Ibransa - instructions for use, doses, side effects, contraindications

Active substancePalbocyclibePalbocyclibe

Similar drugsTo uncover

Ibrans

capsules inwards

Pfizer Inc. USA

Dosage form: & nbspcapsules

Composition:

1 capsule contains:

active substance: pallbocyclob 75 mg, 100 mg, 125 mg

Excipients: cellulose microcrystalline 111,550 mg / 148,733 mg / 185,917 mg, lactose monohydrate 55,775 mg / 74,367 mg / 92,958 mg, sodium carboxymethyl starch 16,200 mg / 21,600 mg / 27,000 mg, silicon dioxide colloid 6,075 mg / 8,100 mg / 10,125 mg, magnesium stearate 5,400 mg / 7,200 mg / 9,000 mg.

Composition of gelatin capsule:

Dosage of 75 mg: capsule body - gelatin 35.46 mg, iron dye oxide red (E172) 0.05 mg, iron dye oxide yellow (E172) 0.39 mg, titanium dioxide (E171) 0.70 mg; capsule capsule - gelatin 23.64 mg, iron dye oxide red (E172) 0.04 mg, iron dye oxide yellow (E172) 0.26 mg, titanium dioxide (E171) 0.46 mg.

Dosage of 100 mg: Capsule body - gelatin 44.18 mg, iron dye red oxide (E172) 0.07 mg, iron dye oxide yellow (E172) 0.48 mg, titanium dioxide (E171) 0.87 mg; capsule capsule - gelatin 29.40 mg, iron dye red oxide (E172) 0.21 mg, iron dye oxide yellow (E172) 0.21 mg, titanium dioxide (E171) 0.58 mg.

Dosage of 125 mg: capsule body - gelatin 55.71 mg, iron dye oxide red (E172) 0.39 mg, iron dye oxide yellow (E172) 0.39 mg, titanium dioxide (E171) 1.11 mg; capsule capsule - gelatin 37.14 mg, iron dye red oxide (E172) 0.26 mg, iron dye oxide yellow (E172) 0.26 mg, titanium dioxide (E171) 0.74 mg.

Ink composition: shellac 51.990%, titanium dioxide 30,000%, isopropanol 14,000%, ammonia solution 28% 2,000%, propylene glycol 1,000%, Butanol 1,000%, simethicone 0,010%.

Description:

Dosage of 75 mg: Hard gelatin capsule size № 2 with lid and body light orange and white shirts "PBC 75" on the housing and "Pfizer" on the lid. The contents of the capsule are from almost white to yellow powder.

Dosage of 100 mg: Hard gelatin capsule size 1 with a housing № light orange with white inscription "PBC 100" and cap pale reddish brown color with a white inscription "Pfizer". The contents of the capsule are from almost white to yellow powder.

Dosage of 125 mg: Hard gelatin capsule size 0 № with a lid and housing a light red-brown and white shirts "PBC 125" on the body and "Pfizer" on the lid. The contents of the capsule are from almost white to yellow powder.

Pharmacotherapeutic group:Protein kinase inhibitor

ATX: & nbsp

L.01 Antineoplastic agents

Pharmacodynamics:

Palbocyclib is an orally administered, highly selective, reversible low molecular weight inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and kinase CDK4/6 are part of a variety of signaling pathways that activate cell proliferation. Inhibiting CDK4/6, pallbocyclib inhibits cell proliferation by blocking the cell transition from G1-phases in Sphase of the cell cycle. The test of palbocyclib on the panel of breast cancer cell lines with established molecular profiles showed high efficacy of the drug against luminal types of breast cancer, in particular against ER-positive (positive receptor estrogen) breast cancer. Analysis of the mechanism of action revealed that the combination of palbocyclib and antiestrogenic agents enhances the reactivation of the protein retinoblastoma (Rb) by inhibiting phosphorylation Rb, which leads to suppression of signal transmission E2F and delayed proliferation. Increased line proliferation delay ER-positive cells of breast cancer treated with palbocyclob and antiestrogenic agents, is accompanied by an increase in cell aging, which leads to a prolonged blockage of the cell cycle after removing the drug and increasing the size of cells associated with the phenotype of aging. Research in vitro on xenotransplantation models from cells obtained from patients ER-positive breast cancer (HBcx-34) showed that the combination of palbocyclib and letrozole further enhances the inhibition of phosphorylation Rb, further signaling and dose-dependent tumor growth. This confirms the involvement of proliferation delay associated with cell aging as one of the mechanisms providing antitumor efficacy of combined action of pallbocyclib and antagonist ER on models ER-positive breast cancer.

The efficacy of palbocyclob therapy in combination with fulvestrant compared with fulvestrant therapy in combination with placebo was evaluated in an international multicenter, double-blind, randomized trial in women, regardless of their menopausal status, with a hormone receptor-positive breast cancer (HR), negative for the receptor of epidermal growth factor of human type 2 (HER2), whose disease progressed after previous endocrine therapy.

Pharmacokinetics:

The pharmacokinetics of palbocyclob have been described in patients with solid tumors, including advanced breast cancer, and in healthy volunteers.

Suction

The average value of the maximum concentration (C_m_Oh) palbocycloba is generally achieved in 4-8 hours (T_m_Oh) after oral administration. The mean absolute bioavailability of pallbocyclib after oral administration of 125 mg is 46%. In the dose range of 25 mg to 225 mg of the area value under the curve of "concentration time" (AUC) and C_m_Oh as a whole increase proportionally to the dose. The equilibrium state was achieved within 8 days after repeated administration of the drug once a day. With repeated administration once a day, the accumulation of palbocyclib takes place, with an average accumulation factor of 2.4 (range: 1.5-4.2).

Effect of food intake

When taken on an empty stomach in approximately 13% of the population, the absorption and exposure of pallbocyclob were very low. Eating increased the exposure of pallbocyclib in a small group of the population, but did not change the exposure of pallbocyclib to a clinically significant size in the rest of the population.

In comparison with pallbocyclob in the morning on an empty stomach, the values AUC_inf and C_m_OhPalbocyclob increased by 21% and 38% when taken with food with a high content fat, 12% and 27% when taken with low-fat food and by 13% and 24% if food with a moderate fat content was taken 1 hour before and 2 hours after taking pallbocyclib. In addition, eating significantly reduced the variability of the results of determining the exposure of pallbocyclib both between different participants, and from the same participant. Based on these results, pallbocyclob should be taken with food.

Distribution

The binding of pallbocyclob with human plasma proteins in vitro was approximately 85%, and no concentration dependence was observed in the concentration range 500-5000 ng / ml. The geometric mean of the apparent volume of the distribution (V_z/F) was 2583 liters (25%).

Metabolism

Research in vitro and in vivo show that in humans pallbocyclob is subjected to intensive metabolic transformation in the liver. After ingestion of a single dose of 125 mg [¹⁴C] -palbocyclob in humans, the main pathways of the primary metabolism of pallbocyclib included oxidation and sulfonation, and acylation and glucuronation served as minor routes. Palbocyclibe was the main circulating compound in the blood plasma associated with the drug. The main circulating metabolite was the conjugate of palbocyclob with glucuronic acid, although it was only 1.5% of the administered dose in the body's secretions.Most of the material was excreted as metabolites. In stool, the main component associated with the drug was the conjugate of pallbocyclob with sulfamic acid, which was 25.8% of the administered dose. Research in vitro using human hepatocytes, a cytosolic fraction and a fraction S9 liver cells and recombinant enzymes of sulfotransferases (SULT) showed that in the metabolism of palbocyclib, isoenzyme is mainly involved CYP3A and SULT2A1.

Elimination

In patients with advanced breast cancer, the geometric mean of apparent oral clearance (CL/F) palbocyclab was 63.08 l / h, and the mean half-life from plasma was 28.8 hours. In 6 healthy male volunteers who received a single oral dose [¹⁴C] -palbocyclob, an average of 91.6% of the total radiolabeled dose administered was withdrawn after 15 days; The main way of elimination was the excretion through the intestine (74.1% of the dose), and 17.5% of the dose was excreted through the kidneys. Outputted unchanged palbocyclob, constituted 2.3% and 6.9% of the administered dose in feces and urine, respectively.

Age, sex and body weight

Based on the results of population pharmacokinetic analysis, the sex affiliation had no effect on the exposure of pallbocyclob, and age and body weight did not have a clinically significant effect on the exposure of pallbocyclob.

Use in children

The pharmacokinetics of palbocyclob in patients aged 18 years and younger have not been studied.

Application in elderly patients

There was no difference in safety or efficacy in patients aged 65 years and older compared with younger patients.

Impaired liver function

Based on the results of population pharmacokinetic analysis of the data, a mild liver function disorder did not affect the exposure of pallbocyclob. The pharmacokinetics of palbocyclob in patients with moderate or severe liver dysfunction (total bilirubin> 1.5 x upper limit of norm (VGN) at any level of activity of aspartate aminotransferase (ACT)) not investigated.

Impaired renal function

Based on the results of population pharmacokinetic analysis of the data, mild to moderate renal dysfunction did not affect the exposure of pallbocyclob. The pharmacokinetics of palbocyclob in patients with severe renal dysfunction were not investigated.

Electrophysiology of the heart

To assess the relationship between a study-specific heart rate adjusted interval QT, relevant criteria established in the study (QTcS), and the concentration of palbocyclob, pharmacokinetic / pharmacodynamic analysis was performed. Between QTcS and the concentration of palbocyclob was positive. At an average value of the observed maximum concentration of palbocyclib in the equilibrium state after taking the drug according to the schedule of therapy (for example, 125 mg daily for 21 days without interruptions followed by 7 days without taking the drug, total for the whole cycle is 28 days) QTcS was 5.60 ms, and the upper boundary of the 1-sided 95% confidence interval (CI) was 8.72 ms, which indicates a low probability that the lengthening of the interval QT has clinical significance. In this study, no effect of pallbocyclob on heart rate was observed.

Indications:

The drug Ibransa in combination with fulvestrantom is indicated for treatment locally advanced or metastatic breast cancer positive for hormonal receptors (HR+), negative for the epidermal growth factor receptor of type 2 human (HER2-), after previous hormonal therapy.

Contraindications:

- increased sensitivity to pallbocyclib and other components of the drug;

- moderate or severe liver dysfunction (total bilirubin> 1.5 x HNG at any activity level ACT) (application in these states has not been studied);

- severe renal impairment (creatinine clearance (CK) <30 mL / min) (no application for this condition has been studied);

- the need for hemodialysis (use in this condition has not been studied);

- pregnancy and the period of breastfeeding (no proper and strictly controlled studies have been conducted);

- children under 18 years of age (safety and efficacy not established).

Carefully:

The drug Ibrans should be used with caution in patients with lactase deficiency, lactose intolerance or glucose-galactose malabsorption.

It should avoid simultaneous administration of pallbocyclib with powerful inducers and inhibitors of isoenzyme CYP3A, as well as inhibitors of the proton pump (see section "Interaction with other drugs").

Pregnancy and lactation:

No proper and strictly controlled studies of the use of pallbocyclob in pregnant women have been conducted. Given the data obtained on animals and the mechanism of action of pallbocyclib, the drug may have a negative effect on the fetus when used in pregnant women.

Women of childbearing age should be informed about the need to avoid pregnancy with a background of therapy with palbocyclob. Women of childbearing age who take this drug, or their partners who take this drug, must use reliable contraceptive methods during therapy and, at least, within 90 days after its completion.

Studies of the impact of pallbocyclob on milk production, the presence of the drug in breast milk or its effect on breast-fed infants have not been conducted in humans. The ability of palebocyclob to penetrate into the human breast milk is not established. Patients receiving pallbocyclob, should not breast-feed.

Dosing and Administration:

The drug Ibrans should be taken inside with food, at about the same time every day.

Capsules should be swallowed whole (without chewing, not breaking and not opening them before swallowing). Do not swallow capsules if they are cracked, cracked or their integrity broken otherwise.

Recommended regimen: 125 mg once daily for 21 days followed by a break for 7 days (Scheme 3/1) (thus a full cycle is 28 days) in combination with fulvestrantom at a dose of 500 mg, intramuscularly at 1, 15 and 29 days and further 1 time per month.

Therapy is continued until the positive effect of the treatment is observed. When developing vomiting or skipping the dose, you should not take an additional dose of the drug, but take the next dose at the usual time for it.

Before and during the treatment with Ibransa in combination with fulvestrant, women in peri- and premenopausal should undergo treatment with a luteinizing hormone releasing hormone (LH-RG) agonist in accordance with local clinical practice.

Modification of the dose

Modification of the dose of Ibrans is recommended taking into account individual safety and tolerability.

Treatment of some unwanted reactions may require a temporary discontinuation of the drug /later and / or dose reduction, or complete discontinuation of the drug in accordance with the dose reduction schedule given in Tables 1, 2 and 3 (also "Special instructions" and "Side effects" sections).

Table 1. Recommended modifications of the dose of Ibrans in case of undesirable events

Dosage level	Dose
Recommended dose	125 mg / day
First dose reduction	100 mg / day
Second dose reduction	75 mg / day *

* If a dose reduction of less than 75 mg / day is required, the drug should be withdrawn.

Table 2. Modification of the dose of the drug Ibrans in the development of hematological toxicity^a

Monitor the results of a general blood test before starting therapy with Ibrans and at the beginning of each cycle, as well as on day 14 of the first two cycles and according to clinical indications.

Degree of severity in STSAE	Modification of the dose
1st or 2nd degree	Correction of the dose is not required.
3rd degree	1st day of the cycle: You should stop taking the drug, repeat the whole blood test for 1 week. - If the severity of the symptoms has decreased to ≤ 2, resume taking the drug in the previous dose. - If severity is 3, do not continue the therapy before the degree decreases to ≤ 2, then resume taking the drug at the previous dose. - If severity is 4, the start of the next cycle should be delayed until the degree decreases to ≤ 2, then resume taking the drug from the previous lower dose. The 14th day of the first two cycles: Continue therapy at the current dose. A general blood test should be performed for 21 days. - If for 21 days the severity is 3, start the subsequent cycles of therapy with the same dose. - If for 21 days the severity is 4, start the subsequent cycles from the previous lower dose. It should be assessed the need to reduce the dose for prolonged (more than 1 week) reduction in severity from grade 3 neutropenia or repeated increases in severity of neutropenia to 3 in subsequent cycles of therapy.
Neutropenia of the 3rd degree + fever ≥ 38.5 ° C and / or infection	It is necessary to cancel the preparation of Ibrans until the symptomatology is resolved to a level ≤ 2. Resume the therapy from the next lower dose.
4th degree	It is necessary to cancel the preparation of Ibrans until the symptomatology is resolved to a level ≤ 2. Resume the therapy from the next lower dose.

The degree of severity is indicated in accordance with СТСАЕ 4.0 (1 degree - АЧН <НГН - 1500 / mm³; 2 degree - ACHN-1000 - <1500 mm³; 3 degree - 500 - <1000 mm³; 4 degree - <500 mm ').

AChN is the absolute number of neutrophils; STAAE - General terminology criteria for undesirable phenomena (Common Terminology Criteria for Adverse Events - CTCAE); NGN - lower bound of the norm.

^a The table refers to all hematologic reactions except for lymphopenia (if it does not refer to clinical manifestations, for example, opportunistic infections).

Table 3. Modification of the dose of the drug Ibrans in the development of nonhematological toxicity

Degree of severity in STSAE

Modification of the dose

1st or 2nd degree

Correction of the dose is not required.

Non -hematological toxic effects ≥ 3rd degree (if they persist despite treatment)

Stop taking the drug until the condition improves to:

≤ 1st degree;

≤ 2 nd degree (if the phenomena do not pose a risk to the patient's safety). Resume the treatment with a lower dose.

The degree of severity is indicated in accordance with STSAE 4.0.

Modification of the dose when combined with potent inhibitors of isoenzyme CYP3A

Simultaneous use of pallbocyclib with potent inhibitors should be avoided isoenzyme CYP3A and consider the possibility of simultaneous use with drugs with minimal or no inhibitory activity with respect to the isoenzyme CYP3A.

If it is impossible to avoid the simultaneous use of pallbocyclib with potent inhibitors of the isoenzyme CYP3A, It is necessary to reduce the dose of pallbocyclib up to 75 mg once a day. If the use of a potent inhibitor of isoenzyme CYP3A discontinued after 3-5 half-lives of the inhibitor of the isoenzyme CYP3A The dose of Ibrans should be increased to the initial dose (used before the onset of a potent inhibitor of isoenzyme CYP3A).

Modification of the dose depending on the patient's age, sex or weight is not required (see section "Pharmacokinetics").

Special patient groups

Elderly patients

For patients aged 65 years and older, dose adjustment is not required (see "Pharmacokinetics").

Use in children

The safety and efficacy of Ibrans in children and adolescents aged 18 years and under are not established.

Impaired liver function

For patients with mild violations of the liver function (total bilirubin ≤ 1 x VGN and ACT > 1 x VGN or total bilirubin> 1.0-1.5 x VGN at any activity level ACT) correction of the dose is not required. Use of Ibrans in patients with moderate or severe liver dysfunction (total bilirubin> 1.5 x HNG at any activity level ACT) was not studied (see the section "Contraindications").

Impaired renal function

Patients with mild to moderate renal insufficiency (CK ≥ 30 mL / min) do not need dose adjustment. The use of Ibrans in patients with severe renal dysfunction (CK <30 ml / min) or in patients requiring hemodialysis has not been studied (sections "Pharmacokinetics" and "Contraindications").

Side effects:

In clinical trials, the dose reduction due to the development of adverse events of any severity was performed in 15.2% patients; who received pallbocyclob in combination therapy. A complete withdrawal of the drug, associated with the development of adverse events, was observed in 3.3% of patients who received pallbocyclob in combination therapy.

The following are side effects and adverse drug reactions noted during clinical trials.

Table 4. Side effects and adverse drug reactions noted in the studies

Class of organ systems	Very often ≥1 / 10	Often ≥1 / 100 and <1/10	Infrequently ≥1 / 1000 and <1/100
Infectious and parasitic diseases	Infections^a
Disorders from the blood and lymphatic system	Neutropenia^b Leukopenia^at Thrombocytopenia^g Anemia^d		Febrile neutropenia
Disturbances on the part of the organ of sight		Blurred vision Increased lacrimation Dry eyes
Disorders from the metabolism and nutrition	Reduced appetite
Disturbances from the nervous system	Headache	Dysgeusia
Disturbances from the respiratory system, chest and mediastinal organs		Nose bleed
Infringements from gastrointestinal tract	Stomatitis^e Nausea Diarrhea Vomiting Constipation
Disturbances from the skin and subcutaneous tissues	Rash^f Alopecia	Dryness of the skin
General disorders and reactions at the injection site	Fatigability	General weakness, hyperthermia

Generalized terms:

^aThe term "infections" includes all the preferred terms (PT) that are part of the class of the "Infection and Infestation" system.

^bThe term "neutropenia" includes the following PTs: neutropenia, a decrease in the number of neutrophils.

^atThe term "leukopenia" includes the following PTs: leukopenia, a decrease in the concentration of blood leukocytes.

^gThe term "anemia" includes the following PTs: anemia, a decrease in hemoglobin, a decrease in hematocrit.

^dThe term "thrombocytopenia" includes the following PTs: thrombocytopenia, decrease in platelet concentration.

^eThe term "stomatitis" includes Fr: aphthous stomatitis, cheilitis, glossitis, glossodiniya, ulcerative stomatitis, inflammation of the oral mucosa, pain in oral discomfort oropharyngeal region, pain in the oropharyngeal region, stomatitis.

^fThe term "rash" includes the following PT: rash, maculopapular rash, itchy rash, erythematous rash, maculopapular rash, dermatitis, acne dermatitis.

The most frequent undesirable medical phenomena of any severity in> 10% of patients who received pallbocyclob in combination therapy were neutropenia, leukopenia, infection, fatigue, nausea, anemia, stomatitis, thrombocytopenia, diarrhea, alopecia, vomiting, decreased appetite, rash. In general, neutropenia of any severity was noted in 335 (78.3%) patients in the combination therapy group, with grade 3 neutropenia observed in 226 (52.8%) of patients and neutropenia of the 4th degree in 35 (8.2%) patients (see section ("Special instructions ").

The most frequent serious undesirable side effect in patients who received pallbocyclob with letrozole, there was diarrhea (2.4%).

The most frequent serious undesirable side effect in patients who received pallbocyclob with fulvestrant, there were infections (2.0%).

Overdose:

The antidote of pallbocyclob is unknown.

Medical assistance for an overdose of Ibrans should include general supportive therapy.

Interaction:

Palbocyclob is mainly metabolized by isoenzyme CYP3A and enzyme sulfotransferase SULT2A1. In vivo Palbocyclob is a time-dependent inhibitor of isoenzyme CYP3A.

Drugs that can increase the concentration of pallbocyclob in plasma

Inhibitor inhibitors CYP3A

Data from the study of inter-drug interactions in healthy volunteers indicate that simultaneous administration of multiple doses of 200 mg of intra -conjazole with a single dose of pallbocyclib 125 mg resulted in an increase AUQ_inf and C_m_Oh pallbocyclib approximately 87% and 34%, respectively, compared with a single dose of 125 mg palbocyclab in the form of monotherapy. It should avoid simultaneous intake of potent inhibitors of isoenzyme CYP3A including, among others: amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole and grapefruit or grapefruit juice.

If the combined use of pallbocyclib with potent inhibitors of isoenzyme CYP3A it can not be avoided, then a dose adjustment is necessary.

Drugs that can reduce the concentration of pallbocyclob in plasma

Inductors of isoenzyme CYP3A

Data from studies of inter-drug interactions in healthy volunteers indicate that simultaneous administration of multiple doses of 600 mg of rifampicin (a powerful inductor CYP3A) with a single dose of pallbocyclib 125 mg resulted in a decrease AUFROM_inf and C_m_Oh palbocyclibe by 85% and 70%, respectively, compared with a single dose of pallbocyclib 125 mg in the form of monotherapy. Data from the study of interaction conducted on healthy volunteers show that repeated intake of 400 mg modafinil (moderate inhibitor CYP3A) simultaneously with a single administration of 125 mg of pallbocyclob reduces AUFROM_inf and C_m_Oh palbocyclibe by 32% and 11% respectively, compared with a single dose of 125 mg of pallbocyclob.

It is necessary to avoid the simultaneous administration of pallbocyclib with powerful inducers of the isozyme SURZA. including, among others, carbamazepine, enzalutamide, felbamate, nevirapine, phenobarbital, phenytoin, primidon, rifabutin, rifampicin, rifapentin and preparations of St. John's wort.

Simultaneous reception of moderate inducers of SURZA (modafinil) can reduce the content of pallbocyclob in plasma in healthy volunteers by 32%. Moderate inhibitors of SURZA (for example, bosentan, efavirenz, etravirine, modafinil and nafcillin) can be used concurrently with palbocyclob only when this can not be avoided. Correction of the dose is not required.

The effect of drugs that reduce the acidity of gastric juice

Data from studies of inter-drug interactions in healthy volunteers indicate that simultaneous administration of a single dose of 125 mg palbocyclob with multiple doses of PPI rabeprazole after meals reduced C_m_Oh Palbocyclob by 41% and slightly influenced by AUFROM_inf (increased by 13%) compared with a single dose of pallbocyclib in the form of monotherapy.

Given the reduced effect of H2 receptor antagonists and local antacids on the pH of gastric juice compared to PPI, there is no clinically significant effect of PPI, H2 receptor antagonists or local antacids on palbociclib after food intake.

Data from studies of inter-drug interactions in healthy volunteers indicate that simultaneous administration of a single dose of 125 mg palbocyclob with multiple doses of PPI rabeprazole on an empty stomach reduced AUFROM_inf and C_m_Oh palbocyclibe by 62% and 80%, respectively, compared with a single dose of pallbocyclib in the form of monotherapy. It is necessary to avoid simultaneous administration of pallbocyclib with PPI.

Effect of the drug Ibrans on other drugs

Palbocyclob with a daily intake of 125 mg and achieving an equilibrium state in humans has a weak inhibitory effect on the time-dependent isoenzyme of SURZA. In the study of inter-drug interactions in healthy volunteers, simultaneous administration of midazolam with multiple doses of palebocyclab led to an increase in AUFROM_inf and C_m_Oh of midazolam by 61% and 37%, respectively, compared with the administration of midazolam inform of monotherapy.

The dose of drugs with a narrow therapeutic index (for example, alfentanil, ciclosporin, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), should be reduced, since the preparation of Ibrans can increase their content.

In vitro palbocyclib has no inhibitory effect on isoenzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19 and 2D6 and is not an inducer of isoenzymes CYP1A2, 2B6, 2C8 and 3A4 at concentrations used in clinical practice.

Letrozole: in clinical studies in patients with breast cancer, it was shown that when combined with palbocyclib and letrozole, there are no clinically significant interactions between these drugs.

Fulvestrant: in clinical studies in patients with breast cancer, it was shown that, when combined with palbocyclib and fulvestrant, there are no clinically significant interactions between these drugs.

Goserelin: in clinical studies in patients with breast cancer, it was shown that when combined with palbocyclob and goserelin, there are no clinically significant interactions between these drugs.

Tamoxifen: data from the study of inter-drug interactions in healthy male volunteers showed that, while using a single dose of palbocyclob with multiple doses of tamoxifen and with the use of pallbocyclib in the form of monotherapy, the degree of medicinal action of pallbocyclob was comparable.

Studies of carrier proteins in vitro

Research in vitro evidence that pallbocyclob has a weakly expressed ability to inhibit the activity of protein-carriers of drugs - P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), the carrier of organic anions (OAT) 1, OAT3, the carrier of organic cations (OCT) 2, the polypeptide-carrier of organic anions (OATP)1B1, OATP1B3 and protein-carrier of bile salts (BSEP) at concentrations used in clinical practice. Based on the data obtained in the studies in vitro transport, mediated P-gp and BCRP it is unlikely to affect the duration of absorption of pallbocyclib for oral administration at therapeutic doses.

Special instructions:

Neutropenia

In clinical studies of the drug Ibrans, there have been cases of a decrease in the number of neutrophils.

In a study of concomitant administration of pallbocyclib and letrozole, a reduction in the number of neutrophils of grade 3 in 57% of cases and 4 in 5% of cases was noted, while a decrease in the number of neutrophils of 3 degrees of severity in 53.2% of cases and 4 degrees of severity in 9.1% of cases. Neutropenia was the most common adverse reaction in Study 1 (74.7%) and Study 2 (61.4%).

In study 1 and 2, the median time to the first episode of neutropenia of any severity, according to laboratory data, was 15 days (range: 13-117 and 13-140 days, respectively) and a median duration of neutropenia ≥ 3 degrees was 7 days. Fetal neutropenia was reported in 0.6% of patients receiving pallbocyclob in combination with fulvestrant.

In clinical studies 1, no cases of febrile neutropenia have been reported.

Throughout the clinical program, febrile neutropenia cases were reported in 1% of patients taking Ibrans preparation.

It is necessary to monitor the results of a general blood test before starting therapy with Ibrans and at the beginning of each cycle, as well as on day 14 of the first two cycles and according to clinical indications.

For patients who develop grade 3 or 4 neutropenia, it is recommended to stop taking the drug, lowering the dose or taking the medication in the initial cycle of therapy.

Infections

Since the Ibransa drug has the ability to suppress bone marrow function, it can be the cause of predisposition of patients to infections.

Cases of infections of any severity were more pronounced in patients receiving Ibrans with letrozole and in patients receiving Ibrans with fulvestrant, compared with patients receiving the corresponding reference preparation. In 2.6% of patients receiving pallbocyclob in the group of combined therapy, there were infections of the 3rd or 4th degree of severity.

Patients should be monitored to identify symptoms of infection. If necessary, appropriate drug therapy should be prescribed (see the "Side effect" section).

Doctors should inform patients about the need to report urgently on any episodes of fever.

Pulmonary embolism

In clinical studies, cases of pulmonary embolism were more likely in patients receiving Ibrans with letrozole (5%) compared with patients receiving letrozole in the form of monotherapy.It is necessary to monitor patients to identify the symptoms of pulmonary embolism and, if necessary, appropriate drug therapy.

Reproductive function

There are no clinical data on the effects of pallbocyclob on reproductive function in women. Men before starting treatment with Ibrans should consider the possibility of preserving sperm.

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

Studies on the effect of the drug Ibrans on the ability to drive vehicles and work with mechanisms have not been carried out. However, patients who experience fatigue when taking Ibrans preparation should exercise caution in managing vehicles and working with mechanisms.

Form release / dosage:

Capsules 75 mg, 100 mg and 125 mg.

Packaging:

For 21 capsules in HDPE bottle with polypropylene lid, which protects from opening by children. The neck of the bottle is sealed with a protective foil disc.

For 1 bottle with instructions for use in a cardboard bundle.

For 7 capsules in a blister of PVC / PCTFE / PVC and aluminum foil.

3 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003878

Date of registration:05.10.2016

Expiration Date:05.10.2021

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

PFIZER MANUFACTURING DEUTSCHLAND, GmbH Germany

Representation: & nbspPfizer LtdPfizer LtdUSA

Information update date: & nbsp25.10.2016

Illustrated instructions

Instructions

Ibrans (Ibrance)