Zenlistic, 200 mg 14 pcs

Interaction

Influence of other drugs on the pharmacokinetics of Zenlystic^TM<

Zenlystic^TM is metabolized primarily by the CYP3A4 isoenzyme.

Inhibitors of isoenzyme CYP3A4

. Concomitant use of CYP3A4 isoenzyme inhibitors and Zenlystic^TM has resulted in increased plasma concentrations of abemaciclib. In patients with advanced and/or metastatic cancer, concomitant use of the CYP3A4 isoenzyme inhibitor clarithromycin increased the plasma exposure of abemaciclib by 3.4 times and the combined free exposure of abemaciclib and its active plasma activity-adjusted metabolites by 2.5 times.

The concomitant administration of potent CYP3A4 isoenzyme inhibitors and ZENLISTIC^TM should be avoided. If concomitant therapy with CYP3A4 isoenzyme inhibitors is necessary, the dose of Zenlystic^TM should be reduced (see section “Dosage and administration”) and further toxicity should be monitored carefully. Examples of strong CYP3A4 isoenzyme inhibitors include, but are not limited to: clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole and voriconazole. Consumption of grapefruit or grapefruit juice should be avoided.

Dose adjustment is not required in patients receiving therapy with moderate or mild CYP3A4 isoenzyme inhibitors. However, signs of toxicity should be monitored.

Inductors of isoenzyme CYP3A4

. Concomitant use of the strong CYP3A4 isoenzyme inducer rifampicin and Zenlistic^TM resulted in a 95% decrease in plasma concentration of abemaciclib and free plasma concentration of abemaciclib and its activity-adjusted active metabolites by 77% based on AUC_0-∞. Concomitant use of Zenlystic^TM with strong CYP3A4 isoenzyme inducers (including, but not limited to, the following: carbamazepine, phenytoin, rifampicin and St John’s wort) should be avoided due to the risk of decreased effectiveness of abemaciclib.

Influence of Zenlystic^TM on the pharmacokinetics of other drugs

Drugs that are vector substrates

Abemaciclib and its major active metabolites inhibit the renal transporters OCT2 (organic cation transporter 2), MATE1 and MATE2-K (multiple resistance and toxin elimination proteins 1 and 2-K). In vivo interactions between abemaciclib and clinically relevant substrates of these transporters, such as dofetilide or creatinine, can occur. In a clinical drug interaction study with metformin (substrate OCT2, MATE1 and 2), its concomitant administration with abemaciclib at a dose of 400 mg resulted in a small clinically insignificant increase (37%) in plasma metformin exposure. This has been shown to be due to decreased renal secretion with unchanged glomerular filtration.

In healthy volunteers, concomitant use of abemaciclib and the P-glycoprotein substrate (P-gp) loperamide resulted in a 9% increase in plasma loperamide exposure based on the AUC_0-∞ and by 35% based on C_max. This increase was not considered clinically significant. However, based on the inhibition of invitro P-gp and breast cancer resistance protein (BCRP) in the presence of abemaciclib, invivo abemaciclib with substrates of these carriers with a narrow therapeutic index, such as digoxin or dabigatran etexilate.

In clinical studies involving patients with breast cancer, there has been no clinically significant effect of Zenlystic^TM on the pharmacokinetics of anastrozole, fulvestrant, exemestane, letrozole or tamoxifen.

It is not known at this time whether Zenlystic^TM can reduce the effectiveness of systemic hormonal contraceptives.

Special Instructions

Neutropenia

There have been reported cases of neutropenia in patients treated with Zenlystick^TM. 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 Zenlystic^TM 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 Zenlystic^TM 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 Zenlystick^tm. 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 Zenlystic^TM 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

Oval tablets are light orange in color with “Lilly” engraved on one side and “200” on the other.

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 Zenlystic^TM 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 Zenlystic^TM 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 Zenlystic^TM 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 Zenlystic^TM 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 Zenlystick^TM.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.TM, and creatinine concentration remained elevated but stable throughout the treatment period, with the increase being reversible after treatment discontinuation. Alternative markers, such as blood urea nitrogen, cystatin C, or calculated GFR, which are not based on creatinine, can be used to determine renal function impairment.

Post-registration experience

Disorders of the respiratory system, thoracic and mediastinal organs: interstitial pulmonary disease/pneumonitis (with an incidence of ≥1.0% to < 10%).