Capsules soft gelatinous, opaque, oblong, from white to almost white, labeled "ENZ" with black ink on one side; the contents of the capsules are an oily liquid of light yellow color.
enzalutamide (MDV3100) 40 mg
Auxiliary substances: caprolocaproil macrogolglycerides - 905.81 mg, butylhydroxyanisole 0.095 mg, butyl hydroxytoluene 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 - 3.1 mg); black ink - insignificant amount (ethanol anhydrous, ethyl acetate, propylene glycol, iron dye oxide black, polyvinyl acetate phthalate, purified water, isopropanol, macrogol 400, concentrated ammonia solution).
28 pcs. - blisters (1) - cardboard cases (4) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
Antitumor drug, antiandrogen. 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.
In a phase III clinical study in patients after ineffectiveness of docetaxel chemotherapy, 54% of patients receiving enzalutamide, compared to 1.5% of patients receiving placebo, had at least a 50% reduction in PSA levels compared to baseline.
Clinical efficacy and safety
The efficacy of enzalutamide was established in two randomized placebo-controlled multicenter Phase III clinical trials [CRPC2 (AFFIRM), MDV3100-03 (PREVAIL)] in patients with progressive metastatic prostate cancer whose progression was observed against antiandrogen therapy (using an analog luteinizing hormone releasing hormone (LHRH) or after bilateral orchiectomy). The PREVAIL trial involved patients who were not treated with chemotherapy; while the AFFIRM study involved patients who had previously received chemotherapy with docetaxel. All patients continued to receive LHRH analogues or underwent a bilateral orchiectomy.
Study MDV3100-03 (PREVAIL) (patients who did not receive chemotherapy)
1717 patients without symptoms or with mild symptoms were randomized to 1: 1 in the enzalutamide group at a dose of 160 mg 1 time / day (n = 872) or placebo 1 time / day (n = 845).
In a pre-planned interim analysis for overall survival, it was shown that treatment with enzalutamide resulted in a statistically significant increase in overall survival compared with placebo with a 29.4% reduction in the risk of death, [hazard 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 the 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 [HR вЂ‹вЂ‹= 0.186 (95% CI: 0.149, 0.231), p <0.0001]. Progression was noted in 118 (14%) patients in the enzalutamide group and in 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, baseline status of 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 rBPV 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 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% (95% CI: 3.0, 7.7) of 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% of patients in the placebo group, a partial response was observed in 39.1% of patients in the enzalutamide group versus 3.9%) 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 receiving enzalutamide, there was a significantly higher PSA response (defined as a decrease> 50% of the baseline level), compared to patients receiving placebo, 78% versus 3.5% (difference = 74.5%, p <0.0001).
The median time to PSA progression according to PCWG2 criteria 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 the FACT-P scale by 37.5% compared with placebo (p <0.001). The median time to worsening on the FACT-P scale 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 (CRPC) who received docetaxel and used an LHRH analogue or had an orchiectomy was evaluated in a randomized, placebo-controlled, multicenter, Phase III clinical trial. 1199 patients were randomized 2: 1 to enzalutamide at a dose of 160 mg once a day (n = 800) or placebo 1 time / day (n = 399). The planned interim analysis after 520 deaths showed a statistically significant improvement in overall survival in patients receiving enzalutamide compared to placebo patients: median survival of 18.4 and 13.6 months, respectively [RR = 0.631 (95% CI: 0.529, 0.752, p <0.0001].
Radiographic progres- siveness without progression (evaluation of researchers using the criteria for evaluation of solid tumor response to therapy (RESICT) version 1.1 for soft tissues and the appearance of 2 or more osteoscintigraphy bone lesions) was 8.3 months in patients receiving 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 50% or 90% reduction in PSA was observed in 54% and 24.8% of patients who received enzalutamide, and 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 months in 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 receiving 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 receiving abiraterone has not been studied.
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 age 75 years and older. These elderly patients and younger patients did not show any difference in safety and efficacy.
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 T 1/2 of enzalutamide in patients after a single oral intake is 5.8 days (from 2.8 to 10.2 days), C ss is reached after about a month. With daily oral administration, enzalutamide cumulates 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). Enzalutamide excretion 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.
C max enzalutamide in blood plasma in patients was observed 1-2 h after administration. Based on the study of the mass balance in humans, absorption by oral administration of enzalutamide is estimated at at least 84.2%. Enzalutamide is not a substrate for efflux transporters of P-glycoprotein or BCRP. The stable level, the average C max value of 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.
The average V d of enzalutamide in patients after a single oral intake is 110 l (CV 29%). V d of enzalutamide 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 BBB.
Enzalutamide is 97-98% bound to plasma proteins, primarily with albumin. The active metabolite binds to plasma proteins by 95%. In vitro studies, there was no substitution of binding to plasma proteins between enzalutamide and other drugs with a high binding ability (warfarin, ibuprofen, and salicylic acid).
In the dose range from 40 to 160 mg, there are no serious deviations from dose proportionality. The values вЂ‹вЂ‹of the stable level of C min of enzalutamide and its active metabolite in individual patients remained unchanged for more than one year of prolonged therapy, demonstrating temporary linear pharmacokinetics after reaching a stable concentration level.
Enzalutamide is actively metabolized. There are two main metabolites in human blood plasma: N-desmethylanzalutamide (active) and a derivative of the carboxylic acid compound (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-desmethylanzalutamide 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-desmethylanzalutamide was not metabolized by CYP enzymes in vitro. Under clinical conditions, 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. Approximately 84.6% of the radioactive dose was excreted by oral administration of labeled 14C-enzalutamide: 71% by the kidneys (primarily as an inactive metabolite with an insignificant amount of enzalutamide and an active metabolite) and 13.6% through the intestine (0.39% of the enzalutamide dose in the unchanged form).
Laboratory data show that enzalutamide is not a substrate for OATP1B1, OATP1B3 or OST1; N-desmethylanzalutamide is not a substrate for P-glycoprotein and BCRP.
Laboratory data show that enzalutamide and its major metabolites do not inhibit the following transporters at clinically significant concentrations: OATP1B1, OATP1B3, OST2 or OAT1.
Pharmacokinetics in specific patient groups
Studies on the use of enzalutamide in patients with renal insufficiency have not been conducted. Patients with serum creatinine> 177 Ојmol / l (2 mg / dL) were excluded from clinical trials. Based on a population analysis of pharmacokinetics, no dose adjustment is required for patients with CC values> 30 ml / min (Cockcroft-Gault formula). Enzalutamide has not been studied in patients with severe renal insufficiency (CC <30 mL / min) or terminal stage of renal failure, therefore it is recommended to prescribe the drug with caution in the treatment of such patients. It is unlikely that enzalutamide will be significantly excreted by intermittent hemodialysis or continuous ambulatory peritoneal dialysis.
The pharmacokinetics of enzalutamide were studied in patients with initial mild (n = 6) or moderate (n = 8) hepatic insufficiency (grade A and B on the Child-Pugh scale, respectively) and in 14 patients in the control group with normal liver function. After a single oral intake of enzalutamide 160 mg, the AUC and C max of theenzalutamide in patients with mild hepatic insufficiency increased by 5% and 24%, respectively, and the values вЂ‹вЂ‹of AUC and C max of 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 unbound active metabolite, the values вЂ‹вЂ‹of AUC and C max in patients with mild impairment increased by 14% and 19%, respectively, and AUC and C max in patients with moderate impairment increased by 14% and decreased by 17% compared with the control group. However, in patients with moderate hepatic insufficiency, there was a slight deterioration in parameters indicating a decrease in 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.
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.
There was no clinically significant effect of age on the pharmacokinetics of enzalutamide. Correction of dose in elderly patients is not required.
- for the treatment of metastatic castration-resistant prostate cancer.
The drug is used inside, regardless of food intake. Capsules should be swallowed whole, washed down with water.
The recommended dose of Kstandi is 160 mg (4 capsules to 40 mg) 1 time / day.
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 has missed taking the drug during the whole day, the treatment should be resumed the following day with the usual daily dose.
If the patient develops a toxicity of grade 3 or higher or dangerous adverse reactions, the drug must cancel 1 week or until reduction of symptoms to a level of 2 degrees or less, and then, if warranted, to resume receiving in the same or a reduced dose (120 or 80 mg).
The simultaneous use of potent inhibitors of the enzyme CYP2C8
If possible, you should avoid the simultaneous use of strong inhibitors of CYP2C8. If the patient has to simultaneously receive a potent inhibitor of CYP2C8, enzalutamida dose should be reduced to 80 mg 1 time / day. If the use of strong inhibitor of CYP2C8 enzyme terminated enzalutamida dose should be raised to the initial level.
The most common adverse reactions were asthenia / fatigue, "tides", headache, and hypertension. Other important adverse reactions include falling, non-pathological fractures, cognitive disorders and neutropenia.
Convulsions have been observed in 0.4% of patients in enzalutamida group and in 0.1% of patients in the placebo group.
Below are distributed in frequency and adverse reactions observed in clinical trials. Frequency categories are distributed as follows: very common (1/10?); common (1/100 to <1/10?); infrequently (? from 1/1000 to <1/100), rarely (1/10 000 to <1/1000?), very rare (<1/10 000); not known (can not be estimated from the available data). All adverse reactions in each group are presented in order of decreasing seriousness.
From hemopoiesis system: seldom - a leukopenia, neutropenia.
Allergic reactions: unknown * - swelling of the tongue, swelling of the lips, throat swelling.
Psychiatric disorders: often - a sense of fear; rarely - visual hallucinations.
From the nervous system: very often - headache; often - memory impairment, memory loss, attention deficits, restless leg syndrome; infrequently - cognitive disorders, convulsions; * unknown - the rear reversible encephalopathy syndrome.
Reproductive system and breast: often - gynecomastia.
Cardio-vascular system: very often - hot flushes, hypertension; * Unknown - lengthening the interval QT.
From the digestive system: unknown * - nausea, vomiting.
Skin and subcutaneous tissue disorders: often - dry skin, itchy skin; * unknown - a rash.
On the part of the musculoskeletal system: often - ** fractures; * Unknown - myalgia, muscle spasm, muscle weakness, pain in the back.
Other: very often - asthenia / fatigue; often - fall.
* Communications received post-marketing period.
** Any fractures, except for pathological.
During phase III clinical studies seizures were observed in 7 patients (0.4%) of 1671 patients who took enzalutamid daily at a dose of 160 mg, and 1 patient (<0.1%) who received placebo. The dose is important predictor of the risk of seizures, as evidenced by preclinical data and research findings with increasing dose. Of both Phase III trials excluded patients with seizures in history or risk factors for seizures.
The study AFFIRM convulsions were observed in 6 out of 800 patients (0.8%) who received enzalutamid at a dose of 160 mg / day after undergoing chemotherapy while patients receiving placebo, seizures were observed. Potentially contributing factors that could increase the risk of seizures, were present in some of these patients. The study PREVAIL convulsions were observed in one out of 871 patients (0.1%) who had not received chemotherapy enzalutamid who received a dose of 160 mg / day, and 1 patient (0.1%) who received placebo.
The mechanism by which enzalutamid can reduce the seizure threshold, unknown. However, it can be associated with data from studies in vitro, we have shown that enzalutamid and its active metabolite bind to and can inhibit the activity of chloride channels GABA receptor.
- increased sensitivity to the active ingredient or any of the excipients of the formulation;
- severe hepatic impairment.
Use of the drug is contraindicated in women and children.
PREGNANCY AND LACTATION
Enzalutamid has not been studied in women. The drug is contraindicated in pregnant women and women of childbearing age.
There is no evidence whether enzalutamid or its metabolites are present in semen. If the patient has sexual intercourse with a pregnant woman during and for 3 months after treatment enzalutamidom it requires the use of a condom. If the patient has a sexual encounter with a woman of childbearing age, you must use a condom in addition to other effective contraceptive methods during and for 3 months after treatment.
Animal studies have shown reproductive toxicity of the drug.
APPLICATION FOR FUNCTIONS OF THE LIVER
Precautions should be prescribed to patients with severe renal insufficiency, because enzalutamida effect in this group of patients has not been studied.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Not use this drug in severe hepatic dysfunction.
Precautions should be prescribed to patients with moderate hepatic failure (class B Child-Pugh), because There are no final data on the use of the drug in patients with moderate hepatic insufficiency.
APPLICATION FOR CHILDREN
Enzalutamid is contraindicated in children and adolescents under the age of 18 years.
APPLICATION IN ELDERLY PATIENTS
There was no clinically meaningful effect of age on the pharmacokinetics of enzalutamida. No dose adjustment in elderly patients is not required.
The risk of seizures
Kstandi 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. Moreover, the risk of seizures may be increased in patients receiving concomitant therapy with medications that lower seizure threshold.
Syndrome rear reversible encephalopathy
In the application of patients Kstandi drug have been reported rare reports of the development of reversible encephalopathy syndrome rear (PRES). Posterior reversible encephalopathy syndrome - a rare reversible neurological disorder that can be characterized by rapidly developing symptoms, such as cramps, headache, confusion, blindness, and other visual and neurological disorders, accompanied or unaccompanied hypertension. Diagnosis rear reversible encephalopathy syndrome results must be confirmed by brain imaging, the best results of MRI. It is recommended to stop taking the drug during Kstandi confirm the diagnosis.
The simultaneous use of other drugs
Enzalutamid is a potent inducer of enzymes and may reduce the effectiveness of many commonly used drugs. Therefore, since enzalutamidom treatment, it is necessary to analyze concomitant therapy. 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 the simultaneous application with warfarin and coumarin-like anticoagulants. If Kstandi used together with an anticoagulant, which is metabolized by the enzyme CYP2C9 (such as warfarin or acenocoumarol), requires additional control of international normalized ratio (MHO).
Precautions should be prescribed to patients with severe renal failure, as enzalutamida effect in this group of patients has not been studied.
Precautions should be prescribed to patients with moderate hepatic failure (class B Child-Pugh), because There are no final data on the use of the drug in patients with moderate hepatic insufficiency. Since there is no data on the use of the drug in patients with severe hepatic insufficiency, and enzalutamid derived mainly through the liver, Kstandi not recommended for use in patients with severe hepatic insufficiency (class C by Child-Pugh).
Recently transferred cardiovascular disease
In the Phase III study did not include patients who have recently had a myocardial infarction (within the last 6 months), or suffer from unstable angina (in the last 3 months), heart failure FC III or IV on the NYHA scale except in patients with left ventricular ejection fraction (LVEF), more than 45%, bradycardia or uncontrolled hypertension. It must be taken into account when appointing Kstandi such patients.
Androgendeprivatsionnaya therapy may prolong the QT interval
In patients with the presence of long QT interval or with predisposing factors, and in patients receiving concomitant therapy with drugs that may prolong the QT interval, and the risk-benefit ratio should be assessed before prescribing Kstandi, including the possibility of ventricular tachycardia type "pirouette".
The use of chemotherapy
The safety and efficacy of the simultaneous application of Kstandi with cytotoxic chemotherapy has not been established. Simultaneous administration enzalutamida has no clinically significant effect on the pharmacokinetics of docetaxel administered in / in; However, increasing the frequency of induced neutropenia receiving docetaxel, can not be excluded.
Kstandi comprises sorbitol (E420). Patients with rare hereditary fructose intolerance should not take this drug.
studies in animals have shown that enzalutamid affects on the reproductive system in male rats and dogs.
Use in Pediatrics
Enzalutamid is contraindicated in children and adolescents under the age of 18 years.
Impact on the ability to drive vehicles and manage mechanisms
Enzalutamid may have a moderate influence on the ability to drive and use machines, since mental and neurological disorders have been reported, including seizures.Patients with seizures or other predisposing factors in history should be warned about the risk when driving or operating machinery. Studies to determine the effect of application enzalutamida driving ability and work with mechanisms not conducted.
Treatment: antidotes enzalutamida does not exist. In case of overdose, treatment should be discontinued enzalutamidom and take general measures in view of the T1/2 , constituting 5.8 days. After overdose, patients may be at increased risk of seizures.
Inhibitors and inducers of CYP2C8
enzyme CYP2C8 plays an important role in removing enzalutamida and in the formation of its active metabolite. After oral administration of strong CYP2C8 inhibitor of gemfibrozil (600 mg, 2 times / day) in healthy male patients enzalutamida AUC increased by 326%, whereas the C max enzalutamida decreased by 18%. Total amount of unbound enzalutamida plus unbound active metabolite, AUC increased by 77%, while C maxIt decreased by 19%. During treatment enzalutamidom avoid reception of strong inhibitors (e.g., gemfibrozil) or inducers (e.g. rifampicin) CYP2C8 enzyme, or use them with caution. If patients must apply together a strong inhibitor of CYP2C8, enzalutamida dose should be reduced to 80 mg 1 time / day.
Inhibitors and inducers of CYP3A4
enzyme CYP3A4 playing a minor role in the metabolism of enzalutamida. Upon receiving a strong inhibitor of CYP3A4 itraconazole (200 mg 1 time / day) to healthy volunteers enzalutamida AUC increased by 41%, while C max did not change. Total amount of unbound enzalutamida plus unbound active metabolite, AUC increased by 27%, whereas the C maxagain remained unchanged. When the joint application Kstandi inhibitors or inducers of CYP3A4 dose adjustment is required.
Enzalutamid is a potent inducer of enzymes and increases the synthesis of many enzymes and transporters, however it interacts with many common drugs which are substrates of enzymes or transporters. Reduced plasma concentrations may be significant and lead to loss or reduction of clinical effect. There is also the risk of the formation of active metabolites. For enzymes, the formation of which can be induced, are CYP3A in the liver and intestine, CYP2C9, CYP2C19, CYP1B6, and uridine-5'-difosfatglyukuronoziltransferaza. It is also possible induction transport protein P-glycoprotein and other transporters, as well as, e.g., multidrug resistance protein 2 (MRP2), protein resistance breast cancer (BCRP) and an organic anion transporting polypeptide 1B1 (OATR1V1).
The in vivo studies showed that enzalutamid is a potent inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Combined use enzalutamida (160 mg 1 time / day) in patients with prostate cancer has led to 86% decrease in AUC of midazolam (CYP3A4 substrate), 56% reduction in AUC S-warfarin (substrate CYP2C9) and 70% reduction in AUC of omeprazole (substrate CYP2C19). Induction of UGT1A1 is also possible. In a clinical study in patients with metastatic KRRPZH reception Kstandi (160 mg 1 time / day) had no clinically significant effect on the pharmacokinetics of docetaxel administered in / in (75 mg / m / every 3 weeks). Docetaxel AUC decreased by 12% [the geometric mean ratio (CDF) = 0.882 (90% CI: 0,767, 1.02)], whereas the C max is decreased by 4% [CDF = 0.963 (90% CI: 0.834, 1.11)].
Also, the drug interacts with specific drugs which are output during the metabolism or active transport. If their therapeutic effect is of great importance for the patient and a correction dose based on the control of efficiency or the plasma concentrations do not so simple, taking these drugs should be avoided or used with caution. It is assumed that the risk of liver damage after ingestion of paracetamol higher in patients who were administered simultaneously inducers of enzymes.
The group of drugs that may interact with the drug are divided into .:
- analgesics (e.g., fentanyl, tramadol);
- antibiotics (e.g., clarithromycin, doxycycline);
- antineoplastic drugs (e.g., cabazitaxel);
- anticoagulants (e.g., acenocoumarol, warfarin);
- antiepileptic agents (e.g., carbamazepine, clonazepam, phenytoin, primidone, valproic acid);
- antipsychotics (e.g. GALOPER
The information is provided for your information, do not self-medicate, it is dangerous for your health.