Adenurik - instructions for use, dose, side effects, contraindications

Active substancePhoebusostatPhoebusostat

Similar drugsTo uncover

Adenurik®

pills inwards

Berlin-Chemie, AG Germany

Azurix®

pills inwards

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Dosage form: & nbspfilm-coated tablets

Composition:

For one tablet:

Tablets, film-coated, 80 mg

Core:

Active substance: febuksostat - 80.0 mg.

Excipients: lactose monohydrate - 76.50 mg, giprolose - 12.00 mg, microcrystalline cellulose (Avicel PH101) - 129.00 mg, microcrystalline cellulose (Avicel PH 102) - 172,50 mg, croscarmellose sodium - 25,00 mg, magnesium stearate - 2,50 mg, silicon dioxide colloidal water - 2,50 mg.

Film sheath: opadraj® II yellow 85F42129, consisting of: polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, yellow iron oxide dye (E 172) 20.84 mg.

Tablets, film-coated, 120 mg

Core:

Active substance: fębuksostat - 120.0 mg.

Excipients: lactose monohydrate - 114.75 mg, giprolose - 18.00 mg, microcrystalline cellulose (Avicel PH 101) - 193.50 mg, microcrystalline cellulose (Avicel PH 102) - 258.75 mg, croscarmellose sodium - 37,50 mg, magnesium stearate - 3,75 mg, silicon dioxide colloidal water - 3,75 mg.

Film sheath: Opapray® II yellow 85F42129, consisting of: polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, dye iron oxide yellow (E 172) - 19.23 mg.

Description:

Tablets, film-coated, 80 mg

Oblong coated tablets covered with a film coating from light yellow to yellow, with an embossing of "80" on one side.

Tablets, film-coated, 120 mg

The oblong tablets are coated with a film coating from light yellow to yellow, with an embossed "120" on one side.

Pharmacotherapeutic group:Antifungal agent - xanthine oxidase inhibitor

ATX: & nbsp

M.04.A.A.03 Phoebusostat

Pharmacodynamics:

Uric acid is the final product of purine metabolism in the human body, formed as a result of the cascade of hypoxanthine-xanthine-uric acid reactions. Phoebusostat is a 2-arylthiazole derivative and is a strong selective non-purine inhibitor of xanthine oxidase (inhibition constant in vitro is less than 1 nM). The enzyme xanthine oxidase catalyzes two stages of purine metabolism: oxidation of hypoxanthine to xanthine, and then oxidation of xanthine to uric acid.

As a result of selective inhibition of phenoxostat xanthine oxidase (oxidized and reduced form), the concentration of uric acid in the blood serum decreases.

In therapeutic concentrations fębuksostat does not inhibit other enzymes involved in the metabolism of purines or pyrimidines such as guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase.

Clinical efficacy and safety profile

Gout

The efficacy and safety of the use of fequusostat has been confirmed in three basic clinical trials of phase III involving 4101 patients with hyperuricemia and gout (APEX, FACT and CONFIRMS).

In each of these studies, the use of febuuxostat resulted in a more effective decrease in the concentration of uric acid and maintenance of its serum level in comparison with allopurinol.

The primary endpoint in research APEX and FACT was the proportion of patients who had a serum uric acid concentration not exceeding 6.0 mg / dl (357 μmol / L) during the last three months. In an additional study CONFIRMS the primary endpoint was the proportion of patients whose serum uric acid concentration was less than 6.0 mg / dl at the last visit.These patients did not include patients who underwent organ transplantation.

In a double-blind, randomized, multicenter, 28-week study APEX (study of the efficacy of fequusostat in comparison with placebo and allopurinol), 1072 patients were included.

Phoebusostat was used in doses of 80 mg, 120 mg or 240 mg once daily; allopurinol - 300 mg once daily for patients with a baseline blood plasma creatinine of ≤1.5 mg / dl and a dose of 100 mg once daily for patients with a baseline plasma creatinine content> 1.5 mg / dl and ≤ 2.0 mg / dl.

The use of fobuxostat in a dose of 240 mg (twice the recommended maximum) was studied in order to assess the safety profile of fębuksostat.

When using fequusostat in doses of 80 mg and 120 mg once a day for 28 weeks, the proportion of patients who had a serum uric acid concentration of 6.0 mg / dL (357 μmol / L) during the last three months was 48% and 65%, respectively, with the use of allopurinol - 22%.

In a double-blind, randomized, multicenter 52-week study FACT (study of febuksostat in comparison with allopurinol) included 760 patients. Phoebusostat was used in doses of 80 mg or 120 mg once daily, allopurinol was used at a dose of 300 mg once a day. When using 80 mg and 120 mg of fequusostat once daily for 52 weeks, the proportion of patients who had a serum uric acid concentration of 6.0 mg / dl (357 μmol / L) during the last three months was 53% and 62%, respectively, and when using allopurinol - 21%.

The use of febuksostat led to a rapid decrease in the concentration of uric acid in the blood plasma; this effect persisted for a long time. A decrease in serum uric acid concentration of less than 6.0 mg / dL (357 μmol / L) was noted already in the second week of use (study FACT), this concentration persisted throughout the entire period of application of fequusostat.

In a randomized controlled 26-week study CONFIRMS (a study of the safety and efficacy of fequusostat in doses of 40 mg and 80 mg once daily in comparison with allopurinol at doses of 300 mg or 200 mg once a day in patients with gout and hyperuricemia) included 2,269 patients. At least 65% of patients in this study had a mild to moderate renal impairment (creatinine clearance 30-89 ml / min).

When using fequusostat in a dose of 40 mg and 80 mg, the proportion of patients who had a plasma uric acid concentration of less than 6.0 mg / dl at the last visit was 45% and 67%, respectively, for allopurinol 300 mg / 200 mg - 42 %.

Extended long-term open research

In a three-year, open, multi-center, randomized, extended safety study EXCEL with allopurinol as a comparison, 1,086 patients were included (who completed the study APEX or FACT), who took fębuksostat in a dose of 80 mg once a day, fębuksostat in a dose of 120 mg once a day; or allopurinol 300 mg (for patients with a baseline creatinine content of ≤1.5 mg / dL) and 100 mg (for patients with baseline creatinine levels> 1.5 mg / dL and ≤ 2.0 mg / dL) 1 once a day. Approximately 69% of patients did not need a dose adjustment to establish a final stable regimen.

The target level of serum uric acid concentration (less than 6.0 mg / dl) achieved with the previous use of fębuxostat has not changed over time (in 91% and 93% of patients who initially took fębuksostat in doses, respectively, of 80 mg and 120 mg, the serum uric acid concentration was less than 6.0 mg / dl at the 36th month of use).

According to three-year observation, there was a decrease in the incidence of gout attacks at 16-24 months and 30-36 months. Less than 4% of patients needed treatment for an acute attack of gout (ie, more than 96% of patients had no need to treat gout attacks). In 46% and 38% of patients who constantly took fębuksostat, respectively, in a dose of 80 and 120 mg once a day, the last visit was marked by the complete disappearance of tofus palpable at the primary visit.

In the five-year open multi-center extended security study FOCUS (Phase II) included 116 patients who received fębuksostat in a dose of 80 mg once a day for 4 weeks. In 62% of patients to maintain a target level of serum uric acid concentration less than 6.0 mg / dl, dose adjustment was not required, and 38% of patients needed a dose adjustment to reach the target level. At the last study visit, the proportion of patients with a serum uric acid concentration of less than 6.0 mg / dL (357 μmol / L) was more than 80% (81-100%) for each study dose of fecbus.

Efficacy and safety profile in patients with impaired renal function

In the study APEX Feebuxostat was used in 40 patients with impaired renal function (creatinine content> 1.5 mg / dL and ≤ 2.0 mg / dL). In patients with impaired renal function, randomized to the allopurinol group, the dose of the latter was limited to 100 mg per day. In the femuxxestat group, the primary endpoint was achieved in 44% of patients who received fębuksostat in a dose of 80 mg once a day, in 45% receiving 120 mg once a day, and in 60% receiving 240 mg once a day of patients compared to 0% in the allopurinol group (100 mg once daily) and placebo group. Clinically significant differences in the degree of decrease in serum uric acid concentration were not observed in comparison with healthy volunteers (a decrease in uric acid concentration in the group of patients with normal renal function was 58%, in the group with renal insufficiency of severe severity - 55%).

Prospective analysis in the study CONFIRMS demonstrated a significantly greater efficacy of fecuksostat in reducing serum uric acid concentrations of less than 6 mg / dl,in comparison with allopurinol in a dose of 300 mg / 200 mg in patients with gout and renal insufficiency from mild to moderate severity (the proportion of these patients in the study was 65%).

The primary endpoint in a subgroup of patients with a serum uric acid concentration of more than 10 mg / dL

The initial concentration of uric acid in the serum of more than 10 mg / dl was observed in approximately 40% of the patients included in the study APEX and FACT. Among these patients, the primary endpoint (a uric acid concentration of less than 6 mg / dl in the last 3 visits) was achieved in 41% of patients taking fębuksostat in a dose of 80 mg once a day, in 48% of patients taking fębuksostat in a dose of 120 mg once a day, and in 66% of patients receiving fębuksostat in a dose of 240 mg once a day in comparison with 9% in the allopurinol group, 300 mg / 100 mg, and 0% in the placebo group.

According to the research CONFIRMS, the proportion of patients achieving the primary endpoint of efficacy (uric acid concentration less than 6.0 mg / dl at the last visit) in the group of patients with a baseline serum uric acid concentration of more than 10 mg / dl receiving 40 mg fepuksostata once a day was 27 %,80 mg once a day - 49% and 300 mg or 200 mg of allopurinol once a day -31%.

The proportion of patients who needed treatment for an acute attack of gout

Study APEX: During the 8-week preventive period in the group of patients taking fębuksostat in a dose of 120 mg per day, in the treatment of an acute attack of gout, a large proportion of patients (36%) needed than in groups receiving fębuksostat in a dose of 80 mg (28%), allopurinol in a dose of 300 mg (23%) and in the placebo group (20%). During the preventive period, the incidence of acute gout attacks increased, subsequently decreasing over time. From 46% to 55% of patients received treatment for an acute attack of gout from the 8th to the 28th week. Acute gout attacks during the last four weeks of the study (weeks 24-28) were observed in 15% of patients in the fecbusosterata group (80 mg, 120 mg), in 14% of patients in the allopurinol group (300 mg), and in 20% of patients in the group placebo.

FACT study: During the 8-week preventive period, in the group of patients taking fębuksostat in a dose of 120 mg per day, in the treatment of an acute attack of gout, a large proportion of patients (36%) needed than in groups receiving fębuksostat in a dose of 80 mg per day (22%), allopurinol in a dose of 300 mg per day (21%). After an 8-week preventive period, the incidence of acute gout attack increased and then gradually decreased over time (64% and 70% of patients received treatment for exacerbation of gout from week 8 to week 52). Acute gout attacks during the last four weeks of the study (weeks 49-52) were observed in 6-8% of patients in the fecbusosterata group (80 mg, 120 mg) and 11% in the allopurinol group (300 mg).

Proportion of patients in need of treatment of acute gout attack (studies APEX and FACT) was numerically lower in groups where the mean serum uric acid concentration of less than 6.0 mg / dL, less than 5.0, was achieved during the last 32 weeks (periods from 20-24 weeks and from 49-52 weeks) mg / dL, or less than 0 mg / dL, compared to the group where the average serum uric acid concentration was greater than 6.0 mg / dl.

During the study CONFIRMS the proportion of patients requiring treatment for an acute attack of gout (from the first day to the sixth month) was 31% and 25% in the 80 mg fbuxostat group and the allopurinol group 200/300 mg, respectively. In the 80 mg fębuksostata and fębuksostat groups, 40 mg of the difference between the proportions of patients requiring treatment for an acute attack of gout was not observed.

Tumor decay syndrome

The effectiveness and safety of the use of fequusostat for the prevention and treatment of tumor disintegration syndrome were studied in a randomized, double-blind phase III trial - FLORENCE. Phoebusostat demonstrated a more powerful and rapid decrease in the concentration of uric acid in the blood serum compared with allopurinol in the absence of a negative effect on kidney function.

The study included 346 patients with hemoblastosis who underwent cytostatic therapy and who had a risk of developing a moderate to high tumor disintegration syndrome. Patients were taking fębuksostat in a dose of 120 mg once a day or allopurinol 200-600 mg per day in order to assess the ability of fębukstat to maintain the concentration of uric acid in the blood serum and assess the effect of fębukstat on the function of the kidneys. Patients who meet the criteria for inclusion in the study should have been candidates for allopurinol treatment or had no opportunity to be treated by swaburicase.

The primary endpoints were: the area under the concentration-time curve (AUC) of uric acid in the serum and changes in serum creatinine for 8 days.

The mean value of the area under the concentration-time curve was statistically significantly lower in the feybuxostat group than in the allopurinol group.

The average concentration of uric acid in the serum 24 hours after the start of the use of fequusostat and in all subsequent measurements was significantly lower than in the allopurinol group.

There were no statistically significant differences in the effect of febuuxostat and allopurinol on creatinine levels in blood plasma.

The frequency of development of the tumor disintegration syndrome with the use of febuksostat and allopurinol did not differ statistically either by the criteria of laboratory diagnosis or by clinical criteria.

The incidence of drug-related effects and incidence of adverse reactions was 67.6% compared to 64.7%, and 6.4%, versus 6.4% in the fobuxostat group and allopurinol group, respectively.

In the study FLORENCE in patients who planned to use allopurinol, fębuksostat showed more pronounced control over the concentration of uric acid in the blood serum in comparison with allopurinol. Data allowing you to compare fębuksostat with the Razburikaze, is currently not available.

The efficacy and safety of febuksostat in patients with acute disintegration syndrome of a severe disease (for example, in patients in which other regimens aimed at reducing the concentration of uric acid proved to be ineffective) has not been studied.

Pharmacokinetics:

The population analysis of pharmacokinetics and pharmacodynamics included data obtained in a study involving 211 patients with hyper-urekemia and gout and who received fębuksostat in a dose of 40-240 mg once a day. The obtained pharmacokinetic parameters of fequusostat were comparable to those of healthy volunteers, which allows to consider the data of studies of pharmacokinetics and fakamakodynamics with the participation of healthy volunteers, representative of the population of patients with gout.

Suction

After oral administration fębuksostat quickly and almost completely (at least 84% of the dose) is absorbed from the gastrointestinal tract. With multiple admission fębuksostata in a dose of 80 mg or a single dose of 120 mg at the same time with the intake of fatty foods the maximum concentration of fecuksostata in the blood plasma (C_mOh) decreased by 49% and 38%, respectively, a AUC - by 18% and 16%, respectively. However, this did not affect the clinical efficacy of reducing the concentration of uric acid in the blood serum (with repeated intake of fequusostat at a dose of 80 mg), in connection with this fębuksostat can be taken regardless of food intake.

C_max is achieved through 1.0-1.5 hours after ingestion and is 2.8-3.2 μg / ml with a single oral dose of 80 mg and 5.0-5.3 μg / ml with a single dose of 120 mg. Absolute bioavailability of fepuksostata in the form of tablets has not been studied.

With repeated intake of fębuksostat in doses of 10 mg - 240 mg once a day, cumulation was not noted.

Linearity / Nonlinearity of Pharmacokinetics

In healthy volunteers with a single or multiple oral administration fecbusostat C_max and AUC increase linearly with increasing dose in the range of 10 mg up to 120 mg, and in the dose range from 120 mg to 300 mg there is an increase AUC more than a proportionate dose.

Distribution

Apparent volume of distribution in the equilibrium state varies from 29 liters to 75 liters after oral administration of 10-300 mg of fepuksostat. The degree of binding to plasma proteins (mainly with albumin) reaches 99.2%,and does not change when the dose increases from 80 mg to 120 mg. For active metabolites, the degree of binding to plasma proteins varies from 82% to 91%.

Metabolism

Phaebusostat is metabolized by conjugation with the participation of uridine diphosphate glucuronyltransferase (UDPGT) and oxidation involving enzymes of the cytochrome P450 system (CYP). Four pharmacologically active hydroxyl metabolites were isolated, of which three are found in human blood plasma. In studies in vitro on microsomes of human liver it was shown that oxidized metabolites are formed mainly under the influence of isozymes CYP1A1, CYP1A2, CYP2C8 or CYP2C9, whereas febuksostata glukuronid formed mainly under the influence of isozymes UGT 1A1, UGT 1A8 and UGT 1A9.

Allocation

Phaebuxostat and its metabolites are excreted from the body through the intestines and kidneys.

After taking the fetus of fecuksostat, labeled with a radioisotope ¹⁴C in a dose of 80 mg, about 49% is secreted by the kidneys: unchanged, about 3%, in the form of acylglucuronide - 30%, in the form of oxidized metabolites and their conjugates - 13%, in the form of other metabolites - 3%.

Approximately 45% of fębuxostat is excreted through the intestine: in the form of unchanged fębuksostat - 12%, acylglucuronide - 1%,oxidized metabolites and their conjugates - 25%, other metabolites - 7%. The apparent half-life of febuksostat (T_1/2) is 5-8 hours.

Pharmacokinetics in special groups

Patients with renal insufficiency

With repeated intake of fębuksostat in a dose of 80 mg in patients with renal insufficiency of mild, moderate or severe severity, C_mOh compared with healthy volunteers did not change. In patients with severe renal insufficiency, the mean total AUC ffuksostat increased approximately 1.8 times - (13.2 μg / ml) compared to healthy volunteers (7.5 μg h / ml); FROM_mOh and AUC pharmacologically active metabolites of fepuksostat increased 2 and 4 times, respectively. Thus, in patients with mild or moderate renal insufficiency, dose adjustment is not required.

Patients with hepatic insufficiency

With repeated intake of fequusostat in a dose of 80 mg, there were no significant changes in the C_mOh and AUC fabuksostata and its metabolites in patients with hepatic insufficiency is mild (class A on the Child-Pugh scale: 5-6 points) and average (grade B on the Child-Pugh scale: 7-9 points) of severity compared to healthy volunteers.Studies of the pharmacokinetics of febuksostat in patients with hepatic insufficiency of severe severity (class C on the Child-Pugh scale: 10-15 points) were not conducted.

Elderly age

With repeated intake of fębuksostat, there were no significant changes in the interior AUC fabuksostata and its metabolites in elderly patients in comparison with young healthy volunteers.

Floor

With repeated intake of fequusostat inside C_mOh and AUC femuxosterate in women were, respectively, 24% and 12% higher than men. However, the C_mOh and AUC, corrected for the patient's body weight, were similar for both groups. Thus, dose adjustment is not required depending on the patient's sex.

Indications:

Chronic hyperuricemia with conditions, accompanied by the deposition of urate crystals (in the presence of tofus and / or gouty arthritis, including in the anamnesis).

Treatment and prophylaxis of hyperuricemia in adult patients with cytostatic therapy of hemoblastoses with the risk of development of the syndrome of the disintegration of the tumor from moderate to high (only for a dosage of 120 mg).

Adenurik® is intended for use in adults.

Contraindications:- PAn increased sensitivity to feguksostat and / or any of the excipients;

- children's age till 18 years;

- pregnancy and the period of breastfeeding;

- hereditary intolerance to galactose, a deficiency of lactase and a syndrome of malabsorption of glucose and galactose.

Carefully:

- Renal failure of severe severity (creatinine clearance <30 mL / min) (efficacy and safety not adequately studied);

- liver failure;

- allergic reactions in the anamnesis;

- cardiac ischemia;

- congestive heart failure;

- Thyroid gland diseases;

- simultaneous use with mercaptopurine / azathioprine (possibly increasing the concentration of these substances in blood plasma and increasing their toxicity);

- state after organ transplantation (experience with the use of fequusostat is limited);

- Lesha-Nihan syndrome (experience of using fębuksostat is limited).

Pregnancy and lactation:

In connection with the lack of data, the potential risk of fębuksostata for a person is not known, so the use of fębuksostat during pregnancy is contraindicated.There is limited experience with the use of fębuksostat during pregnancy, during which no adverse effects on the course of pregnancy and the condition of the fetus / newborn have been observed. In animal studies, there was no direct or indirect adverse effect of the drug on the course of pregnancy, embryo / fetus development, and the birth process.

There is no data on whether the fębuksostat in breast milk. In animal studies, it was noted that fębuksostat penetrates into breast milk and has an adverse effect on the development of feeding young. Thus, it is impossible to exclude the risk for infants. In this regard, the use of fębuksostat is contraindicated in the period of breastfeeding.

Dosing and Administration:

Inside. The drug Adenurik® is taken once a day, regardless of food intake.

Gout

The recommended initial dose is 80 mg fepuksostata once a day.

After 2-4 weeks it is recommended to control the concentration of uric acid in the blood serum; if the indicator exceeds 6 mg / dl (357 μmol / l), the dose of the drug can be increased to 120 mg once a day.

Reducing the concentration of uric acid in the blood serum against the background of the Adenurik® drug is quite fast, and therefore control of the concentration of uric acid can be carried out two weeks after the start of the drug. The goal of the treatment is to reduce and maintain a serum uric acid concentration of less than 6 mg / dL (357 μmol / L).

Preventing the development of acute gout attacks is recommended for at least 6 months.

Tumor decay syndrome

The recommended dose is 120 mg fepuksostata once a day, regardless of food intake. Adenurik® should be taken two days before the start of cytostatic therapy. The duration of application of Adenurik® should not be less than 7 days. Depending on the duration of the course of chemotherapy, the duration of Adenurik® can be increased up to 9 days.

Elderly patients

Correction of the dose is not required.

Patients with hepatic insufficiency

Gout

In patients with mild hepatic insufficiency (grade A on the Child-Pugh scale: 5-6 points), the recommended dose of the drug is 80 mg once a day.The experience of using the drug for hepatic insufficiency of moderate severity is limited.

Tumor decay syndrome

In the study FLORENCE correction of the dose of fequusostat in dependence on liver function was not required (patients with hepatic insufficiency of severe severity were not included in the study).

Studies of the efficacy and safety of the use of fequusostat in patients with hepatic insufficiency of severe severity (class C on the Child-Pugh scale: 10-15 points) were not conducted.

Patients with renal insufficiency

In patients with mild to moderate renal insufficiency, dose adjustment is not required.

In patients with severe renal insufficiency (creatinine clearance <30 ml / min), the efficacy and safety of the drug have not been adequately studied.

Side effects:

Taking into account the different nature of the gout and the tumor disintegration syndrome, the side effects with the use of fequusostat under given action nosologies are presented separately.

Gout

The most common side effects in patients with gout with the use of fequusostat according to the results of clinical studies (4,072 patients taking fębuksostat in a dose of 10 mg to 300 mg) and according to post-marketing surveillance were: a gout attack, a violation of liver function, diarrhea, headache, nausea, skin rash and swelling. In most cases, these phenomena were characterized by mild or moderate severity. During the postmarketing period, rare cases of development of hypersensitivity reactions fębuksostat, accompanied in some cases by systemic symptoms.

Possible side effects are given below in accordance with the classification of the World Health Organization according to the descending frequency of occurrence: very often (≥1 / 10); often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000), very rarely (<1/10000), including individual message.

The frequency of side effects is based on the data of clinical studies and the post-marketing experience of the use of fequusostat.

On the part of the blood and lymphatic system

Rarely: pancytopenia, thrombocytopenia.

From the immune system

Rarely: anaphylactic reactions *, hypersensitivity reactions *.

From the nervous system

Often: headache;

Infrequently: dizziness, paresthesia, hemiparesis, drowsiness, change in taste perception, hypostasis, hyposmia (weakening of smell).

From the endocrine system

Infrequently: an increase in the concentration of thyroid-stimulating hormone (TSH) in the blood plasma.

From the side of metabolism and nutrition

Often: bouts of gout ***;

Infrequently: diabetes mellitus, hyperlipidemia, decreased appetite, weight gain;

Rarely: weight loss, increased appetite, anorexia.

From the side of the psyche

Infrequently: decreased libido, insomnia;

Rarely: nervousness.

From the side of the organ of vision

Rarely: blurred vision.

From the side of the hearing organ and labyrinthine disorders

Rarely: noises in the ears.

From the heart

Infrequently: atrial fibrillation, palpitations, ECG changes, left bundle branch blockade (see "Tumor disintegration syndrome"), sinus tachycardia (see "Tumor disintegration syndrome").

From the side of the vessels

Infrequently: increased blood pressure, "flushes" of blood to the face, a sensation of fever, hemorrhage (see "Tumor Disintegration Syndrome").

On the part of the respiratory system, the organs of the thorax and the mediastinum

Infrequently: dyspnea, bronchitis, upper respiratory tract infection, cough, chest pain, discomfort in the chest.

From the side of the digestive tract

Often: diarrhea **, nausea;

Infrequently: abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dryness of the oral mucosa, dyspeptic phenomena, constipation, rapid stools, flatulence, abdominal discomfort;

Rarely: pancreatitis, ulcerative stomatitis.

From the liver and biliary tract

Often: impaired liver function **;

Infrequently: cholelithiasis;

Rarely: hepatitis, jaundice *, liver damage *.

From the skin and subcutaneous tissues

Often: skin rash (including various types of rashes, mentioned below with a lower frequency);

Infrequently: dermatitis, urticaria, skin itching, discoloration, skin lesions, petechiae, macular rash, maculopapular rash, papular rash;

Rarely: toxicodermal necrolysis *, Stevens-Johnson syndrome *, angioedema, * drug reaction with eosinophilia and systemic symptoms * (see "Special instructions"), severe forms of generalized rash *, erythema, exfoliative rash,follicular rash, vesicular rash, pustular rash, itching rash *, erythematous rash, korepodobnaya rash, alopecia, hyperhidrosis.

From the side of the musculoskeletal system

Infrequently: arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle spasm, muscle tension, bursitis;

Rarely: rhabdomyolysis *, joint stiffness, stiffness of muscles.

Disorders from the kidneys and urinary tract

Infrequently: renal failure, nephrolithiasis, hematuria, pollakiuria, proteinuria;

Rarely: tubulointerstitialnyj a nephritis *, imperative desires on an emiction.

From the side of the reproductive system

Infrequently: erectile disfunction.

General disorders

Often: edema;

Infrequently: increased fatigue;

Rarely: thirst.

Impact on the results of laboratory and instrumental studies

Infrequently: an increase in the activity of amylase in the blood plasma, a decrease in the number of platelets, a decrease in the number of leukocytes, a decrease in the number of lymphocytes, an increase in creatine and creatinine in the blood plasma, a decrease in hemoglobin, an increase in the concentration of urea in the blood plasma, an increase in the concentration of triglycerides in the blood plasma,an increase in the concentration of cholesterol in the blood plasma, a decrease in hematocrit, an increase in lactate dehydrogenase activity in the blood plasma, an increase in the potassium content in the blood plasma.

Rarely: an increase in the concentration of glucose in the blood plasma, prolongation of activated partial thromboplastin time, a decrease in the number of red blood cells, an increase in the activity of alkaline phosphatase in the blood plasma.

* Side effects observed during post-marketing surveillance.

** Noninfectious diarrhea and liver disorders observed in Phase III studies were more common with concurrent use of colchicine.

*** Further information on the development of acute gout attacks in the section "Special instructions".

Description of individual side effects

In the postmarketing period, there have been rare reports of severe allergic reactions (hypersensitivity reactions), including Stevens-Johnson syndrome, toxicodermal necrolysis, anaphylactic reactions, and shock.

Stevens-Johnson syndrome and toxicodermal necrolysis are characterized by the onset of progressive skin rash in combination with bullous skin lesionsor mucous membranes, as well as eye irritation.

Hypersensitivity reactions to fębuksostat can also be manifested by the following symptoms: skin reactions characterized by infiltrative maculopapular rashes; generalized or exfoliative rash, as well as skin lesions, face swelling, fever, hematopoiesis disorders such as thrombocytopenia and eosinophilia, and involvement of one or more organs (liver and kidneys, including tubulointerstitial nephritis).

Attacks of gout are usually observed soon after the start of the Adenurik® and during the first months of therapy. In the following, the frequency of attacks decreases. It is recommended to prevent the development of acute attacks of gout.

Tumor decay syndrome

In the study FLORENCE Side effects were noted in 22 patients (6.4%). In both groups (the fobusostat group and the allopurinol group), the incidence of side effects was the same (11 patients, 6.4%). In most cases, adverse events were characterized by mild or moderate severity. In general, with the exception of three side effects indicated below based on the results of the study FLORENCE, no specific features of the safety profile of fębuksostat in addition to that of gout were noted.

From the heart

Infrequently: blockage of the left leg of the bundle of the Guiss, sinus tachycardia.

From the side of the vessels

Infrequently: hemorrhages (see the section "Tumor Disintegration Syndrome").

Overdose:

When an overdose of the drug shows symptomatic and supportive therapy.

Symptoms: increased side effects.

Interaction:

Mercaptopurine / azathioprine

Simultaneous use with mercaptopurine, azathioprine is not recommended, because the inhibition of xanthine oxidase by fobuxostat may lead to an increase in the concentration of mercaptopurine, azathioprine in the blood plasma, and an increase in their toxic effect. Studies on the study of the interaction of fepuksostata and substances metabolized with xanthine oxidase were not carried out.

Cytotoxic agents

Studies on the study of the drug interaction between febuuxostat and cytotoxic drugs have not been conducted. In the study FLORENCE Febuksostat in a dose of 120 mg was used in the syndrome of tumor disintegration in patients undergoing cytotoxic therapy of various kinds (including, monoclonal antibody therapy).Nevertheless, since no studies have been conducted to study the drug interaction between febuuxostat and cytotoxic drugs, the potential interaction of febuksostat with concomitantly used cytotoxic chemotherapy drugs can not be ruled out.

Rosiglitazone / isoenzymatic substrates CYP2C8

According to in vitro Fębuksostat is a weak isoenzyme inhibitor CYP2C8. In healthy volunteers with the simultaneous use of 120 mg fepuksostata 1 time per day and a single dose of 4 mg rosiglitazona changes in pharmacokinetic indices of rosiglitazone and its metabolite N-disubstituted rosiglitazone was not observed, which indicates the lack of properties of the inhibitor of isoenzyme in ferbuxostat CYP2C8 in vivo. With the simultaneous use of fequusostat and rosiglitazone (or other isoenzyme substrates CYP2C8) dose adjustment is not required.

Theophylline

With the use of other inhibitors of xanthioxidase simultaneously with theophylline, an increase in the concentration of theophylline in the blood plasma was noted. With the simultaneous use in healthy volunteers feybuxostat in a dose of 80 mg 1 time per day and a single dose of theophylline 400 mg changes in pharmacokinetic parameters or the tolerability of theophylline was not observed,thus, while the application febuxostat 80 mg of theophylline and special precautionary measures are required. The study of simultaneous application of febuksostat in a dose of 120 mg and theophylline was not carried out.

Naproxen and other glucuronization inhibitors

Metabolism febuxostat depends on the activity of the enzyme uridindifosfatglyukuroniltransferazy (UDFGT). Drugs that suppress the process of glucuronization, for example, non-steroidal anti-inflammatory drugs (NSAIDs) and probenicides, can affect the excretion of fequusostat. In healthy volunteers, concomitant use of fepuksostat and naproxen 250 mg twice daily increased the C_mOhffuksostata by 28%, AUC - by 41% and T_1/2 - by 26%. In clinical trials, concomitant use of febuuxostat and naproxen or other NSAIDs / COX-2 inhibitors has not been associated with a clinically significant increase in incidence of side effects. Correction of the dose with the simultaneous use of fequusostat and naproxen is not required.

Glucuronization Inductors

With the simultaneous use of fequusostat with strong inducers Glucuronization may increase its metabolism and decrease efficiency. With simultaneous use, it is necessary to control the concentration of uric acid in the blood serum 1-2 weeks after the initiation of therapy. If the glucuronization inducer is canceled, an increase in C_mOh fequusostat. Colchicine / indomethacin / hydrochlorothiazide / warfarin

Phoebusostat can be used concurrently with colchicine or indomethacin without dose adjustment.

Also, correction of the dose of fequusostat without simultaneous application with hydrochlorothiazide is not required.

The simultaneous use of febuksostat (80 mg or 120 mg once daily) with warfarin does not affect the pharmacokinetics of warfarin, INR (international normalized ratio) and factor VII activity in healthy volunteers. With the simultaneous use of fequusostat with warfarin, correction of the dose of warfarin is not required.

Desipramine / isoenzymatic substrates CYP2D6

According to the data received in vitro, fębuksostat is a weak isoenzyme inhibitor CYP2D6. In a study in healthy volunteers, when febuxostat was used at a dose of 120 mg once a day, there was an increase AUC desipramine (substrate isoenzyme CYP2D6) by 22%, which indicates a weak inhibitory effect of fepuksostata on isoenzyme CYP2D6 in vivo. Thus, with the simultaneous use of feybuxostat and isoenzyme substrates CYP2D6 dose adjustment is not required.

Antacids

When used simultaneously with antacids, containing magnesium hydroxide or aluminum hydroxide, there is a decrease in absorption of fębukstat (approximately 1 hour) and a decrease in C_mOh by 32%, however AUC feybuxostat did not change significantly. In this way, fębuksostat can be taken concomitantly with antacids.

Special instructions:

Acute attack of gout

The use of Adenurik® should be started only after the acute gout attack has been stopped. Initiation of Adenurik® can provoke the development of an acute attack of gout due to the release of urates from the tissue depots and the subsequent increase in the concentration of uric acid in the blood serum.

For the prevention of gout attacks in the absence of contraindications, simultaneous use of NSAIDs or colchicine is recommended for at least 6 months.

When the attack develops against the background of the Adenurik® drug, the drug should be continued and simultaneously treated appropriately with an acute attack of gout.With prolonged use of Adenuric®, the incidence and severity of gout attacks decrease.

Xanthine deposition

In rare cases, in patients with accelerated urate formation (for example, against a background of malignant neoplasms or with Lesch-Nihan syndrome), a significant increase in the absolute concentration of xanthines in urine is possible, which may be accompanied by their deposition in the urinary tract. When using Febuksostat in the study FLORENCE in patients with the syndrome of tumor disintegration this phenomenon was not observed. Due to limited data, the use of Adenurik® in patients with Lesh-Nihan syndrome is not recommended.

Mercaptopurine / azathioprine

Simultaneous use with mercaptopurine, azathioprine is not recommended. In case of simultaneous use, a reduction in the dose of mercaptopurine / azathioprine and careful medical observation are recommended to reduce the toxic effect on the hematopoiesis system.

Theophylline

With the simultaneous use in healthy volunteers feybuxostat at a dose of 80 mg once a day and a single dose of theophylline 400 mg, there were no changes in pharmacokinetic parameters.Thus, the simultaneous administration of febuuxostat in a dose of 80 mg and theophylline does not pose a risk of increasing the concentration of theophylline in the blood plasma. The study of simultaneous application of febuksostat in a dose of 120 mg and theophylline was not carried out.

Patients who underwent organ transplantation

The use of Adenurik® in patients who have undergone organ transplantation is not recommended due to lack of experience.

Allergic reactions and hypersensitivity reactions

In most cases, these reactions developed during the first month of application of Adenurik®. Some patients had a history of renal insufficiency and / or hypersensitivity reactions against allopurinol.

In some cases, severe hypersensitivity reactions, including the drug reaction syndrome with eosinophilia and systemic symptoms (DRESS), accompanied by fever, changes in blood levels, impaired liver or kidney function.

Patients should be informed of the possible signs and symptoms of allergic reactions (hypersensitivity reactions), and should be carefully monitored for the development of symptoms of allergic reactions / hypersensitivity reactions.

In case of severe allergic reactions / hypersensitivity reactions, including Stevens-Johnson syndrome, Adenurik® should be discontinued immediately (earlier cancellation is associated with a better prognosis). Repeated use of the drug is not recommended.

Cardiovascular diseases

Adenurik® is not recommended in patients with coronary artery disease or congestive heart failure.

In studies APEX and FACT (in contrast to the study CONFIRMS) in the total group of fecuksostat in comparison with the group of allopurinol, there was an increase in the number of cardiovascular disorders determined according to the system developed by the group for joint analysis of antiplatelet therapy (GAAAT) and including death from cardiovascular causes, non-lethal heart attack myocardium,stroke without a fatal outcome) - 1.3 compared with 0.3 cases per 100 patient-years. According to the combined data of Phase III clinical trials (studies APEX, FACT and CONFIRMS), the incidence of cardiovascular disorders was 0.7 compared with a frequency of 0.6 cases per 100 patient-years.

In the framework of long-term large-scale studies, the frequency of cardiovascular disorders of GAAAT was 1.2 and 0.6 cases per 100 patient-years for febuuxostat and allopurinol, respectively. The differences were not statistically significant, the causal relationship between these disorders and the use of fębukstat was not established. As a risk factor for the development of these events, patients had a history of the following conditions: atherosclerosis and / or myocardial infarction, or congestive heart failure.

Prophylaxis and treatment of hyperuricemia in patients at risk of developing the tumor disintegration syndrome

In patients receiving cytostatic therapy of hemoblastoses with the risk of developing a moderate to severe tumor disintegration syndrome, the use of Adenurik® in the presence of indications should be performed under the supervision of a cardiologist. Diseases of the liver

According to the combined data of phase III clinical trials, fecal anemia of 5% of patients showed mild liver function disorders.

Prior to the appointment of Adenurik®, it is recommended that an evaluation of liver function be performed, and in the presence of indications, also during application.

Thyroid gland diseases

AT extended long-term open studies with prolonged use febuxostat in 5.5% of patients had increased concentration of thyroid stimulating hormone (> 5.5 mkIE / ml), in connection with which patients with thyroid dysfunction Adenurik® drug should be used with caution.

Adenurik® drug contains lactose, therefore its use in patients with lactase deficiency, a hereditary intolerance to lactose, a syndrome of glucose-galactose malabsorption contraindicated.

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

Before the drug Adenurik® may cause drowsiness, dizziness, blurred vision, and paraesthesia and as a consequence, reduction reaction and the ability to concentrate,therefore, during the use of Adenurik®, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Film-coated tablets, 80 mg and 120 mg.

Packaging:

For 14 tablets in a contour mesh package (blister) made of PVC / Aklar / aluminum foil.

For 2, 4 or 6 blisters with instructions for use in a cardboard pack.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep the medicinal product out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003746

Date of registration:20.07.2016

Expiration Date:20.07.2021

The owner of the registration certificate:Berlin-Chemie, AGBerlin-Chemie, AG Germany

Manufacturer: & nbsp

MENARINI-VON HEYDEN, GmbH Germany

Representation: & nbspBERLIN-CHEMI / MENARINI PHARMA GmbH BERLIN-CHEMI / MENARINI PHARMA GmbH Germany

Information update date: & nbsp04.02.2017

Illustrated instructions

Instructions

Adenurik® (Adenuric®)