Xtandi. Instructions for use

Release form, composition and packaging

Available in capsule form.

For 1 capsule:

active substance:

enzalutamide (MDV3100) 40.0 mg;

Excipients

Mechanism of action

Prostate cancer is androgen dependent and responds to androgen receptor downregulation. Despite low or even undetectable levels of androgens in the blood plasma, the activity of androgen receptors on tumor cells continues to contribute to the progression of the disease. Stimulation of tumor cell growth using androgen receptors requires their translocation into the cell nucleus and binding to DNA. Enzalutamide is a potent androgen receptor inhibitor that blocks multiple steps of the androgen receptor signaling pathway. Enzalutamide competitively inhibits the binding of androgens to androgen receptors, inhibits the 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 inhibits the growth of prostate tumor cells and may induce cell death and tumor regression.

Xtandi instructions for use

ingredient : enzalutamide; 1 capsule contains enzalutamide 40 mg excipients: caprylocaproyl macrogolglycerides, butylated hydroxyanisole (E 320), butylated hydroxytoluene (E 321), shell: gelatin, sorbitol-sorbitan solution, glycerin, titanium dioxide (E 171), printing ink. Dosage form Capsules.

Basic physical and chemical properties: capsules are soft, opaque, oblong, white or almost white, marked “ENZ” in black.

Pharmacological group Antiandrogens. ATX code L02BB04.

Pharmacological properties Pharmacological. Mechanism of action. The development of malignant prostate tumors depends on the presence of androgens and responds to the suppression of the activity of androgen receptors on tumor cells. Despite low or very low levels of androgens in the blood plasma, undetectable, the activity of androgen receptors on tumor cells continues to contribute to the progression of the disease. Stimulation of tumor cell growth using androgen receptors requires their translocation into the cell nucleus and binding to DNA. Enzalutamide is a potent androgen receptor inhibitor that blocks multiple steps of the androgen receptor signaling pathway. Enzalutamide competitively inhibits the binding of androgens to androgen receptors, inhibits the 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 inhibits prostate tumor cell growth and may induce cell death and tumor regression. In preclinical studies, enzalutamide lacked androgen receptor agonist activity.

Pharmacodynamic properties During a phase III clinical trial involving patients who had failed chemotherapy with docetaxel, 54% of patients receiving enzalutamide and 1.5% of patients receiving placebo experienced at least a 50% decrease in PSA levels compared to baseline.

Clinical efficacy and safety The efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer treated with docetaxel and a gonadotropin-releasing hormone (GnRH) analogue or undergoing orchiectomy was assessed in a randomized, placebo-controlled, multicenter, phase III clinical trial. The majority of patients (91.2%) had bone metastases, and 23.2% had visceral lesions of the lungs and/or liver. At study entry, 41% of patients had PSA-only progression, whereas 59% of patients had radiographic disease progression. The study showed a statistically significant benefit in overall survival for patients receiving enzalutamide compared to patients in the placebo group (median survival of 18.4 and 13.6 months, respectively). In addition to the improvement in overall survival, enzalutamide was supported by key secondary endpoints (PSA progression, radiographic progression-free survival, and time to first bone disease) that were statistically significantly different from placebo. Confirmed PSA reductions of 50% or 90% were observed in 54.0% and 24.8% of patients receiving enzalutamide and in 1.5% and 0.9% of patients receiving placebo (p < 0.0001). The median time to PSA progression was 8.3 months in patients treated with enzalutamide and 3 months in patients treated with placebo (p < 0.0001).

Pharmacokinetics The pharmacokinetics of enzalutamide have been studied in patients with prostate cancer and in healthy volunteers. The half-life (T 1/2) of enzalutamide in patients after a single oral dose is 5.8 days (from 2.8 to 10.2 days), and equilibrium concentration is reached after about a month. Enzalutamide is eliminated primarily by hepatic metabolism to an active metabolite that is as active as enzalutamide and circulates in the blood plasma at the same concentration as enzalutamide. Absorption The maximum plasma concentration (Cmax) of enzalutamide in patients was observed 1-2 hours after administration. Absorption after oral administration of enzalutamide was estimated at a minimum of 84.2%. Food intake does not have a significant effect on the extent of absorption of enzalutamide. In clinical studies, Xtandi was administered without regard to food intake. Distribution The average volume of distribution of enzalutamide in patients after a single oral dose is 110 L. The volume of distribution of enzalutamide is greater than the volume of total body fluid, indicating active distribution in peripheral tissues. Enzalutamide is 97-98% bound to plasma proteins, primarily albumin. The active metabolite is 95% bound to plasma proteins. Metabolism In human blood plasma there are two main metabolites N-desmethyl enzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide is metabolized by CYP2C8 and to a lesser extent CYP3A4/5 enzymes, which play an important role in the formation of the active metabolite. 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. Conclusion The average clearance of enzalutamide in patients ranges from 0.520 and 0.564 L/hour. When 14C-labeled-enzalutamide was administered orally, approximately 84.6% of the radioactive dose was excreted 71 by the kidneys (primarily as an inactive metabolite with minor amounts of enzalutamide and active metabolite) and 13.6% was excreted through the intestines (0.39% of the enzalutamide dose in unchanged). Renal impairment No studies have been conducted on the use of enzalutamide in patients with renal impairment. Patients with serum creatinine levels >177 µmol/L (2 mg/dL) were excluded from clinical studies. For patients with creatinine clearance ≥ 30 ml/min, no dose adjustment is required. The effectiveness of enzalutamide has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease, so caution should be exercised when treating these patients. Hepatic Impairment The pharmacokinetics of enzalutamide were studied in patients with moderate hepatic impairment (N = 6) or moderate hepatic impairment (N = (Child-Pugh A and B, respectively) and in 14 control patients with normal liver function. After a single dose oral administration of enzalutamide at a dose of 160 mg, the AUC and Cmax of enzalutamide in patients with moderate hepatic impairment increased by 5% and 24%, respectively, and the AUC and Cmax of enzalutamide in patients with moderate impairment increased by 29% and decreased by 11%, respectively. compared with controls. Patients with baseline severe hepatic impairment (Child-Pugh class C) were excluded from clinical studies. Race. Most patients in clinical studies (>92%) were Caucasian, so no conclusions can be drawn about the effect race on the pharmacokinetics of enzalutamide Elderly patients: There was NO clinically significant effect of age on the pharmacokinetics of enzalutamide.

Indications: Xtandi is indicated for the treatment of metastatic castration-resistant prostate cancer in adult men whose disease has progressed during or after chemotherapy including docetaxel.

Contraindications Hypersensitivity to the active substance or to any of the excipients. Interactions with other drugs Medicines that may affect enzalutamide levels. CYP2C8 inhibitors and inducers The CYP2C8 enzyme plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Following administration of gemfibrozil, a potent CYP2C8 inhibitor (600 mg twice daily), in healthy male volunteers, the AUC of enzalutamide increased by 326% and the Cmax of enzalutamide decreased by 18%. For the sum of unbound enzalutamide and unbound active metabolite, the AUC increased by 77% and the Cmax decreased by 19%. Concomitant use of enzalutamide with strong CYP2C8 inhibitors (e.g. gemfibrozil) or CYP2C8 inducers (e.g. rifampicin) should be avoided or used with caution. . If a patient must be co-administered with a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily (see Dosage and Administration). CYP3A4 inhibitors and inducers The CYP3A4 enzyme plays a minor role in the metabolism of enzalutamide. Following oral administration of the potent CYP3A4 inhibitor itraconazole (200 mg once daily) to healthy male volunteers, the AUC of enzalutamide increased by 41%, while the Cmax did not change. For the sum of unbound enzalutamide and unbound active metabolite, the AUC increased by 27%, while Cmax remained unchanged. When using the drug Xtandi simultaneously with inhibitors or inducers of CYP3A4, no dose adjustment is necessary. Effect of enzalutamide on other drugs. Enzyme inducers. Enzalutamide is a potent enzyme inducer that increases the synthesis of many enzymes and transporters, and interactions with numerous drugs that are substrates of enzymes or transporters are expected. The decrease in plasma concentrations may be significant and lead to loss or reduction of clinical effect. There is also a risk of formation of active metabolites. The liver and intestinal enzymes CYP3A, CYP2C9, CYP2C19, CYP1A2 and uridine-5-diphosphate glucuronosyltransferase (UGT-glucuronide conjugation enzymes) may be induced. Induction of the transport protein P-glycoprotein and other transporters, such as multidrug resistance protein 2 (MRP2), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1), are also possible. In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Concomitant use of enzalutamide (160 mg once daily) in patients with prostate cancer resulted in an 86% reduction in the AUC of midazolam (a CYP3A4 substrate), a 56% reduction in the AUC of S-warfarin (a CYP2C9 substrate), and a 56% reduction in the AUC of omeprazole (a CYP2C9 substrate). CYP2C19) by 70%. Induction of UGT1A1 may also be noted. Interactions with the following drugs are also expected and are eliminated through metabolism or active transport. Concomitant use of these drugs should be avoided or used with caution if the therapeutic effect of these drugs is of great importance to the patient and it is difficult to make dose adjustments based on monitoring of efficacy or blood concentrations. Drugs that may interact with this drug include, but are not limited to: Analgesics (e.g. fentanyl, tramadol) Antibiotics (e.g. clarithromycin, doxycycline) Antineoplastic drugs (e.g. cabazitaxel) Anticoagulants (e.g. acenocoumarol, warfarin) Antiepileptic drugs (e.g. e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid) Antipsychotics (e.g. haloperidol) Beta blockers (e.g. bisoprolol, propranolol) Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil) Cardiac glycosides (e.g. digoxin) Corticosteroids (e.g. eg dexamethasone, prednisolone) Antiviral medicines for the treatment of HIV infection (eg indinavir, ritonavir) Hypnotic medicines (eg diazepam, midazolam, zolpidem) Statins that are metabolized by the enzyme CYP3A4 (eg atorvastatin, simvastatin) Thyroid medicines (eg levothyroxine). The induction properties of enzalutamide may occur 1 month after the start of treatment after stable plasma concentrations of enzalutamide have been achieved, although some induction effects may occur earlier. The possible decrease in pharmacological effect (or increase in effect in the case of formation of active metabolites) should be assessed during the first month of treatment with enzalutamide and dose adjustments should be made accordingly. Given the long half-life of enzalutamide (5.8 days, see section "Dosage and Administration"), the effect on enzymes may persist for a month or more after discontinuation of enzalutamide. When stopping enzalutamide, it may be necessary to reduce the dose of the medication. P-glycoprotein substrates In vitro data indicate that enzalutamide may be an inhibitor of the P-glycoprotein efflux transporter. The effects of enzalutamide on P-glycoprotein substrates have NOT been evaluated in vivo, but in clinical use, enzalutamide may be an inducer of P-glycoprotein through activation of the nuclear pregnane receptor (PXR). Drugs with a narrow therapeutic index that are substrates for P-glycoprotein (e.g. colchicine, dabigatrate etexilate, digoxin) should be used with caution when co-administered with Xtandi, and dosage adjustments may be necessary to maintain optimal plasma concentrations. Substrates of breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), human organic anion transporter type 3 (OAT3), and human organic cation transporter 1 (OCT1) Inhibition of BCRP and MRP2 cannot be ruled out based on laboratory data. (in the intestine), as well as human organic anion transporter type 3 (OAT3) and human organic cation transporter 1 (OCT1) (systemic). Induction of these transporters is theoretically possible; the net effect is currently unknown. Effect of food on enzalutamide exposure. There is no clinically determined effect of food on enzalutamide. During clinical studies, Xtandi was administered without regard to meals.

Features of use Risk of developing seizures. Xtandi should be used with caution in patients with a history of seizures or other factors contributing to the development of seizures (including, but not limited to, the following factors: brain injury, stroke, primary brain tumors or brain metastases, alcoholism). In addition, the risk of developing seizures may be increased in patients receiving therapy with drugs that lower the seizure threshold. Concomitant use with other drugs. Enzalutamide is a potent enzyme inducer and can reduce the effectiveness of many drugs and is often used (see section "Interaction with other drugs and other types of interactions"). Therefore, before starting the use of enzalutamide, it is necessary to conduct an analysis of drugs that are simultaneously used with enzalutamide. Concomitant use of enzalutamide with drugs that are sensitive substrates of many enzyme or transporter symbionts should be avoided (see Section "Interaction with other drugs and other types of interactions") if their therapeutic effect is very important to the patient and if it is difficult to adjust the dose based on monitoring effectiveness or blood concentration levels. The simultaneous use of warfarin and coumarin-like anticoagulants should be avoided. When using Xtandi simultaneously with anticoagulants that are metabolized by CYP2C9 (such as warfarin or acenocoumarol), the international normalized ratio (INR) should be additionally monitored (see Section “Interaction with other drugs and other types of interactions”) "). Renal failure The effectiveness of enzalutamide has not been studied in patients with severe renal failure, so the drug is prescribed with caution when treating these patients. Liver failure Caution should be exercised in patients with moderate liver failure (class according to the Child-Pugh classification), since there are no definitive data on the use of the drug in such patients (see Section “Famacokinetics”). Xtandi is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C), since there are no data on the use of enzalutamide in such patients and given the fact that enzalutamide is primarily eliminated by the liver. Recent cardiovascular disease. The AFFIRM study did not include patients with recent myocardial infarction (within the past 6 months) or unstable angina (within the past 3 months), patients with New York Heart Association (NYHA) class III-IV heart failure, with the exception of patients with left ventricular ejection fraction (LVEF) ≥ 45%, prolonged QT interval, QTcF > 470 mc, bradycardia or uncontrolled hypertension. These data should be taken into account when prescribing Xtandi. Concomitant use with chemotherapy. The safety and effectiveness of concomitant use of Xtandi with cytotoxic chemotherapy have not been evaluated. Excipients. Xtandi contains sorbitol (E 420). Patients with rare congenital fructose intolerance should not take this drug. Use during pregnancy or breastfeeding. The drug is not indicated for use in women. Contraception for men and women It is not known whether enzalutamide or its metabolites are present in semen. If the patient has sexual relations with a pregnant woman, condoms should be used during treatment with enzalutamide and for 3 months after stopping treatment with enzalutamide. If the patient has sexual intercourse with a woman of reproductive age, condoms and other methods of contraception should be used during treatment and for 3 months after discontinuation of enzalutamide. Animal studies show the presence of reproductive toxicity.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Since mental and neurological disorders, including seizures, have been observed with the use of enzalutamide, enzalutamide may have a moderate effect on the ability to drive a car or operate other machinery (see section "Adverse Reactions"). Patients with a history of seizures or other factors contributing to the development of seizures (see Section “Peculiarities of Application”) should be warned about the possible risks when driving a car or working with machinery. Studies have not been conducted to evaluate the effect of enzalutamide on the ability to drive vehicles or use other machinery.

Method of administration and dosage The recommended daily dose is 160 mg (4 capsules of 40 mg each) 1 time per day. Capsules should be swallowed whole with water and can be used regardless of meals. If the patient misses taking Xtandi at the usual time, the prescribed dose should be taken as soon as possible at the usual time. If the patient misses taking the drug for a whole day, treatment should be resumed the next day at the usual daily dose. If a patient develops grade 3 or higher toxicity (≥ Grade 3) or dangerous adverse reactions, the drug should be discontinued for one week or until symptoms resolve to grade 2 toxicity or lower, and then, if warranted, restarted at the same time. or in a reduced dose (120 or 80 mg). Concomitant use with strong inhibitors of the CYP2C8 enzyme. If possible, concomitant use of strong CYP2C8 enzyme inhibitors should be avoided. If the patient must simultaneously take a strong CYP2C8 enzyme inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily. If use of a strong CYP2C8 enzyme inhibitor is discontinued, the dose of enzalutamide should be increased to the initial level (see Section "Interactions with other medicinal products and other types of interactions"). Elderly patients. There is no need for dose adjustment for elderly patients. Hepatic impairment No dose adjustment is necessary for patients with moderate hepatic impairment (Child-Pugh Class A). Caution is recommended in patients with moderate hepatic impairment (Child-Pugh class B). Xtandi is not recommended for patients with severe hepatic impairment (Child-Pugh class C). Kidney failure. There is no need for dose adjustment for patients with moderate or moderate renal impairment. Caution should be exercised in patients with severe renal failure or end-stage renal failure (see section "Peculiarities of Application"). Children. Enzalutamide is contraindicated in children (under 18 years of age).

Overdose There is no antidote for enzalutamide. Treatment with enzalutamide should be discontinued in case of overdose and appropriate measures taken, given that the half-life is 5.8 days. In case of overdose, patients may be at increased risk of seizures.

Adverse reactions Overall safety profile. In a placebo-controlled phase III trial (AFFIRM), patients with metastatic castration-resistant prostate cancer treated with docetaxel were treated with enzalutamide 160 mg daily (N = 800) versus placebo (N = 399). The mean duration of treatment with enzalutamide was 8.3 months, compared with 3 months for placebo. Patients were allowed, but not required, to take prednisolone. Seizures occurred in 0.8% of patients receiving enzalutamide. The most common adverse reactions were hot flashes and headache. The following are the adverse reactions, distributed by frequency: very often (≥ 1/10); often (from ≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000). Adverse reactions in each group are presented in descending order of severity. Body system according to the MEDDRA classification Very often Often Not often Blood Neutropenia Leukopenia Psychiatric Visual hallucinations, anxiety Nervous system Headache Cognitive disorders, memory impairment Convulsions, amnesia, attention disorders Vascular hot flashes Arterial hypertension Skin and subcutaneous fiber Dry skin, itching Musculoskeletal system Fractures * Injuries, poisonings, and procedure-related complications Falls * Includes all fractures except pathologic fractures Seizures During the phase III AFFIRM study, seizures were reported in 6 of 800 patients (0.8% ) receiving 160 mg enzalutamide per day, whereas patients receiving placebo did not experience seizures. Potential contributing factors that could increase the risk of seizures existed in some patients. The AFFIRM study excluded patients with a history of seizures or risk factors for seizures. An important predictor of the risk of seizures is dose, as evidenced by data from preclinical studies and data from dose escalation studies. The mechanism through which enzalutamide may lower the seizure threshold is unknown, but data obtained from an in vitro study indicate that enzalutamide and its active metabolites bind to and may inhibit the activity of GAMMA chloride channels.

Shelf life: 2 years.

Storage conditions Store at a temperature not exceeding 30 ° C

Packaging 28 capsules in a blister, 1 blister in a cardboard case; 4 cardboard cases in a cardboard pack.

Vacation category: Prescription.

Manufacturer Astellas Pharma Europe B.V., the Netherlands / Astellas Pharma Europe BV, the Netherlands.

Manufacturer's address Hogemaat 2, 7942 IP Meppel, the Netherlands / Hogemaat 2, 7942 JG Meppel, the Netherlands.

Applicant Astellas Pharma Europe B.V., the Netherlands Astellas Pharma Europe BV, the Netherlands

Contraindications

- Hypersensitivity to the active component or to any of the excipients of the drug;

— contraindicated for women and children;

- severe liver dysfunction.

Carefully:

Risk of developing seizures.

Xtandi should be used with caution in patients with epileptic seizures or other predisposing factors, including brain injury, stroke, primary brain tumors or brain metastases, and alcoholism.

Kidney failure.

Caution should be used in patients with severe renal impairment, since the effect of enzalutamide in this group of patients has not been studied.

Liver failure.

Since there are no definitive data on the use of the drug in patients with hepatic impairment, caution should be used in patients with moderate hepatic impairment (Child-Pugh class B) and is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C). .

Excipients.

Xtandi contains sorbitol (E420). Patients with rare hereditary fructose intolerance should not take this drug.

Directions for use and doses

The recommended daily dose of Xtandi is 160 mg (four 40 mg capsules) once a day. The capsules should be swallowed whole with water and can be taken with or without food.

If the patient misses an appointment

Xtandi at the usual time, the prescribed dose should be taken as close to the usual time as possible. If the patient misses taking the drug for a whole day, treatment should be resumed the next day with the usual daily dose.

If the patient develops toxicity

Grade 3 or higher or serious adverse reactions, the drug should be discontinued for one week or until symptoms decrease to grade 2 or lower, and then, if warranted, resumed at the same or reduced dosage (120 or 80 mg).

Childhood.

Enzalutamide is contraindicated in children under 18 years of age.

Side effect

Taking Xtandi may cause side effects of varying severity. This warning should be taken seriously and information should be provided to the attending physician about intolerance to medicinal components or sudden deterioration in health.

Enzalutamide may cause:

headaches, weakness;
seizures, joint and muscle pain;
painful sensations in the back;
insomnia, anxiety, dizziness;
burning or numbness under the skin;
fatigue, drowsiness;
redness of the skin, swelling of the legs and arms;
cold symptoms (runny nose, sore throat, sneezing);
feeling that the body is engulfed in heat.

Xtandi should be stopped immediately if you experience loss of bowel and bladder control, difficulty walking, blood in the urine, a significant increase in blood pressure, or swelling of the lips, tongue or throat.

The doctor prescribes the drug, and he also decides to interrupt treatment if the patient feels unwell and the harm from taking the drug outweighs the benefit.

Side effects

The most common adverse reactions are convulsions, asthenia/fatigue, hot flashes, headache and hypertension. Other important adverse reactions include falls, nonpathologic fractures, cognitive impairment, and neutropenia.

Effect on the ability to drive a vehicle.

Enzalutamide may have a moderate effect on the ability to drive and use machines, as psychiatric and neurological disturbances, including seizures, have been reported. Patients with a history of seizures or other predisposing factors should be warned about the risks when driving or operating machinery.

Overdose

There are no antidotes for enzalutamide. In case of overdose, treatment with enzalutamide should be stopped and general measures taken, taking into account the half-life of 5.8 days. After overdose, patients may be at increased risk of developing seizures.

Interaction

Enzalutamide is a potent enzyme inducer and may reduce the effectiveness of many commonly used medications. Therefore, when starting treatment with enzalutamide, it is necessary to analyze concomitant medications. The simultaneous 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 also if it is not possible to adjust the dose based on monitoring of efficacy or plasma concentrations.

Combination with other drugs

Xtandi is taken cautiously with other drugs, inhibitors and inducers. During treatment with the drug, it is not recommended to use carbamazepine, rifabutin, rifampicin, phenytoin, phenobarbital.

Taking St. John's wort reduces the effectiveness of Enzalutamide. If taking strong inducers cannot be avoided, then the dose of Xtandi is increased. The drug reduces the effect on the body of midazolam, omeprazole, warfarin, cyclosporine, quinidine, sirolimus, ergotamine and other drugs.

You should consult your doctor and inform about the medications you are taking.