Zenlistic, 200 mg 14 pcs

Pharmacotherapeutic group: antitumor agents, protein kinase inhibitors.

ATX code: L01XE50.

Pharmacological properties

Mechanism of action

Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are activated when they bind to D-cyclins. In estrogen receptor positive (ER+) breast cancer, the cyclin D1 and CDK4/6 complex promotes retinoblastoma protein (Rb) phosphorylation, cell cycle progression and cell proliferation. Prolonged exposure to abemaciclib under in vitro conditions inhibits Rb phosphorylation and blocks cell cycle progression from G1 phase to S phase, leading to senescence and apoptosis. In breast cancer xenograft models, abemaciclib was administered daily continuously in clinically relevant concentrations, either as monotherapy or in combination with anti-estrogens, resulting in a reduction in tumor size.

Pharmacodynamics

In patients with cancer, abemaciclib at doses ranging from 50 mg to 200 mg twice daily suppresses CDK4 and CDK6 activity by inhibiting Rb phosphorylation and topoisomerase II alpha, resulting in cell cycle arrest before the G1 restriction point. Exposure-efficacy analyses in the MONARCH 2 and MONARCH 3 studies identified a dose of 150 mg 2 times daily for initial therapy in combination with endocrine, and confirmed the need to reduce the dose to 50 mg 2 times daily in cases of poor tolerance. In the exposure-effectiveness analysis of the MONARCH 1 study, a dose of 200 mg 2 times daily was determined for initial monotherapy with abemaciclib.

The effect of abemaciclib on Friedericia-adjusted QT interval length (QTcF) was evaluated in 144 patients with advanced cancer. No significant changes (>20 msec) in QTcF interval duration were found at the mean value of the observed maximum equilibrium concentration of abemaciclib after its administration at therapeutic doses.

In an exposure-effectiveness analysis in healthy volunteers at the highest clinically relevant doses, abemaciclib administration was shown not to result in clinically significant QTcF interval prolongation.

Pharmacokinetics

Absorption

. Abemaciclib is characterized by slow absorption with a median time to reach maximum concentration of T_max equal to 8.0 h. Absolute bioavailability of abemaciclib is 45% (90% confidence interval: 40-51%). In the therapeutic dose range of 50 mg to 200 mg, the increase in exposure (C_max and area under the concentration-time curve AUC) is proportional to the drug dose. The equilibrium state is reached within 5 days when abemaciclib is taken twice daily. Abemaciclib accumulates with a geometric mean ratio of 3.7 (58% CV, CV – coefficient of variation) and 5.8 (65% CV) based on C_max and AUC, respectively.

Distribution

Abemaciclib has a high degree of binding to human plasma proteins (mean bound fraction is 96-98%), with binding independent of abemaciclib concentration ranging from 152 ng/mL to 5066 ng/mL. Abemaciclib binds to both human serum albumin and alpha-1-acid glycoprotein. The geometric mean systemic volume of distribution is approximately 747 L (68.6% CV).

In patients with advanced cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to concentrations of unbound metabolites in plasma.

Metabolism

Abemaciclib undergoes metabolism primarily in the liver, primarily with the participation of cytochrome P450 (CYP) 3A to form the major metabolite N-dezethylabemaciclib (M2) and additional metabolites: hydroxyabemaciclib (M20), hydroxy-N-dezethylabemaciclib (M18), and an oxidized metabolite (M1). The activity of the metabolites N-dezethylabemaciclib (M2) and hydroxyabemaciclib (M20) is similar to that of abemaciclib.

Elimation

The geometric mean hepatic clearance (CL) of abemaciclib is 21.8 L/h (39.8% CV) and the mean plasma elimination half-life is 24.8 h (52.1% CV). After a single oral dose of [¹⁴C-labeled abemaciclib, approximately 81% of the administered dose is excreted through the intestine and approximately 3.4% through the kidneys. Most of the dose excreted through the intestine was metabolites.

Special patient groups

Age, sex and body weight

Age, sex, and body weight had no effect on abemaciclib exposure in a population pharmacokinetics analysis in patients with cancer (135 men and 859 women aged 24 to 91 years and with body weights of 36 to 175 kg).

Patients with impaired liver function

Abemaciclib undergoes metabolism in the liver. In patients with severe hepatic impairment, exposure to unbound abemaciclib increased 2.69-fold and the elimination half-life increased from 24 to 55 hours. In patients with severe hepatic dysfunction, the dosing frequency should be reduced to once daily.

Patients with impaired renal function

Abemaciclib and its metabolites are not significantly excreted through the kidneys. No dose adjustment is required in patients with mild to moderate renal dysfunction. There are no data on the use of the drug in patients with severe renal impairment, end-stage renal failure, and patients on dialysis.

Indications

ZenlisticTM is indicated for the treatment of hormone receptor positive (HR+) and human epidermal growth factor receptor type 2 negative (HER2-) advanced or metastatic breast cancer:

– in combination with first-line endocrine therapy with an aromatase inhibitor;

– in combination with fulvestrant administered as first- or second-line endocrine therapy;

– as monotherapy in patients with disease progression after endocrine therapy and one or two lines of prior chemotherapy for metastatic stage disease.

In pre- or perimenopausal women, therapy should be combined with administration of a luteinizing hormone releasing hormone (LHRH) agonist.

Active ingredient

Composition

How to take, the dosage

Recommended Doses and Dosing Regimen

. In combination therapy with a fulvestrant or aromatase inhibitor, the recommended dose of Zenlystic TM is 150 mg orally twice daily.

In monotherapy, the recommended dose of ZenlysticTM is 200 mg orally 2 times daily.

The therapy should be continued until the disease progresses or intolerable toxicity develops. Zenlystic TM can be taken regardless of meals.

The prescribed doses of ZenlysticTM should be taken at approximately the same time each day.

If the patient vomits or misses a dose of ZenlystickTM, the next dose should be taken at the usual time. The tablet should be swallowed in whole; the tablet should not be chewed, crushed or divided. Do not take tablets that are damaged, broken, cracked or showing other signs of damage.

Correction of dosage regimen

Correction of dosage regimen if adverse reactions occurTM to 100 mg 2 times daily, or, if concomitantly used with ketoconazole, to 50 mg 2 times daily. If the dose has been reduced to 100 mg due to adverse reactions, the dose should be further reduced to 50 mg twice daily. If a strong CYP3A isoenzyme inhibitor is cancelled, the dose of Zenlystic TM should be increased (after at least 3-5 times the half-life of the strong inhibitor) to the dose that the patient was taking before starting the strong CYP3A isoenzyme inhibitor (see sections “Interaction with other medicinal products”).

Precaution should be exercised when Zenlystic TM is used concomitantly with mild (e.g., ranitidine) or moderate (e.g., ciprofloxacin) CYP3A isoenzyme inhibitors.

Special patient groups

Patients with hepatic impairment

. No dose adjustment is required when using the drug in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).

In patients with severe hepatic impairment (Child-Pugh class C), the frequency of ZENLISTICTM administration must be reduced to once daily.

The instructions for medical use of an aromatase inhibitor or fulvestrant should be consulted for information on dose adjustments of these drugs in patients with severe hepatic impairment.

Patients with renal impairment

Dose adjustment is not required when using the drug in patients with mild to moderate renal impairment (creatinine clearance ≥30-89 ml/min). Pharmacokinetics of abemaciclib in patients with severe renal impairment (creatinine clearance < 30 ml/min), terminal renal failure, as well as in patients who require hemodialysis have not been studied.

Children and adolescents under 18 years of age

The safety and effectiveness of ZenlysticTM when used in children and adolescents under 18 years of age has not been established.

Elderly patients

Of the 900 patients who received ZenlysticTM in the MONARCH 1, MONARCH 2, and MONARCH 3 trials, 38% of patients were 65 years of age or older and 10% were 75 years of age or older. The most common adverse reactions (≥5%) of grade 3 or 4 severity in patients 65 years of age or older in the MONARCH 1, MONARCH 2, and MONARCH 3 studies were neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and increased ALT activity. Overall, there were no differences in safety or efficacy of ZenlysticTM in patients 65 years of age or older compared to younger patients.

Interaction

Influence of other drugs on the pharmacokinetics of ZenlysticTM

Special Instructions

Neutropenia

There have been reported cases of neutropenia in patients treated with ZenlystickTM. Dose adjustment is recommended for grade 3 or 4 neutropenia (see section “Dosage and administration”). Fatal outcomes have been reported in < 1% of patients. Patients should immediately report all cases of fever to the attending physician.

Infections/parasitic diseases

The frequency of reported infections in patients treated with ZenlysticTM in combination with endocrine therapy was higher compared to the group receiving placebo in combination with endocrine therapy. Cases of lung infection have been reported in patients without concomitant neutropenia. Fatal outcomes have been reported in < 1% of patients. Signs and symptoms of infection should be monitored and, if necessary, appropriate therapy should be given, following current standards of care.

Venous thromboembolism

Venous thromboembolism was observed in 5.3% of patients receiving ZenlysticTM in combination with a fulvestrant or aromatase inhibitor, and 0.8% of patients who received placebo in combination with a fulvestrant or aromatase inhibitor. Signs and symptoms of deep vein thrombosis and pulmonary embolism should be monitored and, if necessary, appropriate therapy should be given, following current treatment standards.

Elevation of aminotransferases

There have been reported increases in ALT and AST in patients treated with Zenlystic TM. Dose adjustments may be necessary depending on the degree of ALT or AST elevation (see section “Dosage and administration”).

Diarrhea

Diarrhea is the most common adverse reaction. In the studies, the median time to development of the first episode of diarrhea was 6 to 8 days and the median duration of diarrhea was 9 to 12 days (for severity 2 diarrhea) and 6 to 8 days (for severity 3 diarrhea). Episodes of diarrhoea may be associated with dehydration. At the first sign of liquid stools, anti-diarrheal medications such as loperamide should be started, fluid intake should be increased, and the problem should be reported to the attending physician. If diarrhea of ≥2 severity develops, dosage adjustment is recommended (see section “Methods of use and dosages”).

Interstitial lung disease/pneumonitis

There have been reported cases of interstitial lung disease/pneumonitis in patients treated with Zenlysticktm. The symptoms of interstitial lung disease/pneumonitis should be monitored and, if necessary, appropriate therapy should be given, following current treatment standards. Depending on the severity of interstitial lung disease/pneumonitis, dosage adjustment may be necessary (see section “Dosage and administration”). If interstitial lung disease/pneumonitis of grade 3 or 4 develops, therapy should be discontinued.

Simultaneous administration of isoenzyme inducers CYP3A4

. Simultaneous use of CYP3A4 isoenzyme inducers should be avoided because of the risk of decreased effectiveness of abemaciclib (see Interaction with other medicinal products).

Visceral crisis

There are no data on the efficacy and safety of ZenlysticTM in patients with visceral crisis.

Lactose

Patients with rare hereditary conditions of galactose intolerance, absolute lactase deficiency or glucose-galactose malabsorption should not take this drug.

Sodium

Each tablet of Zenlystic TM contains less than 1 mmol of sodium (23 mg).

Influence on driving and operating machinery

There have been no studies on the effect of the drug on driving and operating machinery. However, patients who have undesirable effects of the drug on the nervous system should be cautious when driving vehicles and operating machinery.

Synopsis

Contraindications

Hypersensitivity to abemaciclib or any component of the drug; pregnancy and breastfeeding.

Children, severe renal failure, end-stage renal failure, patients on hemodialysis (efficacy and safety not established).

Cautions

Patients with lactase deficiency, lactose intolerance or glucose-galactose malabsorption, patients with severe hepatic impairment, concomitant use with strong CYP3A4 isoenzyme inhibitors. Concomitant use of CYP3A4 isoenzyme inducers should be avoided due to the risk of reduced efficacy of abemaciclib.

Side effects

In combination therapy with fulvestrant or an aromatase inhibitor

The most common adverse reactions are diarrhea, infections, neutropenia, anemia, fatigue, nausea, vomiting and decreased appetite.

The adverse reactions are listed according to organ system classes and frequency as presented in the Medical Dictionary for Regulatory Affairs (MedDRA). Unwanted reactions are categorized and presented by frequency of development: very frequent (≥1/10), frequent (≥1/100 to < 1/10), infrequent (≥1/1000 to < 1/100), rare (≥1/10000 to < 1/1000), very rare (< 1/10000), with unknown frequency (frequency cannot be determined based on available data). Within each group, adverse reactions are ranked in descending order of severity.

Infectious and parasitic diseases: very common: infections1.

1 – Includes all preferred terms that are part of the Infectious and Parasitic Diseases organ system class.

Disorders of the blood and lymphatic system: very often – neutropenia, leukopenia, anemia, thrombocytopenia; often – decreased number of lymphocytes; infrequently – febrile neutropenia.

Disorders of metabolism and nutrition: very often – decreased appetite.

Nervous system disorders: very often – dysgeusia, dizziness.

Visual organ disorders: often – increased lacrimation.

vascular disorders: often – venous thromboembolism2.

2 – Venous thromboembolism phenomena included: deep vein thrombosis, pulmonary artery thromboembolism, dura sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, deep vein thrombosis of the inferior vena cava and renal vein systems.

Disorders of the respiratory system, thorax and mediastinum:often – interstitial pulmonary disease/pneumonitis.

Gastrointestinal tract disorders: very often – diarrhea, vomiting, nausea.

Skin and subcutaneous tissue disorders: very often – alopecia, itching, rash; often – dry skin.

Muscular system and connective tissue disorders: often – muscle weakness.

General disorders and disorders at the site of administration: very often – fatigue, pyrexia.

Laboratory and instrumental data: very often – increased ALT, increased AST.

Description of individual adverse reactions

Neutropenia

There have been frequently reported cases of neutropenia (41.5%) in patients treated with ZenlysticTM in combination with an aromatase inhibitor or fulvestrant, with 28.2% of patients developing grade 3 and 4 neutropenia (based on laboratory studies). The median time to development of the first episode of grade 3 or 4 neutropenia was 29 to 33 days, with a median duration of neutropenia of 11 to 15 days. The development of febrile neutropenia was reported in 0.9% of patients. In case of neutropenia of severity 3 or 4, a dose adjustment is recommended (see section “Dosage and administration”).

Diarrhea

Diarrhea was the most frequently reported adverse reaction. The incidence of diarrhea was higher during the first month of therapy with ZenlysticTM and decreased thereafter. In the studies, the median time to first episode of diarrhea was 6 to 8 days, and the median duration of diarrhea was 9 to 12 days (for grade 2 diarrhea) and 6 to 8 days (for grade 3 diarrhea). Diarrhea was managed with concomitant therapy with medications such as loperamide and/or with dose adjustments (see “Dosage and administration”).

Elevation of aminotransferases

There have been frequent reports of elevated ALT and AST (15.1% and 14.2%, respectively) in patients treated with ZenlysticTM in combination with an aromatase inhibitor or fulvestrant, with increases in ALT and AST of grade 3 and 4 severity (based on laboratory testing) observed in 6.1% and 4.2% of patients, respectively. In patients with ALT elevation of grade 3 or 4, the median time to development of this phenomenon was 57 days to 61 days, and the median time to its resolution was 14 days. In patients with grade 3 or 4 elevated AST, the median time to onset was 71 days to 185 days, and the median time to resolution was 13 to 15 days. In case of ALT or AST elevation of grade 3 or 4, a dose adjustment is recommended (see section “Dosage and administration”).

Creatinine concentration

It has been shown that 98.3% of patients with ZenlysticTM elevated serum creatinine concentrations (based on laboratory testing), with elevated creatinine concentrations of severity 3 or 4 noted in 1.9% of patients (based on laboratory testing). Creatinine elevations (all severities) have been reported in 78.4% of patients receiving aromatase inhibitor or fulvestrant monotherapy. Abemaciclib has been shown to increase serum creatinine concentrations due to inhibition of renal tubular secretion transporters without affecting glomerular filtration rate (GFR) as determined by yohexol clearance.

In clinical studies, an increase in serum creatinine concentration was noted during the first month of use of ZenlystickTM.and creatinine concentrations remained elevated but stable throughout the treatment period, and these increases were reversible after discontinuation and were not accompanied by changes in renal function markers such as blood urea nitrogen, cystatin C or GFR calculated from cystatin C levels.

As monotherapy

The most common adverse reactions reported in the clinical trial with an incidence of ≥20% were: Diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia.

The most common adverse reactions reported with an incidence of ≥10% were:

gastrointestinal disorders: diarrhea, nausea, abdominal pain, vomiting, constipation, dry mouth, stomatitis;

infectious and parasitic diseases: infections;

general disorders and disorders at the site of administration: Fatigue1, pyrexia;

1 – Includes asthenia, fatigue;

disorders of the blood and lymphatic system: Neutropenia2, anemia3, thrombocytopenia4, leukopenia5;

2 – Includes neutropenia, decreased neutrophil count;

3 – Includes anemia, decreased hematocrit, decreased hemoglobin count, decreased red blood cell count;

4 – Includes decreased platelet count, thrombocytopenia;

5 – Includes leukopenia, decreased leukocyte count.

disorders of metabolism and nutrition: decreased appetite, dehydration;

disorders of the respiratory system, thoracic and mediastinal organs: cough;

disorders of the musculoskeletal system and connective tissue: arthralgia;

disorders of the nervous system: headache, dysgeusia, dizziness;

dermal and subcutaneous tissue disorders: alopecia;

laboratory and instrumental findings: increased serum creatinine concentration, decreased body weight, decreased white blood cell count, decreased neutrophil count, anemia, decreased lymphocyte count, decreased platelet count, increased ALT count, increased AST count.

Description of individual adverse reactions

Elevated creatinine concentration

. Abemaciclib has been shown to increase serum creatinine concentrations due to inhibition of renal tubular secretion transporters without impairing glomerular function.

Overdose

Pregnancy use

Pregnancy

Preclinical animal studies have shown that ZenlysticTM when used during pregnancy can be harmful to the fetus. In animal reproductive studies, use of abemaciclib during organogenesis had teratogenic effects and resulted in decreased fetal weight during pregnancy, which was similar to human exposure data based on AUC when the maximum recommended human dose was used. There are no data on the risks associated with the use of the drug in humans. A pregnant woman should be advised of the possible risk to the fetus.

Breastfeeding period

. There are no data on the possibility of abemaciclib penetrating into breast milk, the effect of abemaciclib on the breastfed baby, or the effect on milk production. Since a breastfed infant may have serious adverse reactions associated with abemaciclib penetration into breast milk, breastfeeding women should be advised to stop breastfeeding while taking Zenlystic TM and for at least 3 weeks after completion of therapy.

Women and men of reproductive potential

Pregnancy testing

. Data from preclinical animal studies have shown that use of ZenlysticTM during pregnancy can be harmful to the fetus. A pregnancy test is recommended for women of childbearing age before starting therapy with ZenlystickTM.

Contraception in women

The use of ZenlysticTM during pregnancy may cause fetal harm. Women of childbearing age should be advised to use an effective contraceptive method during therapy with ZenlysticTM and for at least 3 weeks after the last dose.

Infertility in men

Based on animal studies, ZenlysticTM may affect fertility in men of reproductive age.