT

    In a Phase III clinical study, a review of ECG data (based on the average of the three ECGs) showed that in 1 patient (0.3%) the value QTcF after the initial level was> 500 msec, in 9 patients (2.7%) there was an increase in the interval QTcF > 60 ms from the reference level. No cases of ventricular tachycardia of the "pirouette" type were reported.

    Before starting treatment, an ECG should be performed. Treatment with Kiskaly should be started only in patients with duration QTcF less than 450 ms. Repeated ECG is required to be performed approximately on day 14 of the first cycle and at the beginning of the second cycle, then according to clinical indications.

    Conduct a proper control of the electrolyte content (including potassium, calcium, phosphate and magnesium) in the serum prior to treatment, at the beginning of the first 6 cycles and then according to clinical indications. Before starting therapy with Kiskali, it is necessary to correct any changes in the electrolyte content.

    Avoid the use of the drug in patients with a significant risk of lengthening the interval QTc, including:

    - lengthening syndrome QT;

    - uncontrolled or clinically significant heart disease, including recent myocardial infarction, chronic heart failure, unstable angina and bradyarrhythmia;

    - changes in the content of electrolytes.

    It should avoid the use of Kiskaly drug with drugs that are able to extend the interval QTc and / or are potent inhibitors of the isoenzyme CYP3A. since this can lead to clinically significant lengthening of the interval QTcF. If an interval is detected QT may require a temporary withdrawal of the dose, a reduction in the dose, or a complete withdrawal of the Kiskali preparation (cf. Table 4 of the "Application and dose" section).

    With an elongation on the ECG QTcF>480 msec:

    - Treatment with the drug Kiskaly should be canceled.

    - If the interval QTcF decreases to <481 msec, the use of the drug in the same dose should be resumed.

    - If the interval QTcF again increased to ≥481 msec, the use of the Kiskali preparation should be interrupted to a length of QTcF <481 msec, then the application should be resumed in a dose reduced to the next level.

    With length QTcF > 500 msec in at least 2 separate ECG studies, the following measures should be taken:

    - temporarily stop treatment with Kiskaly.

    - if QTcF decreased to <481 msec, the application can be resumed at a dose reduced to the next level.

    When the interval is extended QTcF up to more than 500 msec or the presence of changes more than 60 ms from the baseline value in combination with ventricular pirouette tachycardia or polymorphic ventricular arrhythmia or symptoms / signs of severe arrhythmia, the Ciskali preparation should be permanently discontinued.

    Effect on the ability to drive transp. cf. and fur:

    The drug Kiskali has little effect on the ability to drive vehicles and / or machinery. Patients should be careful in managing vehicles and / or mechanisms, given the possibility of developing increased fatigue during the use of the drug.

    Form release / dosage:Tablets, film-coated, 200 mg.
    Packaging:For 14 or 21 tablets in a blister of GGGFHE / PVC and aluminum foil or PA / Al / PVC and aluminum foil. For 3 blisters together with instructions for medical use in a cardboard box.
    Storage conditions:

    At a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    The drug should not be used after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004670
    Date of registration:25.01.2018
    Expiration Date:25.01.2023
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC
    Information update date: & nbsp26.03.2018
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