Xtandi capsules 40mg, 112pcs

Composition

1 capsule enzalutamide (MDV3100) 40 mg

Auxiliary substances:

aprilcapil macrogolglycerol – 905.81 mg,

butylhydroxyanisole – 0.095 mg

butylhydroxytoluene the – 0.095 mg,

gel mass – 444.3 mg (gelatin – 260.6 mg, purified water – 191.7 mg, sorbitol solution and sorbitan – 90.3 mg, glycerol – 90.3 mg, titanium dioxide – 3.1 mg);

ink black – a small number (anhydrous ethanol, ethyl acetate, propylene glycol, dye iron oxide black, polyvinylacetate, purified water, isopropyl alcohol, macrogol 400, ammonia concentrated).

Pharmacological action

Antitumor drug, antiandrogen. Prostate cancer depends on the presence of androgens and responds to the suppression of androgen receptor activity. Despite low or even undetectable levels of androgens in blood plasma, the activity of androgen receptors on tumor cells continues to contribute to the progression of the disease. Stimulating the growth of tumor cells using androgen receptors requires their translocation into the cell nucleus and binding to DNA. Enzalutamide is a potent androgen receptor inhibitor that blocks several steps of the androgen receptor signaling pathway. Enzalutamide competitively inhibits the binding of androgens to androgen receptors, inhibits nuclear translocation of activated receptors, and inhibits the binding of activated androgen receptors to DNA even in conditions of overexpression of androgen receptors and in tumor cells resistant to antiandrogens. Treatment with enzalutamide suppresses the growth of prostate tumor cells and can induce cell death and tumor regression. In preclinical studies, enzalutamide lacked androgen receptor agonist activity. Pharmacokineticspharmacokinetics of enzalutamide were studied in patients with prostate cancer and in healthy volunteers. The average T 1/2 of enzalutamide in patients after a single oral dose is 5.8 days (from 2.8 to 10.2 days), Css is reached in about a month. With daily oral use, enzalutamide accumulates approximately 8.3 times faster than a single dose. Daily fluctuations in blood plasma concentrations are insignificant (the ratio from peak to minimum is 1.25). The elimination of enzalutamide is mainly carried out by hepatic metabolism with the formation of an active metabolite, which is as active as enzalutamide and circulates in plasma at approximately the same concentration as enzalutamide. Cmax of enzalutamide in blood plasma in patients was observed 1-2 hours after use. Based on studies of human weight balance, oral absorption of enzalutamide is estimated to be at least 84.2%. Enzalutamide is not a substrate for efflux transporters of P-glycoprotein or BCRP. Stable level, mean Cmax of enzalutamide and its active metabolite is 16.6 pg / ml (coefficient of variation [CV] 23%) and 12.7 pg / ml (CV 30%), respectively. The average Vd of enzalutamide in patients after a single oral dose is 110 l (CV 29%). The Vd of enzalutamide is greater than the volume of total body fluid, which indicates an active distribution in peripheral tissues. Rodent studies have shown that enzalutamide and its active metabolite can cross the BBB. Enzalutamide binds 97-98% to plasma proteins, primarily albumin. The active metabolite binds to plasma proteins by 95%. Enzalutamide is actively metabolized. There are two main metabolites present in human blood plasma: N-desmethylenzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide is metabolized by the enzymes CYP2C8 and, to a lesser extent, CYP3A4 / 5, which play an important role in the formation of the active metabolite. In an in vitro study, N-desmethylenzalutamide is metabolized to a carboxylic acid metabolite by carboxylesterase 1, which also plays a small role in the metabolism of enzalutamide to a carboxylic acid metabolite. N-desmethylenzalutamide was not metabolized by CYP enzymes in vitro. In clinical use, enzalutamide is a strong inducer of the CYP3A4 enzyme, a moderate inducer of the CYP2C9 and CYP2C19 enzymes, and has no clinically significant effect on the CYP2C8 enzyme. The average apparent clearance of enzalutamide in patients is between 0.52 and 0.564 l/h. Oral use of 14C-labeled enzalutamide eliminated approximately 84.6% of the radioactive dose by day 77: 71% – via the kidneys (primarily as an inactive metabolite with a small amount of enzalutamide and the active metabolite) and 13.6% – via the intestine (0.39% of the enzalutamide dose unchanged).

Indications

Treatment of metastatic castration-resistant prostate cancer.

Contraindications

Severe liver dysfunction; hypersensitivity to the Active ingredient. The drug is contraindicated in women and children.

Side effects

From the hematopoietic system: infrequently-leukopenia, neutropenia. Immune system disorders: unknown-tongue edema, lip edema, pharyngeal edema. Mental disorders: often-feeling of fear; infrequently-visual hallucinations. From the nervous system: very often – headache; often-memory impairment, memory loss, attention disorders, restless legs syndrome; infrequently-cognitive disorders, seizures; unknown-posterior reversible encephalopathy syndrome. From the side of the reproductive system and breast: often-gynecomastia. From the cardiovascular system: very often-hot flashes, hypertension; unknown-prolongation of the QT interval. From the digestive system: unknown – nausea, vomiting. From the skin and subcutaneous tissues: often-dry skin, pruritus; unknown-rash. Musculoskeletal disorders: common-fractures; unknown-myalgia, muscle spasm, muscle weakness, back pain. Other: very often – asthenia/fatigue; often-falls.

Interaction

The enzyme CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. After oral use of the strong CYP2C8 inhibitor gemfibrozil (600 mg twice daily) in healthy male patients, the AUC of enzalutamide increased by 326%, while the Cmax of enzalutamide decreased by 18%. For the sum of unbound enzalutamide plus the unbound active metabolite, AUC increased by 77%, while Cmax decreased by 19%. During enzalutamide treatment, strong inhibitors (e. g. gemfibrozil) or inducers (e. g. rifampicin) of the CYP2C8 enzyme should be avoided or used with caution. If patients need to co-administer a strong CYP2C8 inhibitor, the enzalutamide dose should be reduced to 80 mg once daily. Enzalutamide is a powerful enzyme inducer and increases the synthesis of many enzymes and transporters, so it interacts with many conventional drugs that are enzyme substrates or transporters. A decrease in the plasma concentration may be significant and lead to a loss or decrease in the clinical effect. There is also a risk of formation of active metabolites. Enzymes that can be induced include CYP3A in the liver and intestines, CYP2C9, CYP2C19, CYP1B6, and uridine-5′ – diphosphate glucuronosyltransferase. It is also possible to induce P-glycoprotein transport protein and other transporters, as well as, for example, multi-drug resistance protein 2 (MRP2), breast cancer resistance protein (BCRP) and organic anion-transporting polypeptide 1 In 1 (OATP 1 in 1). In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Co-use of enzalutamide (160 mg 1 time / day) in patients with prostate cancer resulted in an 86% decrease in the AUC of midazolam (a CYP3A4 substrate), a 56% decrease in the AUC of S-warfarin (a CYP2C9 substrate), and a 70% decrease in the AUC of omeprazole (a CYP2C19 substrate). UGT1A1 induction is also possible. In a clinical study in patients with metastatic CRPC, Kstandi (160 mg once daily) had no clinically significant effect on the pharmacokinetics of intravenous docetaxel (75 mg/m IV every 3 weeks). The AUC of docetaxel decreased by 12% [geometric mean ratio (COR) = 0.882 (90% CI: 0.767,1.02)], while Cmax decreased by 4% [COR = 0.963 (90% CI: 0.834,1.11)]. The drug also interacts with certain drugs that are eliminated during metabolism or active transport. If their therapeutic effect is of great importance to the patient and dose adjustment based on monitoring of efficacy or plasma concentrations is not so easy, these medications should be avoided or used with caution. It is assumed that the risk of liver damage after taking paracetamol is higher in patients who were simultaneously administered enzyme inducers. The group of drugs that may interact with the drug includes:: analgesics (for example, fentanyl, tramadol); antibiotics (for example, clarithromycin, doxycycline); antitumor drugs (for example, cabazitaxel); anticoagulants (for example, acenocoumarol, warfarin); antiepileptic drugs (for example, carbamazepine, clonazepam, phenytoin, primidone, valproic acid); neuroleptics (for example, haloperidol); beta-blockers adrenoblockers (for example, bisoprolol, propranolol); calcium channel blockers (for example, diltiazem, felodipine, nicardipine, nifedipine, verapamil); cardiac glycosides (for example, digoxin); corticosteroids (for example, dexamethasone, prednisone); antiviral drugs for the treatment of HIV infection (for example, indinavir, ritonavir); hypnotics (for example, diazepam, midazolam, zolpidem); statins that are metabolized with the participation of the CYP3A4 isoenzyme (for example, atorvastatin, simvastatin); thyroid agents (for example, levothyroxine). All of the induction capabilities of enzalutamide may occur approximately 1 month after the start of treatment, after reaching a stable plasma concentration of enzalutamide, although some induction effects may become noticeable even earlier. In patients taking drugs that are substrates of the CYP2B6, CYP3A4, CYP2C9, CYP2C19 isoenzymes, as well as UGT1A1, a possible decrease in pharmacological exposure (or an increase in exposure in the case of active metabolite formation) during the first month of enzalutamide treatment should be evaluated and the dose adjusted accordingly. Given the long-term T 1/2 of enzalutamide (5.8 days), the effect on the formation of enzymes may persist for 1 month or more after discontinuation of enzalutamide use. When enzalutamide treatment is discontinued, it may be necessary to gradually reduce the dose of concomitant medications. In vitro data indicate that enzalutamide may be an inhibitor of the P-glycoprotein efflux transporter. The effect of enzalutamide on P-glycoprotein substrates in vivo has not been evaluated, but in clinical use enzalutamide can be an inducer of P-glycoprotein through activation of the nuclear pregnan receptor (pregnan-X-receptor). Drugs with a narrow therapeutic range that are substrates for P-glycoprotein (for example, colchicine, dabigatran etexylate, digoxin), when used simultaneously with Kstandi, should be used with caution, and dose adjustment may be required to maintain optimal plasma concentrations. Substrates of breast cancer resistance proteins (BCRP), multidrug resistance proteins 2 (MRP2), human organic anion transporters type 3 (OAT 3) and human organic cation transporter 1 (OT 1): based on laboratory data, inhibition of BCRP and MRP2 (in the gut), as well as human organic anion transporters type 3 (OAT 3) and human organic cation transporters 1 (OT 1) (systemic) cannot be excluded. Theoretically, the induction of these transporters is also possible, and the total effect is currently unknown. Due to the fact that androgen deprivation therapy may prolong the QT interval, the concomitant use of enzalutamide with drugs that prolong the QT interval, as well as drugs that may cause ventricular tachycardia of the “pirouette” type, including class IA antiarrhythmic drugs (for example, quinidine, disopyramide) or Class III (for example, amiodarone, sotalol, dofetilide, ibutilide), methadone should be carefully evaluated, moxifloxacin, neuroleptics.

How to take, course of use and dosage

Take orally at a dose of 160 mg 1 time/day. Drug castration using an LHRH analog should be continued during treatment in patients who have not undergone surgical castration. If a patient develops grade 3 or higher toxicity or dangerous adverse reactions, enzalutamide should be discontinued for 1 week or until symptoms decrease to grade 2 or lower, and then, if justified, resume taking the same or reduced dose (120 or 80 mg). If possible, concomitant use of strong CYP2C8 inhibitors should be avoided. If the patient must simultaneously take a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg 1 time / day. If the use of a strong inhibitor of the CYP2C8 enzyme is discontinued, the dose of enzalutamide should be increased to the initial level.

Special instructions

It should be used with caution in patients suffering from epileptic seizures or other predisposing factors, including brain injury, stroke, primary brain tumors or brain metastases, alcoholism. In addition, the risk of seizures may be increased in patients receiving concomitant therapy with medications that lower the seizure threshold. Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported with enzalutamide. Posterior reversible encephalopathy syndrome is a rare reversible neurological disorder that can be characterized by rapidly developing symptoms such as seizures, headache, confusion, blindness, and other visual and neurological disorders accompanied or unaccompanied by hypertension. The diagnosis of posterior reversible encephalopathy syndrome should be confirmed by the results of brain tomography, preferably by MRI. It is recommended to stop taking enzalutamide if the diagnosis is confirmed. Enzalutamide is a powerful inducer of enzymes and can reduce the effectiveness of many commonly used medications. Therefore, when starting treatment with enzalutamide, it is necessary to analyze the concomitant therapy. Concomitant use of enzalutamide with drugs that are sensitive substrates of many metabolizing enzymes or transporters should be avoided if their therapeutic effect is of great importance to the patient, and if it is impossible to adjust the dose based on monitoring of efficacy or plasma concentration. Concomitant use with warfarin and coumarin-like anticoagulants should be avoided. When used in combination with an anticoagulant that is metabolized by the CYP2C9 enzyme (for example, warfarin or acenocoumarol), additional MHO monitoring is required. Caution should be exercised in patients with severe renal insufficiency, as the effect of enzalutamide in this group of patients has not been studied. Caution should be exercised in patients with moderate hepatic insufficiency (Child-Pugh class B), as there are no definitive data on the use of the drug in patients with moderate hepatic insufficiency. Since there are no data on the use of enzalutamide in patients with severe hepatic insufficiency, and enzalutamide is mainly excreted through the liver, it is not recommended to use it in patients with severe hepatic insufficiency (Child-Pugh class C). In patients with an extended QT interval or predisposing factors, and in patients receiving concomitant therapy with drugs that may prolong the QT interval, the benefit-risk ratio should be evaluated before starting enzalutamide, including the possibility of ventricular tachycardia of the “pirouette”type. Concomitant use of enzalutamide does not have a clinically significant effect on the pharmacokinetics of intravenous docetaxel; however, an increase in the incidence of neutropenia caused by docetaxel cannot be excluded. Effects on the ability to drive vehicles and mechanisms Enzalutamide may have a moderate effect on the ability to drive a car and work with mechanisms, as mental and neurological disorders, including seizures, have been reported. Patients with a history of seizures or other predisposing factors should be warned about the risk of driving or operating machinery. Studies to determine the effect of enzalutamide on the ability to drive a car and work with mechanisms have not been conducted.

Active ingredient

Enzalutamide

Conditions of release from pharmacies

By prescription

Dosage form

Capsules