Kstandy (Xtandi)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Active substanceEnzalutamideEnzalutamide
Similar drugsTo uncover
  • Kstandy
    capsules inwards 
    Astellas Farma Europe BV     Netherlands
    • Dosage form: & nbsptoapsules
    Composition:

    For 1 capsule:

    Filler solution

    Active substance: enzalutamide (MDV3100) 40.0 mg;

    Excipients: caprolocaproyl macrogolglycerides 905.81 mg, butyl hydroxy anisole 0.095 mg, butyl hydroxy toluene 0.095 mg; gel weight 444.3 mg (gelatin 260.6 mg, purified water 191.7 mg, sorbitol and sorbitan solution 90.3 mg, glycerol 90.3 mg, titanium dioxide 3.10 mg); black ink - insignificant amount (ethanol anhydrous, ethyl acetate, propylene glycol, iron dye oxide black, polyvinyl acetate phthalate, purified water, isopropyl alcohol, macrogol 400, concentrated ammonia solution).

    Description:

    Opaque, oblong soft gelatin capsule from white to almost white with "ENZ"with black ink on one side.

    The contents of the capsule are an oily liquid of light yellow color.

    Pharmacotherapeutic group:Antiandrogen
    ATX: & nbsp

    L.02.B.B.04   Enzalutamide

    Pharmacodynamics:

    Mechanism of action

    Prostate cancer depends on the presence of androgens and reacts to the inhibition of androgen receptor activity. Despite the 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 the growth of tumor cells with the help of androgen receptors requires their translocation into the nucleus of the cell and binding to DNA. Enzalutamide is a potent inhibitor of androgen receptors, which blocks several stages 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 under conditions of excessive expression of androgen receptors and tumor cells resistant to antiandrogens. Treatment with enzalutamide suppresses the growth of prostate cancer cells and can induce cell death and tumor regression.

    In pre-clinical studies, enzalutamide lacked the activity of the androgen receptor agonist.

    Pharmacodynamics

    In a phase III clinical study in patients after docetaxel inefficacy, 54% of patients who received enzalutamide, compared with 1.5% of patients receiving placebo, there was at least a 50% decrease in PSA levels compared to baseline.

    Clinical efficacy and safety

    The efficacy of enzalutamide was established in two randomized, placebo-controlled, multicenter clinical trials of Phase III [CRPC2 (AFFIRM), MDV3100-03 (PREVAIL)] in patients with progressive metastatic prostate cancer, in whom progression of the disease was observed against anti-androgen therapy [with the use of the luteinizing hormone releasing hormone (LHRH) analogue or after bilateral orchiectomy]. In the study PREVAIL patients who did not receive treatment with chemotherapy participated; while in the study AFFIRM patients who had previously received chemotherapy with docetaxel were participating. All patients continued to receive LHRH analogues or underwent a bilateral orchiectomy.

    Study MDV3100-03 (PREVAIL) (patients who did not receive chemotherapy)

    1717 patients with no symptoms or with mild symptoms were randomized 1: 1 to enzalutamide groups at a dose of 160 mg once daily (N = 872) or placebo 1 time per day (N = 845).

    In a pre-planned interim analysis for overall survival, it was shown that enzalutamide treatment resulted in a statistically significant increase in overall survival compared with placebo with a 29.4% reduction in the risk of death,[Risk Ratio (RR) = 0.706 (95% CI: 0.596, 0.837), p <0.0001]. At the time of the midterm analysis, 27.6% (241 of 872) of patients in the enzalutamide group died compared to 35.4% (299 of 845) of patients in the placebo group. The estimated median overall survival was 32.4 months (95% CI: 30.1, not achieved) in the enzalutamide group and 30.2 months (95% CI: 28.0, not achieved) in the placebo group. In addition, 40% of patients in the enzalutamide group and 70% of patients in the placebo group received follow-up therapy with a proven increase in overall survival.

    A statistically significant improvement between treatment groups with a reduction in the risk of radiographic progression or death of 81.4% in the enzalutamide group was demonstrated in the planned analysis of rBPV [RR = 0.186 (95% CI: 0.149, 0.231), p <0.0001]. Progression was noted in one hundred eighteen (14%) patients in the enzalutamide group and 321 (40%) patients in the placebo group. The median of rBPV was not achieved (95% CI: 13.8, not achieved) in the enzalutamide group and was 3.9 months (95% CI: 3.7, 5.4) in the placebo group. A similar improvement in rBPV was observed among all predetermined subgroups of patients (age, initial status ECOG, baseline PSA and LDH, Gleason score at the time of diagnosis, visceral disease in screening).A statistically significant improvement between treatment groups with a reduction in the risk of radiographic progression or death of 69.3% in the enzalutamide group was demonstrated in a planned analysis of rBRS during follow-up based on radiographic progression by the investigator [OR = 0.307 (95% CI: 0.267 , 0.353), p <0.0001]. The median BPBV was 19.7 months in the enzalutamide group and 5.4 months in the placebo group.

    In addition to composite primary efficacy indicators, a statistically significant improvement was demonstrated for the following prospectively identified endpoints.

    The median time to initiation of cytotoxic chemotherapy was 28.0 months in the enzalutamide group and 10.8 months in the placebo group (RR = 0.350, 95% CI: [0.303, 0.403], p <0.0001).

    The percentage of patients in the enzalutamide group with the initially defined disease and who had an objective soft tissue response was 58.8% (95% CI: 53.8, 63.7) compared with 5.0% (95% CI: 3.0 , 7.7) patients in the placebo group. The absolute difference in the objective response from the soft tissue between the enzalutamide and placebo groups was 53.9% (95% CI: 48.5%, 59.1%, p <0.0001).A complete response was observed in 19.7% of patients in the enzalutamide group compared with 1.0% of patients in the placebo group, and a partial response was observed in 39.1% of patients in the enzalutamide group versus 3.9% of patients in the placebo group.

    Enzalutamide significantly reduced the risk of the first bone complication by 28% [RR = 0.718 (95% CI: 0.610, 0.844) p <0.0001]. In patients who received enzalutamide, a significantly higher PSA response was observed (defined as a decrease> 50% of baseline), compared with patients receiving placebo, 78.0% versus 3.5% (difference = 74.5%, p <0.0001 ).

    Median time to PSA progression by criteria PCWG2 was 11.2 months for patients in the enzalutamide group and 2.8 months for patients in the placebo group [RR = 0.169 (95% CI: 0.147, 0.195), p <0.0001].

    Treatment with enzalutamide reduced the risk of worsening on a scale FACT-Р by 37.5% compared with placebo (p <0.001). Median time to deterioration on a scale FACT-P was 11.3 months in the enzalutamide group and 5.6 months in the placebo group.

    Study CRPC2 (AFFIRM) (patients who received chemotherapy)

    The efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (CRRF) who received docetaxel and used an analogue of LHRH or had an orchiectomy, was evaluated in a randomized, placebo-controlled, multicenter clinical phase III study. 1199 patients were randomized 2: 1 to the enzalutamide group at a dose of 160 mg once daily (N = 800) or placebo 1 time per day (N = 399).

    The planned interim analysis after 520 deaths showed a statistically significant superiority in overall survival in patients who received enzalutamide, compared with patients in the placebo group: median survival of 18.4 and 13.6 months, respectively (RR = 0.631 95% CI: [0.529, 0.752], p <0.0001).

    Radiographic prognosis without progression (evaluation of researchers using criteria for evaluating the response of solid tumors to therapy (RESICT) version 1.1 for soft tissues and the appearance of 2 or more bone lesions on osteoscintigraphy) was 8.3 months in patients who received enzalutamide, and 2.9 months in patients receiving placebo (RR = 0.404, 95% CI: [0.350, 0.466], p <0.0001). The analysis included 216 deaths without documented progression and 645 documented progressions, 303 of which (47%) were associated with progression in soft tissues, 268 (42%) were due to bone metastasis progression and 74 (11%) were associated with soft tissue injury and bone tissue.A confirmed decrease in PSA levels by 50% or 90% was observed in 54.0% and 24.8% of patients who received enzalutamide, and in 1.5% and 0.9% of patients who received placebo (p <0.0001). The median time to PSA progression was 8.3 months in patients who received enzalutamide, and 3.0 months for patients in the placebo group (RR = 0.248, 95% CI: [0.204, 0.303], p <0.0001).

    The median time to the onset of the first bone complication was 16.7 months in patients who received enzalutamide, and 13.3 months in patients receiving placebo (RR = 0.688, 95% CI: [0.566, 0.835], p <0.0001). The effectiveness of enzalutamide in patients who received abiraterone, has not been studied.

    Aged people

    Of the 1671 patients receiving enzalutamide in Phase III studies, 1261 patients (75%) were 65 years of age or older and 516 patients (31%) were aged 75 years and older. These elderly patients and younger patients did not show any difference in safety and efficacy.

    Pharmacokinetics:

    Enzalutamide is poorly soluble in water. In this preparation, the solubility of enzalutamide is enhanced by the use of caprolocaproil macrogolglycerides and emulsifier / surfactant. In preclinical studies, enzalutamide absorption increased with the dissolution in caprylocaproyl macroglycerides.

    The pharmacokinetics of enzalutamide has been studied in patients with prostate cancer and in healthy volunteers. The mean half-life (T1/2) of enzalutamide in patients after a single oral intake is 5.8 days (from 2.8 to 10.2 days), and equilibrium concentration is reached after about a month. With daily oral administration enzalutamide accumulates about 8.3 times faster than a single dose. The daily fluctuations in plasma concentration are insignificant (the ratio from peak to minimum is 1.25). The excretion 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 about the same concentration as enzalutamide.

    Absorption

    The maximum concentration in plasma (CmOh) of enzalutamide in patients was observed 1-2 hours after admission. Based on the study of the mass balance in humans, absorption by oral administration of enzalutamide is estimated at at least 84.2%. Enzalutamide It is not a substrate for efflux conveyors of P-glycoprotein or BCRP. Stable level, average value of CmOh enzalutamide and its active metabolite is 16.6 pg / ml (coefficient of variation [CV] 23%) and 12.7 pg / ml (CV 30%), respectively.

    Eating does not have a significant effect on the absorption of enzalutamide. In clinical studies, Kstandi was used regardless of food intake.

    Distribution

    The average volume of enzalutamide distribution in patients after a single oral intake is 110 l (CV 29%). The volume of enzalutamide distribution is greater than the volume of the total amount of fluid in the body, indicating an active distribution in peripheral tissues. Studies on rodents have shown that enzalutamide and its active metabolite can penetrate the blood-brain barrier.

    Enzalutamide is 97-98% bound to plasma proteins, primarily with albumin. The active metabolite binds to plasma proteins by 95%. In studies in vitro there was no substitution of binding to plasma proteins between enzalutamide and other drugs with a high binding ability (warfarin, ibuprofen and salicylic acid).

    Metabolism

    Enzalutamide is actively metabolized. In the human blood plasma there are two main metabolites: N-desmethyl enzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide metabolized by enzymes CYP2C8 and, to a lesser extent, CYP3A4/5, which play an important role in the formation of an active metabolite. In the study in vitro N-desmethyl enzalutamide is metabolized to the carboxylic acid metabolite by carboxyl esterase 1, which also plays a small role in the metabolism of enzalutamide to the carboxylic acid metabolite. N-desmethyl enzalutamide not metabolized by enzymes CYP in vitro.

    In conditions of clinical use enzalutamide is a strong inducer of the enzyme CYP3A4, a moderate inducer of enzymes CYP2C9 and CYP2C19, and has no clinically significant effect on the enzyme CYP2C8.

    Excretion

    The average apparent clearance of enzalutamide in patients is between 0.520 and 0.564 l / h. When administered orally to a labeled 14C-enzalutamide, approximately 84.6% of the radioactive dose was excreted by the 77th day: 71.0% was excreted by the kidneys (primarily as an inactive metabolite with a small amount of enzalutamide and an active metabolite), and 13.6% was excreted through the intestine (0.39% dose of enzalutamide in unchanged form).

    Data from laboratory studies show that enzalutamide It is not a substratum for OATP1B1, OATP1B3 or OST1; and N-desmethyl enzalutamide is not a substrate for P-glycoprotein and BCRP.

    Data from laboratory studies show that enzalutamide and its main metabolites do not inhibit the following transporters at clinically significant concentrations: OATP1B1, OATP1B3, OST2 or OAT1.

    Linearity

    In the dose range from 40 to 160 mg, there are no serious deviations from dose proportionality. Stable level values Cmin enzalutamide and its active metabolite in individual patients remained unchanged for more than one year of prolonged therapy, demonstrating temporary linear pharmacokinetics after achieving a stable level of concentration.

    Peculiarities of pharmacokinetics in certain categories of patients

    Patients with renal insufficiency

    Studies on the use of enzalutamide in patients with renal insufficiency have not been conducted. Patients with serum creatinine> 177 μmol / l (2 mg / dL) were excluded from clinical trials. Based on the population analysis of pharmacokinetics, correction of the dose is not required for patients with creatinine clearance values> 30 ml / min (Cockcroft and Gault formula). Enzalutamide It has not been studied in patients with severe renal insufficiency (creatinine clearance <30 ml / min) or terminal stage of renal failure, therefore it is recommended to prescribe the drug with caution in the treatment of these patients. It is unlikely that enzalutamide will be significantly excreted by intermittent hemodialysis or continuous ambulatory peritoneal dialysis.

    Patients with hepatic insufficiency

    The pharmacokinetics of enzalutamide has been studied in patients with the initial lung (N = 6) or moderate (N = 8) hepatic insufficiency (classes A and B on the Child-Pugh scale, respectively) and in 14 patients from the control group with normal liver function. After a single oral intake of enzalutamide in a dose of 160 mg, the values AUC and CmOh enzalutamide in patients with mild insufficiency increased by 5% and 24%, respectively, and the values AUC and CmOh enzalutamide in patients with moderate impairment increased by 29% and decreased by 11%, respectively, compared with the control group. For the amount of unbound enzalutamide plus an unbound active metabolite, the values AUC and Cmax in patients with mild impairment increased by 14% and 19%, respectively, a AUC and CmOh in patients with moderate impairment increased by 14% and decreased by 17%, respectively, compared with the control group. However, in patients with moderate hepatic insufficiency, there was a slight deterioration in the parameters, indicating a decrease in the metabolic function (albumin, prothrombin time), and therefore it can not be excluded that this effect in patients with moderate hepatic insufficiency may be higher.

    Patients with baseline severe hepatic insufficiency (grade C on the Child-Pugh scale) were excluded from clinical trials.

    Race

    The majority of patients who participated in clinical trials (> 84%) were Europeans. According to a study of pharmacokinetics in patients with prostate cancer in Japan, there were no clinically significant differences in the pharmacokinetics between Europeans and Japanese. Data for assessing the potential differences in the pharmacokinetics of enzalutamide between other races is not enough.

    Aged people

    There was no clinically significant effect of age on the pharmacokinetics of enzalutamide.Correction of dose in the elderly is not required.

    Indications:

    Kstandy is indicated for the treatment of metastatic castration-resistant prostate cancer.

    Contraindications:

    Hypersensitivity to the active ingredient or to any of the excipients of the drug.

    Contraindicated in women and children.

    Severe liver dysfunction.

    Carefully:

    The risk of seizures

    Kestandy should be used with caution in patients suffering from epileptic seizures or other predisposing factors, including but not limited to brain trauma, stroke, primary brain tumors or brain metastases, alcoholism. In addition, the risk of seizures may be increased in patients receiving concomitant drug therapy, which reduces the convulsive threshold.

    Syndrome of posterior reversible encephalopathy

    During the use of patients Kstandi, rare reports of the development of the syndrome of the posterior reversible encephalopathy (PRES). The syndrome of a posterior reversible encephalopathy is a rare reversible neurologic disease that can be characterized by rapidly developing symptoms,such as convulsions, headache, confusion, blindness and other visual and neurological disorders, accompanied or unaccompanied by hypertension. Diagnosis of a syndrome of a posterior reversible encephalopathy should be confirmed by the results of a tomography of the brain, best of all with the results of an MRI. It is recommended to stop taking the drug Kstandi with a confirmed diagnosis.

    Simultaneous use with other drugs

    Enzalutamide is a powerful inducer of enzymes and can lead to a decrease in the effectiveness of many commonly used drugs. Therefore, starting treatment with enzalutamide, it is necessary to analyze the concomitant medications. Avoid the simultaneous application enzalutamida with drugs that are sensitive substrates many metabolizing enzymes or transporters, if the therapeutic effect is of great importance for the patient, and if, based on the control of efficiency or plasma concentration can not be corrected dose.

    Avoid simultaneous use with warfarin and coumarin-like anticoagulants. If Kstandi is used in conjunction with an anticoagulant that is metabolized by an enzyme CYP2C9 (e.g., warfarin or acenocoumarol), additional control of the international normalized relationship (INR) is required.

    Renal insufficiency

    Caution should be given to patients with severe renal failure, since the action of enzalutamide in this group of patients has not been studied.

    Liver failure

    Caution should be given to patients with moderate hepatic insufficiency (class B on the Child-Pugh scale), since there is no final data on the use of the drug in patients with moderate hepatic impairment. Since there is no data on the use of the drug in patients with severe hepatic impairment, and enzalutamide derived mainly through the liver, Kstandi is not recommended for patients with severe hepatic insufficiency (class C on the Child-Pugh scale).

    Recently suffered cardiovascular diseases

    Phase III studies did not include patients,who have recently had myocardial infarction (within the last 6 months) or who suffer from unstable angina (within the last 3 months), cardiac insufficiency of grade III or IV on the scale of the New York Heart AssociationNYHA) except for patients with a left ventricular ejection fraction (LVEF) of more than 45%, bradycardia or uncontrolled hypertension. This must be taken into account when assigning Kstandy to such patients.

    Androgen deprivation therapy can prolong the QT interval

    In patients with an elongated interval QT or with predisposing factors and in patients receiving concomitant therapy with drugs that can lengthen the interval QT, physicians before the appointment of Kstandi should assess the relationship between benefit and risk, including the possibility of ventricular tachycardia such as pirouette.

    Use with chemotherapy

    The safety and effectiveness of simultaneous application of Kstandi with cytotoxic chemotherapy has not been established. Simultaneous administration of enzalutamide does not have a clinically significant effect on the pharmacokinetics of docetaxel administered intravenously; However, an increase in the frequency of neutropenia,The use of docetaxel can not be ruled out.

    Excipients

    Kstandi contains sorbitol (E420). Patients with a rare hereditary intolerance to fructose should not take this medication.

    Pregnancy and lactation:

    Women of childbearing age

    There is no data on the use of Kstandi in women during pregnancy, and this drug is not intended for use in women of childbearing age.

    Contraception for men and women

    No data, is there enzalutamide or its metabolites in semen. If a patient has sexual contact with a pregnant woman, condom use is required during and for 3 months after treatment with enzalutamide. If a patient has sexual contact with a woman of childbearing age, a condom should be used along with other effective contraceptive methods during and for 3 months after treatment. Studies in animals showed reproductive toxicity of the drug.

    Pregnancy and lactemia

    Enzalutamide has not been studied in women. Enzalutamide contraindicated in pregnant women and women of childbearing age.

    Ability to conceive

    Studies in animals have shown that enzalutamide has an effect on the reproductive system in male rats and dogs.

    Dosing and Administration:

    Doses

    The recommended daily dose of Kstandi is 160 mg (four 40 mg capsules) once a day. Capsules should be swallowed whole, washed down with water, they can be taken regardless of food intake.

    Drug castration using the LHRH analogue should be continued during treatment in patients who have not undergone surgical castration.

    If the patient misses taking Kestandy at the usual time, the prescribed dose should be taken as close as possible to the usual time. If the patient missed taking the medication for a whole day, the treatment should be resumed the next day from the usual daily dose.

    If the patient develops toxicity of grade 3 or higher or dangerous unwanted reactions, the drug should be withdrawn for one week or until symptoms decrease to grade 2 or lower, and then, if justifiable, resume at the same or reduced dosage (120 or 80 mg).

    Simultaneous application with strong enzyme inhibitors CYP2C8

    If possible, simultaneous use of strong enzyme inhibitors should be avoided CYP2C8.If the patient must simultaneously take a strong enzyme inhibitor CYP2C8, the dose of enzalutamide should be reduced to 80 mg once a day. If the use of a strong enzyme inhibitor CYP2C8 discontinued, the dose of enzalutamide should be raised to the original level.

    Childhood

    Enzalutamide is contraindicated in children under 18 years of age.

    Side effects:

    The most frequent undesirable reactions are asthenia / fatigue, "hot flashes", headache and hypertension. Other important adverse reactions include falls, non-pathological fractures, cognitive disorders, and neutropenia.

    Seizures were observed in 0.4% of patients in the enzalutamide group and in 0.1% of patients in the placebo group.

    Below are listed and frequency-related undesirable reactions observed during clinical trials. Frequency categories are distributed as follows: very often (≥1 / 10); often (from ≥1 / 100 to <1/10); infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10,000 to <1/1, 000), very rarely (<1/10 000); unknown (can not be estimated based on available data). All adverse reactions in each group are presented in descending order of severity.

    System of organs

    Frequency

    Disturbances from the hematopoietic and lymphatic system

    infrequently: leukopenia, neutropenia

    Immune system disorders

    unknown *: swelling of the tongue, swelling of the lips, swelling of the pharynx

    Systemic disorders

    very often: asthenia / u became awn

    Mental disorders

    often: a sense of fear

    infrequently: visual hallucinations

    Disturbances from the nervous system

    very often: headache

    often: memory impairment, memory loss, attention impairment, restless leg syndrome

    infrequently: cognitive disorders, convulsions

    Unknown *: reverse reversible encephalopathy syndrome

    Disorders from the reproductive system and breast

    often: gynecomastia

    Violation of the cardiovascular system

    very often: "hot flashes", hypertension

    unknown *: interval lengthening QT

    Disorders from the gastrointestinal tract

    Unknown *: nausea, vomiting

    Disturbances from the skin and subcutaneous tissues

    often: dry skin, itchy skin

    Unknown *: rash

    Disturbances from the musculoskeletal system and connective tissue

    often: fractures **

    Unknown *: myalgia, muscle spasm, muscle weakness, back pain

    Injuries, poisoning and complications caused by the conduct of research procedures

    often: falls

    * Messages received in the postmarketing period

    ** Any fractures, with the exception of pathological

    Convulsions

    In Phase III clinical trials, seizures occurred in 7 patients (0.4%) of 1671 patients who received daily enzalutamide in a dose of 160 mg, and in 1 patient (<0.1%) who received a placebo. The dose seems to be an important predictor of the risk of seizures, as evidenced by preclinical studies and research data with increasing doses. From both studies of phase III, patients with a history of seizures or risk factors for seizures were excluded.

    In the study AFFIRM seizures were observed in six of the 800 patients (0.8%) who took 160 mg of enzalutamide daily after the chemotherapy, while patients who received placebo had no seizures. Potentially contributing factors that could increase the risk of seizures were present in some of these patients. In the study PREVAIL seizures were observed in one of 871 patients (0.1%) who did not receive chemotherapy, who took 160 mg of enzalutamide per day, and one patient (0.1%) who received a placebo.

    The mechanism by which enzalutamide can reduce the convulsive threshold, is unknown. However, it can be associated with research data in vitro, which showed that enzalutamide and its active metabolite bind and can inhibit the activity of the chlorine channels of GABA-receptors.

    Overdose:

    Antidotes of enzalutamide do not exist. In case of an overdose, treatment with enzalutamide should be discontinued and general measures taken taking into account the half-life of 5.8 days. After an overdose, patients may have an increased risk of seizures.

    Interaction:

    Inhibitors and inducers of CYP2C8

    Enzyme CYP2C8 plays an important role in the excretion of enzalutamide and in the formation of its active metabolite. After oral administration of a strong inhibitor CYP2C8 gemfibrozil (600 mg twice daily) in healthy male patients AUC Enzalutamide increased by 326%, whereas CmOh enzalutamide decreased by 18%. For the amount of unbound enzalutamide plus an unbound active metabolite, AUC increased by 77%, while Cmax decreased by 19%. During treatment with enzalutamide, strong inhibitors (eg, gemfibrozil) or inducers should be avoided (for example, rifampicin) of the enzyme CYP2C8, or apply them with caution. If patients need to use a strong inhibitor together CYP2C8, the dose of enzalutamide should be reduced to 80 mg once a day.

    Inhibitors and inducers CYP3A4

    Enzyme CYP3A4 plays an insignificant role in the metabolism of enzalutamide. After taking a strong enzyme inhibitor CYP3A4 itraconazole (200 mg once daily) by healthy volunteers, AUC Enzalutamide increased by 41%, while CmOh has not changed. For the amount of unbound enzalutamide plus an unbound active metabolite, AUC increased by 27%, while Cmax again remained unchanged. With the joint application of Kstandy with inhibitors or inducers CYP3A4 dose adjustment is not required.

    Induction of enzymes

    Enzalutamide is a potent enzyme inducer and enhances the synthesis of many enzymes and transports, so it interacts with many conventional drugs that are enzyme substrates or transports. A decrease in plasma concentration can be significant and lead to a loss or decrease in the clinical effect. There is also a risk of formation of active metabolites.To enzymes, the formation of which can be induced, include CYP3A in the liver and intestines, CYP2C9, CYP2C19, CYP1B6 and uridine-5'-diphosphate glucuronosyltransferase. It is also possible to induce the transport protein of the P-glycoprotein and other transporters, as well as, for example, the protein of multiple drug resistance 2MRP2), the protein resistance of breast cancer (BCRP) and the organic anion-transporting polypeptide 1B1 (OATP1B1). Research in vivo showed that enzalutamide is a strong inducer CYP3A4 and a moderate inductor CYP2C9 and CYP2C19. The combined use of enzalutamide (160 mg once daily) in prostate cancer patients resulted in an 86% reduction AUC midazolam (substrate CYP3A4), a 56% reduction AUC S-warfarin (substrate CYP2C9) and a 70% reduction AUC omeprazole (substrate CYP2C19). Induction is also possible UGT1A1. In a clinical trial in patients with metastatic CRIMD, the Kstandi administration (160 mg once daily) did not have a clinically significant effect on the pharmacokinetics of intravenous docetaxel (75 mg / m2 in / in every 3 weeks). AUC docetaxel decreased by 12% [geometric mean ratio (SRT) = 0.882 (90% CI: 0.776, 1.02)], whereas CmOh decreased by 4% [SRT = 0.963 (90% CI: 0.834, 1.11)].

    Also, the drug interacts with certain drugs that are excreted in the process of metabolism or active transport. If their therapeutic effect is of great importance to the patient and dose adjustment based on control of efficacy or plasma concentration is not so easy, the intake of these medicines should be avoided or applied with caution. It is suggested that, the risk of liver damage after paracetamol is higher in patients who were simultaneously injected with enzyme inducers.

    A group of drugs that can interact with the drug include, but is not limited to,:

    - Analgesics (for example, fentanyl, tramadol)

    - Antibiotics (for example, clarithromycin, doxycycline)

    - Antineoplastic agents (e.g., cabazitaxel)

    - Anticoagulants (for example, acenocoumarol, warfarin)

    - Antiepileptics (for example, carbamazepine, clonazepam, phenytoin, primidon, valproic acid)

    - Neuroleptics (for example, haloperidol)

    - Beta-blockers (for example, bisoprolol, propranolol)

    - Calcium channel blockers (eg, diltiazem, felodipine, nicardipine, nifedipine, verapamil)

    - Cardiac glycosides (for example, digoxin)

    - Corticosteroids (for example, dexamethasone, prednisolone)

    - Antiviral drugs for the treatment of HIV infection (for example, indinavir, ritonavir)

    - Sleeping pills (for example, diazepam, midazolam, zolpidem)

    - Statins metabolized with the participation of an enzyme CYP3A4 (e.g., atorvastatin, simvastatin)

    - Thyroid drugs (eg, levothyroxine)

    All induction possibilities of enzalutamide may appear approximately 1 month after the start of treatment, after achieving a stable plasma concentration of enzalutamide, although some induction effects may become noticeable earlier. In patients taking medications that are enzyme substrates CYP2B6, CYP3A4, CYP2C9, CYP2C19, or UGT1A1, the possible decrease in the pharmacological effect (or an increase in the effect in the case of the formation of active metabolites) should be evaluated during the first month of treatment with enzalutamide and the dose should be adjusted accordingly. Given the long half-life of enzalutamide (5.8 days), the effect on the formation of enzymes can persist for one month or more after discontinuing the use of enzalutamide.When discontinuing treatment with enzalutamide, it may be necessary to gradually reduce the dose of concomitant medications.

    Substrates CYP2C8

    Enzalutamide (160 mg once a day) does not cause clinically significant changes in AUC or with max pioglitazone (substrate CYP2C8). AUC pioglitazone increased by 20%, while FROMmax decreased by 18%. If the substrate CYP2C8 is used in conjunction with Kstandi, dose adjustment is not required.

    Substrates of P-glycoprotein

    Data in vitro show that enzalutamide may be an inhibitor of the efflux P-glycoprotein transporter. The effect of enzalutamide on P-glycoprotein substrates in vivo were not evaluated, however, in the clinical setting enzalutamide can be an inducer of the P-glycoprotein through the activation of the nuclear pregnan receptor (pregnan-X receptor). Drugs with a narrow therapeutic range, which are substrates for P-glycoprotein (for example, colchicine, dabigatran etexilate, digoxin), with simultaneous application with Kstandi should be used with caution, and to maintain the optimal concentration in the plasma may require dose adjustment.

    Substrates of breast cancer resistance proteins (BCRP), of multiple drug resistance proteins 2 (MRP2), transporters of organic anions of human type 3 (OAT3) and the conveyor of organic cations of man 1 (OST1)

    Based on laboratory data, inhibition can not be ruled out BCRP and MRP2 (in the intestine), as well as transporters of organic type 3 (OAT3) organic anions and human organic cation transporters 1 (OST1) (systemic). Theoretically, the induction of these transports is also possible, and the total effect is currently unknown.

    Drugs that extend the QT interval

    Due to the fact that androgen deprivation therapy can extend the interval QT, the simultaneous application of Kstandy should be carefully evaluated together with the drugs that extend the interval QT, as well as drugs that can cause the occurrence of ventricular tachycardia such as pirouettes, such as antiarrhythmic drugs of the class IA (eg, quinidine, disopyramide) or class III (for example, amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, neuroleptics, etc.

    Effect of food on the effect of enzalutamide

    The intake of food has no clinically significant effect on the degree of exposure to enzalutamide. In clinical studies, Kstandi was used regardless of food intake.

    Effect on the ability to drive transp. cf. and fur:

    Enzalutamide can have a moderate effect on the ability to drive and work with machinery, since mental and neurological disorders, including convulsions, have been reported. Patients with seizures or other predisposing factors in a history should be warned about the risks when driving or operating the mechanisms. Studies to determine the effect of enzalutamide on the ability to drive and work with mechanisms have not been conducted.

    Form release / dosage:

    Capsules, 40 mg.

    Packaging:

    For 28 capsules in a PVC / PCTFE / aluminum foil blister.

    1 blister in a cardboard box.

    On 4 cardboard cases (112 capsules) together with instructions for medical use in a cardboard bundle.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    The drug should not be used after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003605
    Date of registration:04.05.2016 / 05.06.2017
    Expiration Date:04.05.2021
    The owner of the registration certificate:Astellas Farma Europe BVAstellas Farma Europe BV Netherlands
    Manufacturer: & nbsp
    Representation: & nbspASTELLAS PHARMA YUROP BV ASTELLAS PHARMA YUROP BV Netherlands
    Information update date: & nbsp06.02.2018
    Illustrated instructions
      Instructions
      Up