Cytochrome P450 (isoenzymes CYP2C19 and CYP3A4)

Cytochrome P450 (isoenzymes CYP2C19 and CYP3A4)

Cytochrome P450

(CYP450) is a large group of enzymes responsible for the metabolism of foreign organic compounds and drugs. Enzymes of the cytochrome P450 family carry out oxidative biotransformation of drugs and a number of other endogenous bioorganic substances and, thus, perform a detoxification function. Cytochromes are involved in the metabolism of many classes of drugs, such as proton pump inhibitors, antihistamines, retroviral protease inhibitors, benzodiazepines, calcium channel blockers and others. Cytochrome P450 is a protein complex with a covalently bound heme (metalloprotein), which ensures the addition of oxygen. Heme, in turn, is a complex of protoporphyrin IX and a divalent iron atom. The number 450 indicates that the reduced heme associated with CO has a maximum light absorption at a wavelength of 450 nm.

Cytochromes P-450 are involved not only in the metabolism of drugs, but also in the conversion of hemoglobin into bilirubin, the synthesis of steroids, etc. All isoforms of cytochrome P-450 are grouped into the families CYP1, CYP2, CYP3. Within the families, subfamilies A, B, C, D, E are distinguished. Within the subfamilies, isoforms are designated by serial number. For example, CYP2C19 is the name of the 19th in order cytochrome of the “C” subfamily, family “2”. In total, there are about 250 different types of cytochrome P-450, of which approximately 50 are found in the human body and only six of them (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4) are relevant to drug metabolism.

The activity of cytochromes P-450 is influenced by many factors - smoking, alcohol, age, genetics, nutrition, disease. These factors are responsible for the formation of individual characteristics of the work of P-450 enzymes and determine the effects of drug interactions in a particular patient.

Importance of cytochromes P450 for gastroenterology

The recently increased interest of gastroenterologists in the isoforms of cytochrome P450 CYP2C19 and CYP3A4 is due to their role in the metabolism of benzimidazole derivatives, which include all drugs from the ATC group A02BC “Proton pump inhibitors” (omeprazole, panthorazole, lansoprazole, rabeprazole and esomeprazole) .
It is clinically significant that the CYP2C19 gene is polymorphic, and the magnitude of the therapeutic effect of various PPIs largely depends on the state of this gene in the patient. Among PPIs, lansoprazole exhibits the greatest inhibitory effect on CYP2C19, followed by omeprazole and esomeprazole to a lesser extent. The effect of rabeprazole is even lower, but its thioester, formed during non-enzymatic metabolism, has a significant inhibitory effect on the activity of CYP2C19. Pantoprazole has the least effect on CYP2C19. Pantoprazole has the greatest inhibitory effect on CYP3A4 in vitro, followed by (as the effect decreases) omeprazole, esomeprazole, rabeprazole and lansoprazole. For patients receiving multiple medications, pantoprazole is preferable among PPIs (Bordin D.S.).

Metabolism of five proton pump inhibitors.
Darker arrows indicate more significant metabolic pathways. The figure is taken from the article by Marelli S., Pace F. With the active participation of CYP3A4, the metabolism of domperidone, cisapride and a large number of other drugs occurs.

A number of gastroenterological drugs inhibit cytochrome CYP3A4, thereby affecting the pharmacokinetics of drugs taken together.

Drug interaction problem

In modern clinical practice, the combined use of drugs is widespread, which is associated with the presence of several diseases in the patient or the insufficient effectiveness of monotherapy.
With combination therapy, drug interactions are possible. Approximately 56% of patients under 65 years of age and 73% of patients over 65 years of age are taking more than one medication. Taking two medications leads to their interaction in 6% of patients. Prescribing 5 (or 10) drugs increases the interaction rate by up to 50 (or 100)%. Potentially dangerous drug combinations are a serious clinical problem. There is evidence that from 17 to 23% of drug combinations prescribed by doctors are potentially dangerous. In the United States alone, 48 thousand patients die each year due to unintended drug interactions. The FDA has deregistered several drugs (including the prokinetic drug cisapride) due to their potentially dangerous interactions with other drugs, including fatalities.

The main mechanisms of drug interactions are associated with changes in their pharmacokinetics or pharmacodynamics. The most significant, according to modern concepts, are changes in pharmacokinetics during drug metabolism with the participation of cytochromes P-450.

An example of a dangerous interaction is the recently discovered interaction between PPIs and clopidogrel, which is widely used in the treatment of patients with coronary heart disease. To reduce the risk of gastrointestinal complications, patients receiving acetylsalicylic acid in combination with clopidogrel are prescribed a PPI. Since the bioactivation of clopidogrel occurs with the participation of CYP2C19, taking PPIs metabolized by this cytochrome may reduce the activation and antiplatelet effect of clopidogrel. In May 2009, at the Society for Cardiovascular Angiography and Interventions (SCAI) conference, data were presented showing that concomitant use of clopidogrel and PPIs significantly increases the risk of myocardial infarction, stroke, unstable angina, the need for repeat coronary interventions and coronary death (Bordin D .WITH.).

Cytochrome CYP2C19

The cytochrome P450 isoform CYP2C19 (S-mephenytoin hydroxylase) catalyzes the reactions of 5-hydroxylation of the pyridine ring and 5′-demethylation of the benzimidazole ring.
In the human body, CYP2C19 is located in hepatocytes. All types of CYP2C19 gene mutations can be divided into three groups:

1. Without mutations (homozygotes), they are also fast metabolizers of PPIs.
2. Having a mutation in one allele (heterozygotes), an intermediate type of metabolism.
3. Having mutations in both alleles, they are also slow metabolizers of PPIs.

The prevalence of CYP2C19 genotypes, type of metabolism and the effect of PPIs in the treatment of acid-related diseases are given in the table:

Slow metabolizers are distinguished from fast and intermediate metabolizers by a twofold higher concentration of PPI in the blood plasma and half-life. Polymorphism of the gene encoding the 2C19 isoform determines different rates of PPI metabolism in patients. In connection with the above, the selection of PPIs is recommended to be carried out under the control of daily pH-metry

(Khavkin A.I., Zhikhareva N.S., Drozdovskaya N.V.).

• CYP2C19 actively metabolizes the following drugs: tricyclic antidepressants (amitriptyline, clomipramine, imipramine), antidepressant - selective serotonin reuptake inhibitor citalopram, antidepressant - MAO inhibitor moclobemide, anticonvulsants and antiepileptic drugs (diazepam, primidone, phenytoin, phenobarbital, nordazepam), proton pump inhibitors (omeprazole, panthorazole, lansoprazole, rabeprazole and esomeprazole), the antimalarial drug proguanil, NSAIDs diclofenac and indomethacin, as well as: warfarin, gliclazide, clopidogrel, propranolol, cyclophosphamide, nelfinavir, progesterone, teniposide, tetrahydrocannabinol, carisoprodol, voriconazole and others
• strong CYP2C19 inhibitors: moclobemide, fluvoxamine, chloramphenicol (chloramphenicol)
• nonspecific inhibitors of CYP2C19: PPI omeprazole and lansoprazole, H2-blocker cimetidine, NSAID indomethacin, as well as fluoxetine, felbamate, ketoconazole, modafinil, oxcarbazepine, probenecid, ticlopidine, topiramate
• CYP2C19 inducers: rifampicin, artemisinin, carbamazepine, norethisterone, prednisone, St. John's wort.

The influence of different CYP2C19 genotypes on the effectiveness of Helicobacter pylori eradication

Patients with the genotype of “fast” metabolizers have a rapid metabolism of proton pump inhibitors, therefore, the antisecretory effect of taking the latter is less pronounced in them than in individuals with the phenotypes of “intermediate” and “slow” metabolizers. The difference in the antisecretory effect may determine a lower level of Helicobacter pylori
in “fast” metabolizers. Thus, there is a higher effectiveness of eradication therapy in patients with genotypes of “slow” (88.9%) and “intermediate” (82.7%) metabolizers compared to “fast” metabolizers (see figure).

The influence of different CYP2C19 genotypes on the effectiveness of Helicobacter pylori eradication.
BM – “fast” metabolizers, PM – “intermediate” metabolizers, MM – “slow” metabolizers (Maev I.V. et al.) Due to the fact that molecular genetic studies are inaccessible to a practicing physician, you can suspect “fast” metabolizers by focusing to preserve abdominal pain syndrome on the 3rd–4th day from the start of taking PPIs, and also taking into account the slow endoscopic dynamics during epithelization of erosions and scarring of ulcerative defects in the patient. In turn, the insufficiency of the antisecretory effect of PPI therapy can be verified by the method of 24-hour intragastric pH-metry (Maev I.V. et al.).

Cytochrome CYP3A4

The CYP3A4 enzyme catalyzes the sulfoxidation reaction, leading to the formation of a sulfonic group.
CYP3A4 is one of the most important cytochromes for pharmaceuticals, since it biotransforms, at least partially, about 60% of oxidized drugs. Although the activity of CYP3A4 varies widely, it is not subject to genetic polymorphism. The location of CYP3A4 on the apical membranes of small intestinal enterocytes and hepatocytes facilitates the metabolism of drugs prior to the drug entering the systemic circulation, which is known as the “first pass effect.” A genetic defect in CYP3A4 may be the cause of the development of secondary long QT syndrome when taking cisapride and, as a consequence, the development of cardiac dysrhythmia (Khavkin A.I. et al.).

• CYP3A4 is the main enzyme in the metabolism of the following drugs: immunosuppressants (cyclosporine, sirolimus, tacrolimus), drugs used in chemotherapy (anastrozole, cyclophosphamide, docetaxel, erlotinib, tyrphostin, etoposide, ifosfamide, paclitaxel, tamoxifen, teniposide, vinblastine, vindesine, gefitinib) , antifungal agents (Clotrimazole, ketoconazole, itraconazole), macrolides (clarithromycin, erythromycin), tricyclic antidepressants (amitriptyin, clomipramine, Imipramine), antidepressants - selective inhibitors of the reverse capture of serotonin (cityloprams, escitaloprams, fluoxetine, serpentine, sertrain lin), antipsychotic (aripiprazole, haloperidol , ziprasidone, risperidone), opioid analgesics (alfentanil, codeine, methadone, fentanyl), benzodiazepines (alprazolam, clonazepam, midazolam, flunitrazepam), lipid-lowering statins (atorvastatin, lovastatin, simvastatin), calcium channel blockers (amlodipine, verapamil, diltiazem, nifedipine , felodipine), sex hormones (levonorgestrel, mifepristone, testosterone, estradiol, ethinyl estradiol, finasteride), as well as amiodarone, buspirone, venlafaxine, sildenafil and others
• CYP3A4 is also involved (but is not the main enzyme) in the metabolism of PPIs (omeprazole and esomeprazole), cisapride and many other drugs
• strong CYP3A4 inhibitors: HIV protease inhibitors (indinavir, nelfinavir, ritonavir), macrolide antibiotics (clarithromycin, telithromycin, erythromycin), grapefruit juice components (bergamottin), antifungals (itraconazole, ketoconazole, fluconazole, as well as aprepitant, quercetin, nefazodone and others
• CYP3A4 inhibitors: H2-blocker cimetidine, pain reliever buprenorphine, coffee component caffestol and many others
• CYP3A4 inducers: anticonvulsants and mood stabilizers (carbamazepine, oxcarbazepine, phenytoin), the St. John's wort component hyperforin, as well as cyproterone, modafinil, nevirapine, rifampicin, phenobarbital, etravirine, efavirenz and many others.

Resources for healthcare professionals regarding the role of CYP2C19 and CYP3A4 and their genotypes in gastrointestinal therapy

Video

Still from video: Simanenkov V.I. Acid suppressive therapy for refractory forms of GERD

Still from video: Embutnieks Yu.V. Principles of management of patients with refractory GERD

Still from video: Kareva E.N.
Could a patient's genetic makeup be the cause of refractory GERD? Pharmacogenetic management of the effectiveness of PPIs On the GastroScan.ru website in the “Video” section there is a subsection for patients “Popular Gastroenterology” and a subsection “For Doctors”, containing video recordings of reports, lectures, webinars in various areas of gastroenterology for healthcare professionals.

Articles and abstracts

• Nikonov E.L. Clinical and pathogenetic features of various types of antisecretory therapy in patients with acid-dependent diseases. Abstract of the dissertation for the scientific degree of Doctor of Medical Sciences. Moscow, 2004.
• Morozov S.V., Tsodikova O.M., Isakov V.A., Gushchin A.E., Shipulin G.A. Comparative effectiveness of the antisecretory effects of rabeprazole and esomeprazole in individuals who rapidly metabolize proton pump inhibitors. // Experimental and clinical gastroenterology. - 2003. - No. 6.
• Isakov V.A. Safety of proton pump inhibitors during long-term use // Clinical pharmacology and therapy. – 2004. – No. 13(1).
• Pasechnikov V.D. Keys to choosing the optimal proton pump inhibitor for the treatment of acid-dependent diseases // RZHGGK. - No. 3. – 2004.
• Bordin D.S. Safety of treatment as a criterion for choosing a proton pump inhibitor in a patient with gastroesophageal reflux disease // Consilium Medicum. – 2010. – Volume 12. – No. 8.
• Lebedeva E.G., Maev I.V., Bely P.A. The influence of polymorphism of the CYP2C19 gene on the effectiveness of the use of proton pump inhibitors in the treatment of gastroesophageal reflux disease // Treating Doctor. No. 7. 2011.
• Yurenev G.L., Kazyulin A.N., Yureneva-Tkhorzhevskaya T.V. The influence of acid suppressive therapy on the clinical course of coronary heart disease with refractory pain syndrome in the chest // Therapy. 2015. No. 2(2).
• Kareva E.N. Rabeprazole through the prism of “metabolism - effectiveness” // RMJ. 2021. October.
• Leonova M.V. Genetic polymorphism of CYP2C19 is a predictor of the clinical effectiveness of proton pump inhibitors // Medical Affairs. – 2015. No. 4. pp. 30-39.
• Bely P.A. The influence of CYP2C19 gene polymorphism on the effectiveness of the use of proton pump inhibitors in the treatment of gastroesophageal reflux disease. Author's abstract. diss. PhD, 01/14/04 – internal diseases. Moscow, 2011.

On the GastroScan.ru website in the “Literature” section there is a subsection “Proton pump inhibitors”, which contains publications for healthcare professionals, including discussions of the metabolism of PPIs with the participation of cytochromes P450 CYP2C19 and CYP3A4. Back to section

Propafenone

Proarrhythmogenic effect

Propafenone hydrochloride may cause new or worsen existing heart rhythm disturbances. This proarrhythmogenic effect ranges from an increase in the frequency of premature ventricular contractions (ventricular extrasystoles) to the development of ventricular tachycardia (including polymorphic ventricular tachycardia of the “pirouette” type) and ventricular fibrillation. Some of these arrhythmias are life-threatening and may require resuscitation to prevent death.

Therefore, each patient who is planned to be prescribed or who is already receiving the drug Propafenone should undergo an electrocardiographic and clinical examination before and during therapy to early detect side effects, assess the effectiveness of the drug and the advisability of continuing therapy.

Treatment should begin in a hospital setting. Before prescribing Propafenone, disturbances in water and electrolyte balance must be eliminated. It is recommended that previous antiarrhythmic therapy be discontinued before starting treatment. The period between discontinuation of a previously prescribed antiarrhythmic drug and the prescription of Propafenone should be at least 5 half-lives of the corresponding antiarrhythmic drug.

Treatment should be carried out by an arrhythmologist experienced in the treatment of relevant cardiac arrhythmias. When treating paroxysmal ventricular tachyarrhythmias, the patient should be under close cardiac monitoring (including ECG monitoring and blood pressure control) in a specialized department equipped with a defibrillator and other equipment to provide emergency medical care.

It is necessary to consider discontinuing treatment if any of the following ECG changes occur: 1) widening of the QRS complex or prolongation of the QT interval by more than 25% of the original; 2) prolongation of the PQ interval by more than 50% of the original; 3) prolongation of the QT interval beyond 500 ms; or 4) increase in the frequency or severity of arrhythmias.

Brugada syndrome

The use of propafenone hydrochloride can reveal the asymptomatic course of Brugada syndrome and cause Brugada-like changes on the ECG. Therefore, after starting therapy, an electrocardiographic examination should be performed to exclude the presence of Brugada syndrome and Brugada-like changes on the ECG.

In patients with verified Brugada syndrome, the use of Propafenone is contraindicated.

Supraventricular cardiac arrhythmias

The use of propafenone in patients with persistent atrial fibrillation, in patients with isolated atrial flutter or paroxysmal supraventricular tachycardia has not been studied.

Propafenone should not be used to control the ventricular rate in patients with persistent atrial fibrillation.

Experience with the use of propafenone in patients with sick sinus syndrome is limited, and therefore the use of propafenone is contraindicated (except for patients with a functioning pacemaker).

There is a risk of conversion of paroxysmal atrial fibrillation to atrial flutter with atrioventricular conduction 2:1 or 1:1.

Some patients with atrial flutter have developed 1:1 conduction of impulses when treated with propafenone, leading to an increase in ventricular rate. In such cases, it is possible to simultaneously use drugs that increase the functional refractory period of the atrioventricular connection.

Ventricular heart rhythm disturbances

Due to the risk of proarrhythmogenic effects, the use of Propafenone in patients with less severe (non-life-threatening) ventricular arrhythmias is not recommended, even if these rhythm disturbances are accompanied by symptoms that are unpleasant for the patient.

The use of Propafenone is indicated only for patients in whom, in the opinion of the physician, the potential benefits outweigh the possible risks.

The effect of propafenone hydrochloride therapy on mortality in patients with ventricular arrhythmias has not been established.

Cardiac conduction disorders

Propafenone hydrochloride slows cardiac conduction, which can lead to a dose-dependent prolongation of the PQ interval, widening of the QRS complex, the development of first or higher degree atrioventricular block, bundle branch block and intraventricular conduction disturbances. The occurrence of cardiac conduction disturbances during therapy with Propafenone requires dose reduction or discontinuation of the drug (unless the heart rate is adequately controlled by a pacemaker).

Heart failure

Propafenone hydrochloride has a negative inotropic effect on the myocardium, has beta-blocking activity and can cause decompensation of heart failure.

As with other class 1C antiarrhythmic drugs, serious side effects may occur in patients with significant organic changes in the myocardium when taking Propafenone.

Myocardial infarction

The effectiveness and safety of the use of propafenone hydrochloride in patients with recent myocardial infarction have not been sufficiently studied, and therefore the use of propafenone in such patients is contraindicated.

There are no results from controlled clinical studies confirming the beneficial effect of Propafenone on survival or the incidence of sudden death in patients who have suffered myocardial infarction.

Effect on pacing threshold

Propafenone may increase pacing and pacemaker or implantable cardioverter defibrillator detection thresholds. During propafenone therapy and after its cessation, it is necessary to regularly check and, if necessary, reprogram the parameters of these devices.

Obstructive pulmonary diseases

Propafenone hydrochloride, like other drugs with beta-blocking activity, should be used with extreme caution in patients with obstructive pulmonary diseases such as bronchial asthma and chronic obstructive pulmonary disease (COPD). In severe obstructive pulmonary diseases, the use of Propafenone is contraindicated.

Liver dysfunction

Propafenone hydrochloride is actively metabolized in the liver. In severely impaired liver function, the bioavailability of propafenone increases to approximately 70% (compared to 3%-40% in patients with normal liver function). In 8 patients with moderate or severe hepatic impairment, the mean elimination half-life was approximately 9 hours. In cases of liver dysfunction, there is also a decrease in systemic clearance of the drug and a decrease in binding to plasma proteins. This leads to excessive accumulation of propafenone hydrochloride.

In patients with impaired liver function, Propafenone should be used with caution. The dose of the drug should be reduced. It is recommended to regularly monitor clinical and electrocardiographic parameters for signs of excessive pharmacological effects and/or side effects until an individualized dosage regimen can be determined.

In the post-marketing period, cases of liver damage associated with the use of propafenone hydrochloride preparations have been described. Some patients had hepatocellular liver disease, other cases were associated with cholestasis, and some were of a mixed nature. In some cases, liver damage was detected only by a biochemical blood test, while others manifested with clinical symptoms. In one case, recurrence of liver damage was observed after resumption of propafenone hydrochloride, with a favorable outcome after discontinuation of therapy.

Agranulocytosis

Cases of agranulocytosis have been described in patients receiving propafenone. As a rule, agranulocytosis developed during the first 2 months of use of propafenone; upon discontinuation of therapy, the white blood cell count usually returned to normal within 14 days. Unexplained fever or decreased white blood cell counts, especially during the first 3 months of therapy, require careful evaluation to identify possible agranulocytosis or granulocytopenia. If agranulocytosis is suspected, you should immediately stop taking Propafenone. Patients should be warned to seek immediate medical attention if any signs of an infectious disease (eg, fever, sore throat, or chills) occur.

Myasthenia gravis

When using propafenone, an exacerbation of myasthenia gravis was observed, and therefore the use of the drug Propafenone in such patients is contraindicated.

Increased titer of antinuclear antibodies

Positive antinuclear antibody titers have been reported in patients receiving propafenone. They were reversible after cessation of treatment and could disappear even with continued use of propafenone. These laboratory values ​​were generally not associated with clinical symptoms. However, there is one published case of drug-induced lupus erythematosus (with recurrence of symptoms after restarting the drug); the disease resolved completely after cessation of therapy. Patients who develop abnormal antinuclear antibodies should be carefully evaluated. If elevated antinuclear antibody titers persist or increase, discontinuation of therapy should be considered.

Spermatogenesis disorder

A clinical evaluation of spermatogenesis was carried out in 11 healthy volunteers receiving oral propafenone hydrochloride at a dose of 300 mg twice daily for four days, followed by an increase in the dose to 300 mg three times daily for an additional four days. Volunteers were observed for 128 days after treatment. A 28% reduction in ejaculate volume was demonstrated after the last dose of propafenone (day) and a 27% reduction in sperm count at day 72. Follicle-stimulating hormone (FSH) and blood testosterone levels were also slightly reduced. Neither a decrease in sperm count nor a decrease semen volume was not detected at other visits. Both values ​​remained within the laboratory's normal reference range. Reduced spermatogenesis was also observed in animal experiments. The clinical significance of these results remains uncertain.

Erleada 60 mg No. 120 tablets

Content

Pharmacological properties Indications for use Contraindications Use with caution Use during pregnancy and breastfeeding Method of administration and doses Certain groups of patients Side effects Overdose Interaction with other drugs Children Special instructions Effect on the ability to drive vehicles and other mechanisms Storage conditions Expiration date

Pharmacological properties

Apalutamide is an orally administered selective androgen receptor inhibitor that binds directly to the ligand binding domain of the androgen receptor. Apalutamide interferes with androgen receptor nuclear translocation, inhibits DNA binding, disrupts androgen receptor-mediated transcription, and has no androgen receptor agonist activity in preclinical studies. In mouse models of prostate cancer, administration of apalutamide led to a decrease in tumor cell proliferation and an increase in apoptosis, which was accompanied by significant antitumor activity. The activity of the main metabolite, N-desmethylapalutamide, was one third of the in vitro activity of apalutamide.

Indications for use

Erleada is indicated for the treatment of adult men with non-metastatic castration-resistant prostate cancer (PCa) at high risk of metastasis.

Contraindications

• Women of childbearing age, pregnant women
• Hypersensitivity to the active substance or any excipient of the drug
• Children under 18 years old
• Severe renal and liver dysfunction

Carefully

In patients at risk of developing seizures or with a history of seizures, at risk of falls and fractures; combined use with drugs that are substrates of CYP3A4 enzymes (for example, darunavir, felodipine, midazolam, simvastatin), CYP2C19 (for example, diazepam, omeprazole), CYP2C9 (for example, warfarin, phenytoin), UDP-glucuronosyltransferase (UGT) (for example, levothyroxine, valproic acid), with drugs that are substrates of the P-glycoprotein (P-gp) transporters (e.g., colchicine, dabigatran etexilate, digoxin), breast cancer resistance protein (BCRP), or organic anion transport polypeptide 1B1 (OATP1B1) (e.g., lapatinib, methotrexate , rosuvastatin, repaglinide), with an anticoagulant metabolized by CYP2C9 (such as warfarin or acenocoumarol); in patients with clinically significant cardiovascular diseases that occurred within the last 6 months; in patients with a history of prolonged QT interval or relevant risk factors, as well as in patients receiving concomitant medications that may prolong the QT interval (see Precautions).

Use during pregnancy and breastfeeding

Pregnancy

Erleada should not be used during pregnancy or if it is possible. Information on the mechanism of action suggests that taking Erleada during pregnancy may adversely affect the condition of the fetus. There is insufficient data on the use of Erleada during pregnancy. Studies of the effect of Erleada on reproductive function and fetal development in animals have not been conducted.

Contraception

Erleada may be harmful to the developing fetus. Patients who have sexual intercourse with fertile partners should use highly effective methods of contraception throughout treatment, as well as for 3 months after taking the last dose of the drug.

Breastfeeding period

It is not known whether apalutamide or its metabolites passes into breast milk or has an effect on the health of breast-fed infants or on the mother's milk production.

Fertility

An animal study showed that Erleada may reduce fertility in fertile men.

Directions for use and doses

The drug should be prescribed and used under the regular supervision of a physician experienced in the treatment of cancer, and in specialized departments.

The recommended dose of Erleada is 240 mg (4 tablets of 60 mg), taken orally once a day. The tablets should be swallowed whole. Erleada can be taken with or without food.

Dose adjustment

If the patient experiences grade ≥3 toxicity or intolerance, withhold until symptoms improve to grade ≤1 or baseline, then resume at the same dose or, if necessary, a reduced dose (180 or 120 mg).

Missing a dose

If the patient misses a dose, it should be taken as soon as possible on the same day; the next day you should follow the usual regimen. The patient should not take additional tablets to correct a missed dose.

Selected patient groups

Children under 18 years old

The safety and effectiveness of Erleada in children have not been established.

There are no significant data on the use of Erleada in patients under 18 years of age.

Elderly patients (65 years and older)

Of the 803 patients treated with Erleada in Study 1 (ARN-509-003), 88% were 65 years of age or older and 26% were 80 years of age or older. There were no significant differences in safety or effectiveness between these patients and younger patients.

Impaired
renal function
Erleada has not been specifically studied in patients with impaired renal function. Based on pharmacokinetic data from clinical studies in subjects with castration-resistant PCa and healthy subjects, there were no significant differences in systemic levels in subjects with mild to moderate renal impairment at baseline (GFR 30 to 89 mL). /min/1.73 m²) compared with subjects with normal renal function (GFR ≥90 ml/min/1.73 m²). For patients with mild to moderate renal impairment, no dose adjustment is required. There are no data for patients with severe renal impairment or end-stage renal failure (GFR ≤29 ml/min/1.73 m²).

Liver dysfunction

The Hepatic Impairment Study compared systemic levels of apalutamide and N-desmethylapalutamide in subjects with baseline mild to moderate hepatic impairment (Child-Pugh A or B, respectively) versus healthy subjects with normal hepatic function. Systemic levels of apalutamide and N-desmethylapalutamide were similar in patients with mild to moderate hepatic impairment compared with patients with normal hepatic function. No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data on patients with severe liver dysfunction (Child-Pugh class C).

Side effect

• Endocrine system disorders: hypothyroidism.
• Metabolic and nutritional disorders: hypercholesterolemia, hypertriglyceridemia.
• Nervous system disorders: seizures.
• Cardiac disorders: prolongation of the QT interval.
• Skin and subcutaneous tissue disorders: skin rash, itching.
• Musculoskeletal and connective tissue disorders: fracture, arthralgia.
• General disorders and administration site disorders: fatigue.
• Laboratory and instrumental data: weight loss.

Overdose

There is no specific antidote for apalutamide. At a dose of 480 mg once daily (2 times the recommended daily dose), no dose-limiting toxicity was observed. Therapy If an overdose occurs, it is necessary to stop taking Erleada and begin general supportive treatment until clinical toxicity decreases or resolves.

Interaction with other drugs

The metabolism of apalutamide and the formation of its active metabolite, N-desmethylapalutamide, is mediated at steady state by both the CYP2C8 and CYP3A4 isoenzymes to the same extent. Clinically significant changes in their overall exposure are not expected as a result of interaction of the drug with inhibitors or inducers of the CYP2C8 or CYP3A4 isoenzyme. Apalutamide is an enzyme and transporter inducer and may be responsible for increased elimination of many commonly used drugs.

Effect of other medicinal products on apalutamide exposure

CYP2C8 isoenzyme inhibitors

The CYP2C8 isoenzyme plays a role in the excretion of apalutamide and in the formation of its active metabolite. In a drug interaction study, a 21% decrease in apalutamide Cmax and a 68% increase in AUC were observed when a single 240 mg dose of Erleada was co-administered with gemfibrozil (a potent CYP2C8 inhibitor). For the active substance (sum of apalutamide and adjusted for active metabolite potency), Cmax decreased by 21%, while AUC increased by 45%. There is no need to adjust the initial dose when Erleada is co-administered with a strong CYP2C8 inhibitor (e.g. gemfibrozil, clopidogrel), however, a dose reduction of Erleada should be considered based on tolerability (see Dosage and Administration - Dosage Adjustment). It is assumed that weak or moderate inhibitors of the CYP2C8 isoenzyme do not affect the pharmacokinetics of apalutamide. CYP3A4 isoenzyme inhibitors

The CYP3A4 isoenzyme plays a role in the excretion of apalutamide and in the formation of its active metabolite. In a drug interaction study, apalutamide Cmax was reduced by 22% while AUC remained unchanged when a single 240 mg dose of Erleada was coadministered with itraconazole (a strong CYP3A4 inhibitor). For the active substance (the total value for apalutamide and adjusted for the potency of the active metabolite), Cmax decreased by 22% while maintaining AUC at the same level. There is no need to adjust the initial dose when co-administering Erleada with a strong CYP3A4 inhibitor (e.g. ketoconazole, ritonavir, clarithromycin), however, a dose reduction of Erleada should be considered based on tolerability (see Dosage and Administration - Dosage Adjustment). It is assumed that weak or moderate inhibitors of the CYP3A4 isoenzyme do not affect the pharmacokinetics of apalutamide.

Inducers of the isoenzyme CYP3A4 or CYP2C8

The effects of inducers of CYP3A4 or CYP2C8 isoenzymes on the pharmacokinetics of apalutamide have not been assessed in in vivo studies. Based on the results of an interaction study with strong inhibitors of the isoenzyme CYP3A4 and CYP2C8, inducers of CYP3A4 or with CYP2C8 are not expected to have clinically significant effects on the pharmacokinetics of apalutamide and the active substance, therefore, when co-administering Erleada with inducers of CYP3A4 or CYP2C8, no dose adjustment is required .

Effect of apalutamide on exposure to other drugs

Apalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, apalutamide is expected to interact with many common drugs that are substrates of enzymes or transporters. The decrease in their plasma concentrations can be significant and lead to loss or reduction of the clinical effect. There is also a risk of increased formation of active metabolites.

Effect of apalutamide on drug metabolizing enzymes

In vitro studies have shown that apalutamide and N-desmethylapalutamide are moderate to strong inducers of CYP3A4 and CYP2B6, moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19 and CYP3A4. Apalutamide and N-desmethylapalutamide do not affect the CYP1A2 and CYP2D6 isoenzymes at therapeutically significant concentrations. The effect of apalutamide on CYP2B6 substrates has not been assessed in vivo and the final outcome is currently unknown. When CYP2B6 substrates (eg, efavirenz) are coadministered with Erleada, monitor for adverse reactions and evaluate for loss of substrate efficacy, and substrate dosage adjustments may be necessary to maintain optimal plasma concentrations.

In humans, Erleada is a strong inducer of the CYP3A4 and CYP2C19 isoenzymes and a weak inducer of the CYP2C9 isoenzyme. In a drug interaction study using a cocktail approach, coadministration of Erleada with a single oral dose of sensitive CYP substrates resulted in a 92% reduction in the AUC of midazolam (a CYP3A4 substrate), an 85% reduction in the AUC of omeprazole (a CYP2C19 substrate), and a 85% reduction in the AUC of S-warfarin. (CYP2C9 substrate) by 46%. Erleada did not cause clinically significant effects on the CYP2C8 substrate. Co-administration of Erleada with medicinal products that are metabolized primarily by CYP3A4 (for example, darunavir, felodipine, midazolam, simvastatin), CYP2C19 (for example, diazepam, omeprazole) or CYP2C9 (for example, warfarin, phenytoin) may lead to a weakening of the effect of these enzymes. drugs. If possible, it is recommended to replace these drugs, or monitor for a decrease in their effectiveness if it is decided to continue therapy. When co-administering Erleada with warfarin, the level of international normalized ratio (INR) should be monitored.

The induction of CYP3A4 by apalutamide suggests that UDP-glucuronosyltransferase (UDP-GT) can also be induced through activation of the nuclear pregnane X receptor (PXR). Co-administration of Erleada with drugs that are substrates of UDP-HT (for example, levothyroxine, valproic acid) may lead to a decrease in systemic levels of these drugs. When Erleada is co-administered with UDP-HT substrates, loss of substrate efficacy should be assessed and substrate dosage adjustments may be necessary to maintain optimal plasma concentrations.

Effect of apalutamide on drug transporters

Apalutamide has been shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1). A drug interaction study using a cocktail approach showed that coadministration of Erleada with single oral doses of sensitive transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (a P-gp substrate) and a 41% decrease in the AUC of rosuvastatin (a BCRP/OATP1B1 substrate). , but did not affect Cmax. Co-administration of Erleada with drugs that are substrates of P-gp, BCRP or OATP1B1 may lead to a weakening of the effect of these drugs. When Erleada is coadministered with P-gp, BCRP, or OATP1B1 substrates, loss of substrate efficacy should be assessed and substrate dosage adjustments may be necessary to maintain optimal plasma concentrations. Based on in vitro data, inhibition of organic cationic transporter 2 (OCT2), organic anion transporter 3 (OATC) and drug and toxin extrusion (MATE) proteins by apalutamide and its N-desmethyl metabolite cannot be ruled out. No in vitro inhibition of organic anion transporter 1 (OAT1) was observed.

Drugs that prolong the QT interval

Because antiandrogen therapy may contribute to QT prolongation, concomitant use of Erleada with other drugs known to prolong the QT interval or have the potential to cause torsade de pointes (TdP), such as Class IA (eg, quinidine, disopyramide) or Class IA antiarrhythmics III (eg, amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotics (eg, haloperidol) and so on, should be carefully evaluated.

Children

Drug interaction studies were conducted in adults only.

special instructions

Convulsions

Erleada is not recommended in patients with a history of seizures or other predisposing factors, such as traumatic brain injury, recent stroke (within one year), primary brain tumors or brain metastases. If convulsions develop while using Erleada, the use of the drug should be permanently discontinued. The risk of seizures is higher in patients receiving additional drugs that lower the seizure threshold.

In clinical studies, seizures were observed in 0.2% of patients receiving Erleada. These studies excluded patients with a history of seizures or predisposing factors for them. There is no clinical experience with restarting Erleada in patients who have experienced seizures.

Falls and fractures

Cases of falls and fractures have been reported in patients receiving Erleada (see Adverse Reactions). The risk of falls and fractures should be assessed before using Erleada, patients should be monitored during treatment, and the use of specialized bone medications should be considered.

Concomitant use with other drugs

Apalutamide is a potent enzyme inducer and may reduce the effectiveness of many commonly used drugs (see Interactions with Other Drugs). Therefore, the use of concomitant medications should be reviewed before initiating treatment with apalutamide. Concomitant use of apalutamide with drugs that are sensitive substrates of multiple metabolizing enzymes or transporters should be avoided if their therapeutic effect is of significant importance to the patient and if dose adjustments cannot be easily made based on monitoring of efficacy or plasma concentrations. Concomitant use with warfarin and coumarin-like anticoagulants should be avoided. If Erleada is co-administered with an anticoagulant metabolized by CYP2C9 (such as warfarin or acenocoumarol), additional monitoring of the international normalized ratio (INR) should be performed (see Interactions with Other Drugs).

Recent cardiovascular disease

Patients with clinically significant cardiovascular disease occurring within the last 6 months, including severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident, including transient ischemic attack ), or clinically significant ventricular arrhythmias, were excluded from clinical studies. Therefore, the safety of apalutamide in these patients has not been established. When prescribing Erleada, patients should be monitored for cardiovascular risk factors such as hypercholesterolemia, hypertriglyceridemia, or other cardiometabolic disorders (see Adverse Reactions). These pathological conditions should be treated as necessary, after starting the use of Erleada, according to the established treatment protocol. Antiandrogen therapy may prolong the QT interval

In patients with a history of QT prolongation or associated risk factors, or in patients receiving concomitant medications that may prolong the QT interval (see Drug Interactions), the benefit-risk ratio, including the potential for torsade de pointes (TdP), should be assessed. , before starting Erleada therapy.

Impact on the ability to drive vehicles and other mechanisms

Studies have not been conducted to study the effect of Erleada on the ability to drive vehicles or operate machines. There is no information that Erleada affects the ability to drive vehicles or operate machinery. Given the profile of side effects, including the occurrence of seizures, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Storage conditions

Store at a temperature not exceeding 30 °C in the original packaging (bottle).

Keep out of the reach of children.

Best before date

2 years.

Do not use after the expiration date stated on the package.