Adenuric pills 80mg, 28pcs

Composition

Core:

Active ingredient:

febuxostat – 80.0 mg.

Auxiliary substances:

lactose monohydrate – 76.50 mg,

hyprolose-12.00 mg,

microcrystalline cellulose (Avicel PH 101) – 129.00 mg,

microcrystalline cellulose ( Avicel PH 102) – 172.50 mg,

croscarmellose sodium-25.00 mg,

magnesium stearate-2.50 mg,

colloidal water silicon dioxide-2.50 mg.

Film shell:

opadray ® II yellow 85 F 42129, consisting of: polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, yellow iron oxide dye (E 172) – 20.84 mg

Pharmacological action

Anti-gouty agent-xanthine oxidase inhibitorpharmacodynamicamoic acid is the end product of purine metabolism in the human body, formed as a result of a cascade of hypoxanthine-xanthine-uric acid reactions. Febuxostat is a derivative of 2-arylthiazole and is a highly selective non-purine xanthine oxidase inhibitor (the in vitro inhibition constant is less than 1 nM). The enzyme xanthine oxidase catalyzes two stages of purine metabolism: the oxidation of hypoxanthine to xanthine, and then the oxidation of xanthine to uric acid. As a result of selective inhibition of xanthine oxidase by febuxostat (oxidized and reduced forms), the concentration of uric acid in the blood serum decreases. At therapeutic concentrations, febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, such as guanindesaminase, hypoxanthinguanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase. Clinical efficacy and safety Profile The efficacy and safety of febuxostat was confirmed in three baseline phase III clinical trials involving 4,101 patients with hyperuricemia and gout (APEX, FACT, and CONFIRMS). In each of these studies, the use of febuxostat resulted in a more effective reduction of uric acid concentration and maintenance of its serum level compared to allopurinol. The primary endpoint in the APEX and FACT studies was the proportion of patients whose serum uric acid concentrations did not exceed 6.0 mg/dl (357 mmol/L) over the past three months. In the additional CONFIRMS study, 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 studies did not include patients who had undergone organ transplantation. 1072 patients were enrolled in the double-blind, randomized, multicenter,28-week APEX trial (evaluating the efficacy of febuxostat versus placebo and allopurinol). Febuxostat was administered at doses of 80 mg,120 mg, or 240 mg once daily; allopurinol was administered at a dose of 300 mg once daily in patients with baseline plasma creatinine <1.5 mg / dl and 100 mg once daily in patients with baseline plasma creatinine > 1.5 mg / dl and < 2.0 mg / dl. The use of febuxostat at a dose of 240 mg (twice the recommended maximum) was studied to assess the safety profile of febuxostat. When using febuxostat at doses of 80 mg and 120 mg once a day for 28 weeks, the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg/dl (357 mmol/l) in the last three months was 48% and 65%, respectively, when using allopurinol – 22%. The double-blind, randomized, multicenter,52-week FACT study (febuxostat versus allopurinol) included 760 patients. Febuxostat was used in doses of 80 mg or 120 mg once a day, allopurinol was used in a dose of 300 mg once a day. When using febuxostat 80 mg and 120 mg once a day for 52 weeks, the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg/dl (357 mmol/l) in the last three months was 53% and 62%, respectively, and when using allopurinol – 21%. The use of febuxostat led to a rapid decrease in the concentration of uric acid in blood plasma; this effect persisted for a long time. A decrease in serum uric acid concentration of less than 6.0 mg / dl (357 mmol/L) was noted as early as the second week of use (FACT study ), and this concentration was maintained throughout the entire period of use of febuxostat. The 26-week randomized controlled trial CONFIRMS (a study of the safety and efficacy of febuxostat 40 mg and 80 mg once daily versus allopurinol 300 mg or 200 mg once daily in patients with gout and hyperuricemia) included 2,269 patients. At least 65% of patients in this study had mild to moderate renal impairment (creatinine clearance 30-89 ml / min). When using febuxostat at a dose of 40 mg and 80 mg, the proportion of patients whose plasma uric acid concentrations were 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-label studiesin a three-year open-label, multicenter, randomized, extended-release EXCEL safety trial with allopurinol as a comparison included 1,086 patients (who completed the APEX or FACT study) who received febuxostat 80 mg once daily, febuxostat 120 mg once daily; or allopurinol 300 mg (for patients with baseline plasma creatinine < 1.5 mg/dl) and 100 mg (for patients with baseline creatinine in blood plasma >1.5 mg/dl and ≤2.0 mg/dl) 1 time per day. Approximately 69% of patients did not need a dose adjustment to establish a final stable regimen. The target level of uric acid concentration in the blood serum (less than 6.0 dl) achieved with the previous use of febuxostat did not change over time (in 91% and 93% of patients who initially took febuxostat at doses of 80 mg/ mg and 120 mg, respectively, the concentration of uric acid in the blood serum was less than 6.0 mg/dl at the 36th month of use). According to a three-year follow-up, 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 (i. e., more than 96% of patients did not need treatment for gout attacks). In 46% and 38% of patients who were constantly taking febuxostat, respectively, at a dose of 80 and 120 mg once a day, by the last visit, complete disappearance of tophi palpable at the initial visit was noted. The five-year open-label multicenter extended safety study FOCUS (Phase II) included 116 patients who initially received febuxostat 80 mg once daily for 4 weeks. In 62% of patients, no dose adjustment was required to maintain the target serum uric acid concentration of less than 6.0 mg/dl, and 38% of patients needed a dose adjustment to reach the target level. At the last visit of the study, the proportion of patients whose serum uric acid concentration was less than 6.0 mg / dl (357 mmol/L) was more than 80% (81-100%) for each study dose of febuxostat. Efficacy and safety profile in patients with impaired renal function In the APEX study, febuxostat was used in 40 patients with impaired renal function (with creatinine >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 febuxostat group, the primary endpoint was reached in 44% of patients receiving febuxostat 80 mg once daily,45% receiving 120 mg once daily, and 60% receiving 240 mg once daily, compared to 0% in the allopurinol group (100 mg once daily) and placebo groups. There were no clinically significant differences in the degree of decrease in the concentration of uric acid in the blood serum compared with healthy volunteers (a decrease in the concentration of uric acid in the group of patients with normal renal function was 58%, in the group with severe renal insufficiency – 55%). A prospective analysis in the CONFIRMS study showed significantly greater efficacy of febuxostat in reducing serum uric acid concentrations below 6 mg / dl, compared with allopurinol at a dose of 300 mg / 200 mg in patients with gout and mild to moderate renal insufficiency (the proportion of these patients in the study was 65%). The primary endpoint in the subgroup of patients with a serum uric acid concentration greater than 10 mg / dl, the initial serum uric acid concentration greater than 10 mg / dl was observed in approximately 40% of patients included in the APEX and FACT studies. Among these patients, the primary endpoint (uric acid concentration less than 6 mg / dl in the last 3 visits) was achieved in 41% of patients taking febuxostat 80 mg once daily,48% of patients taking febuxostat 120 mg once daily, and 66% of patients taking febuxostat 240 mg once daily, compared to 9% in the allopurinol 300 mg /100 mg group and 0% in the placebo group.According to the CONFIRMS study, the proportion of patients who achieved the primary efficacy endpoint (uric acid concentration less than 6.0 mg/dl at the last visit) in the group of patients with an initial serum uric acid concentration of more than 10 mg/dl who received 40 mg of febuxostat once a day was 27%,80 mg once a day – 49% and 300 mg or 200 mg of allopurinol once a day-31%. Proportion of patients who needed treatment for an acute gout attack APEX study : During the 8-week prevention period, a larger proportion of patients (36%) needed treatment for an acute gout attack in the group of patients taking febuxostat at a dose of 120 mg per day than in the groups taking febuxostat at a dose of 80 mg (28%), allopurinol at 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. Between 46% and 55% of patients received treatment for an acute attack of gout from week 8 to 28. Acute gout attacks during the last four weeks of the study (weeks 24-28) were observed in 15% of patients in the febuxostat group (80 mg,120 mg), in 14% of patients in the allopurinol group (300 mg), and in 20% of patients in the placebo group. FACT study: During the 8-week prevention period, a larger proportion of patients (36%) who received febuxostat 120 mg / day needed treatment for an acute attack of gout than those who received febuxostat 80 mg / day (22%) and allopurinol 300 mg / day (21%). After the 8-week prevention period, the incidence of acute gout attack increased and then gradually decreased over time (64% and 70% of patients received treatment for gout exacerbation from week 8 to 52). Acute gout attacks during the last four weeks of the study (weeks 49-52) were observed in 6-8% of patients in the febuxostat group (80 mg,120 mg), and in 11% of patients in the allopurinol group (300 mg). The proportion of patients requiring treatment for an acute attack of gout (APEX and FACT studies) was numerically lower in the groups where the average serum uric acid concentration was less than 6.0 mg/dl, less than 5.0 mg/dl, or less than 0 mg/dl during the last 32 weeks (periods from 20-24 weeks and from 49-52 weeks), compared to the group where the average serum uric acid concentration was more than 6.0 mg/dl. In the CONFIRMS study, the proportion of patients requiring treatment for an acute attack of gout (from day one to month six) was 31% and 25% in the febuxostat 80 mg group and the allopurinol 200/300 mg group, respectively. In the febuxostat 80 mg and febuxostat 40 mg groups, there were no differences between the proportions of patients requiring treatment for an acute gout attack. Tumor breakdown syndrome The efficacy and safety of febuxostat for the prevention and treatment of tumor breakdown syndrome were studied in a randomized, double – blind, phase III trial-FLORENCE. Febuxostat showed a more powerful and rapid decrease in the concentration of uric acid in the blood serum compared to allopurinol in the absence of a negative effect on kidney function. The study included 346 patients with hemoblastosis who received cytostatic therapy and who had a moderate to high risk of developing tumor collapse syndrome. Patients received febuxostat 120 mg once daily or allopurinol 200-600 mg daily to evaluate the ability of febuxostat to maintain serum uric acid concentrations and evaluate the effect of febuxostat on renal function. Patients who met the criteria for inclusion in the study had to be candidates for allopurinol treatment or did not have the opportunity to be treated with rasburicase. The primary endpoints were: the area under the concentration-time curve ( AUC ) of uric acid in the blood serum and the change in serum creatinine content over 8 days. The mean area under the concentration-time curve was significantly lower in the febuxostat group than in the allopurinol group. The mean serum uric acid concentration 24 hours after the start of febuxostat and all subsequent measurements was significantly lower than in the allopurinol group. There were no statistically significant differences in the effect of febuxostat and allopurinol on plasma creatinine. The incidence of tumor disintegration syndrome when using febuxostat and allopurinol did not statistically differ either by laboratory diagnostic criteria or by clinical criteria. The incidence of drug-related effects and the incidence of adverse reactions were 67.6% vs. 64.7%, and 6.4% vs. 6.4% in the febuxostat group and the allopurinol group, respectively. In the FLORENCE study, febuxostat showed more pronounced control over serum uric acid concentrations in patients who were scheduled to receive allopurinol compared to allopurinol. There are currently no data available to compare febuxostat with rasburicase. The efficacy and safety of febuxostat in patients with severe acute tumor collapse syndrome (for example, in patients whose other treatment regimens aimed at reducing uric acid concentrations were ineffective) have not been studied. Pharmacokinetics A population – based analysis of pharmacokinetics and pharmacodynamics included data from a study involving 211 patients with hyperuricemia and gout who received febuxostat at a dose of 40-240 mg once a day. The obtained pharmacokinetic parameters of febuxostat were comparable to those in healthy volunteers, which allows us to consider the data of pharmacokinetic and pharmacodynamic studies involving healthy volunteers representative of the population of patients with gout. Absorption After oral use, febuxostat is rapidly and almost completely absorbed (at least 84% of the dose taken) from the gastrointestinal tract. With repeated use of febuxostat at a dose of 80 mg or a single dose of 120 mg simultaneously with a fatty meal, the maximum concentration of febuxostat in blood plasma (cmax ) decreased by 49% and 38%, respectively, and AUC – by 18% and 16%, respectively. However, this did not affect the clinical effectiveness of reducing the concentration of uric acid in the blood serum (with repeated use of febuxostat at a dose of 80 mg), and therefore febuxostat can be taken regardless of food intake. Cmax is reached in 1.0-1.5 hours after oral use and is 2.8-3.2 mcg/ml with a single oral dose of 80 mg and 5.0-5.3 mcg/ml with a single dose of 120 mg. The absolute bioavailability of febuxostat in tablet form has not been studied. With repeated oral use of febuxostat in doses of 10 mg – 240 mg once a day, accumulation was not observed. Linearity / non-linearity of pharmacokinetics in healthy volunteers with a single or multiple oral use of febuxostat, Cmax and AUC increase linearly with increasing dose in the range from 10 mg to 120 mg, and in the dose range from 120 mg to 300 mg, an increase in AUC is observed to a greater extent than proportional to the dose. Distribution The apparent volume of distribution at steady state varies from 29 l to 75 L after oral use of 10-300 mg of febuxostat. The degree of binding to plasma proteins (mainly albumin) reaches 99.2%, and does not change when the dose is increased from 80 mg to 120 mg. For active metabolites, the degree of binding to plasma proteins varies from 82% to 91%. Metabolism Febuxostat is metabolized by conjugation with uridine diphosphate-glucuronyltransferase (UDPHT) and oxidation with cytochrome P450 ( CYP) enzymes. Four pharmacologically active hydroxyl metabolites were identified, of which three are found in human blood plasma. In vitro studies on human liver microsomes have shown that oxidized metabolites are formed mainly under the influence of the isoenzymes CYP 1 A 1, CYP 1 A 2, CYP 2 C 8 or CYP 2 C 9, while febuxostat glucuronide is formed mainly under the influence of the isoenzymes UGT 1 A 1, UGT 1 A 8 and UGT 1 A 9. Excretionbuxostat and its metabolites are eliminated from the body through the intestines and kidneys. After oral use of febuxostat labeled with radioisotope 14C at a dose of 80 mg, approximately 49% is excreted by the kidneys: in unchanged form-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 febuxostat is excreted through the intestine: in the form of unchanged febuxostat-12%, acylglucuronide-1%, oxidized metabolites and their conjugates-25%, other metabolites-7%. The apparent half-life of febuxostat (Half-life) is 5-8 hours. Pharmacokinetics in special groups of patients with renal insufficiency With repeated oral use of febuxostat at a dose of 80 mg in patients with mild, moderate or severe renal insufficiency, Cmax compared with healthy volunteers did not change. In patients with severe renal insufficiency, the mean total AUC of febuxostat increased approximately 1.8-fold (13.2 mcg/ml) compared to healthy volunteers (7.5 mcg / ml); Cmax and AUC of pharmacologically active metabolites of febuxostat increased 2-fold and 4-fold, respectively. Therefore, no dose adjustment is required in patients with mild or moderate renal insufficiency. Patients with hepatic insufficiency With repeated oral use of febuxostat at a dose of 80 mg, there were no significant changes in the Cmax and AUC of febuxostat and its metabolites in patients with mild (Child-Pugh class A: 5-6 points) and moderate (Child-Pugh class B: 7-9 points) hepatic insufficiency compared to healthy volunteers.The pharmacokinetics of febuxostat have not been studied in patients with severe hepatic insufficiency (Child-Pugh class C: 10-15 points). Elderly No significant changes in the AUC of febuxostat and its metabolites were observed with repeated oral use of febuxostat in elderly patients compared to young healthy volunteers. After repeated oral use of febuxostat, the cmax and AUC of febuxostat in women were 24% and 12% higher, respectively, than in men. However, the Cmax and AUC values adjusted for the patient’s body weight were similar for both groups. Thus, no dose adjustment is required depending on the patient’s gender.

Indications

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

Treatment and prevention of hyperuricemia in adult patients undergoing cytostatic therapy for hemoblastoses with a moderate to high risk of developing tumor collapse syndrome (120 mg dosage only).

The drug Adenurik® is intended for use in adults.

Contraindications

-hypersensitivity to febuxostat and/or any of the excipients; – children under 18 years of age; – pregnancy and lactation;- hereditary problems of galactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.

With caution:

– severe renal insufficiency (creatinine clearance;- liver failure; – a history of allergic reactions;- coronary heart disease; – congestive heart failure; – thyroid diseases;- simultaneous use with mercaptopurine/azathioprine (possibly increasing the concentration of these substances in blood plasma and increasing their toxicity);- conditions after organ transplantation (experience with febuxostat is limited);- Lesch-Nihan syndrome (experience with febuxostat is limited).

Side effects

Taking into account the different nature of the course of gout and tumor collapse syndrome, side effects when using febuxostat in these nosologies of action are presented separately. The most frequent side effects in patients with gout when using febuxostat according to the results of clinical studies (4072 patients taking febuxostat at a dose of 10 mg to 300 mg) and according to post-marketing surveillance were: gout attack, impaired liver function, diarrhea, headache, nausea, skin rash and edema. In most cases, these phenomena were characterized by mild or moderate severity. During the post-marketing follow-up period, rare cases of hypersensitivity reactions to febuxostat were reported, accompanied in some cases by systemic symptoms. Possible side effects are listed below according to the World Health Organization’s descending frequency classification: very common (≥1/10); common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (The frequency of side effects is based on data from clinical trials and post-marketing experience with febuxostat. From the side of the blood and lymphatic system Occasionally: pancytopenia, thrombocytopenia. From the immune system Occasionally: anaphylactic reactions*, hypersensitivity reactions*. Nervous system disorders Often: headache; Infrequently: dizziness, paresthesia, hemiparesis, drowsiness, changes in taste perception, hyposthesia, hyposmia (weakening of the sense of smell). From the endocrine systemyasto: increased concentration of thyroid-stimulating hormone (TSH) in blood plasma. From the side of metabolism and nutrition Often: gout attacks***; Infrequently: diabetes mellitus, hyperlipidemia, decreased appetite, weight gain; Rarely: weight loss, increased appetite, anorexia. From the side of the psychicinechasto: decreased libido, insomnia; Rarely: nervousness. From the side of the visual organ Occasionally : blurred vision. From the side of the hearing organ and labyrinth disorders: tinnitus. From the side of the heart often: atrial fibrillation, palpitation sensation, ECG changes, blockage of the left bundle branch (see the section “Tumor collapse syndrome”), sinus tachycardia (see the section”Tumor collapse syndrome”). From the side of the blood vessels often: increased blood pressure, “flushes” of blood to the face, a feeling of heat, hemorrhages (see the section “Tumor collapse syndrome”). Respiratory, thoracic and mediastinal disorders Often: dyspnoea, bronchitis, upper respiratory tract infections, cough, chest pain, chest discomfort. From the digestive tract Infrequently: diarrhea**, nausea; Infrequently: abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dry oral mucosa, dyspeptic phenomena, constipation, rapid stools, flatulence, abdominal discomfort; Rarely: pancreatitis, ulcerative stomatitis. From the liver and biliary tract Infrequently: impaired liver function**; Infrequently: cholelithiasis; Rarely: hepatitis, jaundice*, liver damage*. From the skin and subcutaneous tissue Infrequently: skin rash (including various types of rash mentioned below with a lower frequency); Infrequently: dermatitis, urticaria, pruritus, discoloration, skin lesions, petechiae, macular rash, maculopapular rash, papular rash;  Rare: toxic dermal necrolysis*, Stevens-Johnson syndrome*, angioedema*, drug reaction with eosinophilia and systemic symptoms* (see section “Special instructions”), severe generalized rash*, erythema, exfoliative rash, follicular rash, vesicular rash, pustular rash, pruritic rash*, erythematous rash, bark-like rash, alopecia, hyperhidrosis. Musculoskeletal system disorders: Often: arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle spasm, muscle tension, bursitis; Rarely: rhabdomyolysis*, joint stiffness, muscle stiffness. Renal and urinary tract disorders Often: renal failure, nephrolithiasis, hematuria, pollakiuria, proteinuria; Rarely: tubulointerstitial nephritis*, imperative urge to urinate. From the side of the reproductive system Infrequently: erectile dysfunction. Common disorders:Often: Edema;Infrequently: increased fatigue; Rarely: thirst. Influence on the results of laboratory and instrumental studiesinchasto: increased amylase activity in blood plasma, decreased platelet count, decreased white blood cell count, decreased lymphocyte count, increased creatine and creatinine in blood plasma, decreased hemoglobin, increased urea concentration in blood plasma, increased triglyceride concentration in blood plasma, increased cholesterol concentration in blood plasma, decreased hematocrit, increased lactate dehydrogenase activity in blood plasma, increased potassium content in blood plasma. Rarely: increased plasma glucose concentration, prolongation of activated partial thromboplastin time, decreased red blood cell count, increased activity of alkaline phosphatase in blood plasma. * Side effects observed during the post-marketing follow-up period. ** Non-infectious diarrhea and liver disorders observed in phase III studies were more common when colchicine was co-administered. *** For more information about the development of acute attacks of gout, see the “Special Instructions”section. Description of individual side effects During the post-marketing 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 appearance of a progressive skin rash in combination with bullous lesions of the skin or mucous membranes, as well as eye irritation. Hypersensitivity reactions to febuxostat can also be manifested by the following symptoms: skin reactions characterized by infiltrative maculopapular rashes; generalized or exfoliative rash, as well as skin lesions, facial edema, fever, hematopoietic disorders such as thrombocytopenia and eosinophilia, as well as involvement of one or more organs (liver and kidneys, including tubulointerstitial nephritis). Gout attacks usually occur shortly after the start of Adenuric® and during the first months of therapy. Subsequently, the frequency of seizures decreases. It is recommended to prevent the development of acute attacks of gout. Tumor breakdown syndrome In the FLORENCE study, adverse events were reported in 22 patients (6.4%). In both groups (febuxostat group and allopurinol group), the incidence of side effects was the same (11 patients each,6.4%). In most cases, adverse events were characterized by mild or moderate severity. Overall, with the exception of the three side effects listed below in the FLORENCE study, no specific safety profile features of febuxostat were observed in addition to those for gout. From the side of the heart often: blockage of the left bundle branch, sinus tachycardia. From the vascular side often: hemorrhages (see the section “Tumor collapse syndrome”).

Interaction

Mercaptopurine/Azathioprine Simultaneous use with mercaptopurine, azathioprine is not recommended, because inhibition of xanthine oxidase by febuxostat can lead to an increase in the concentration of mercaptopurine, azathioprine in blood plasma and increase their toxic effect. Studies on the interaction of febuxostat and substances metabolized with the participation of xanthine oxidase have not been conducted.Cytostatic studies on the drug interaction between febuxostat and cytostatic drugs have not been conducted. In the FLORENCE study, febuxostat 120 mg was used for tumour breakdown syndrome in patients undergoing various types of cytostatic therapy (including monoclonal antibody therapy). However, since studies on the drug interaction of febuxostat with cytotoxic drugs have not been conducted, a potential interaction of febuxostat with simultaneously used cytotoxic chemotherapy drugs cannot be excluded. Rosiglitazone / substrates of the CYP 2C8 isoenzyme According to in vitro data, febuxostat is a weak inhibitor of the CYP 2c8 isoenzyme. No changes in the pharmacokinetic parameters of rosiglitazone and its metabolite N-dismethyl rosiglitazone were observed in healthy volunteers with simultaneous use of 120 mg of febuxostat 1 time per day and a single dose of 4 mg of rosiglitazone, which indicates that febuxostat does not have the properties of an inhibitor of the CYP 2C8 isoenzyme in vivo. No dose adjustment is required when febuxostat is co-administered with rosiglitazone (or other substrates of the CYP 2C8 isoenzyme). Theophylline When using other xanthine oxidase inhibitors simultaneously with theophylline, an increase in the concentration of theophylline in blood plasma was noted. No changes in the pharmacokinetic parameters or tolerability of theophylline were observed with the simultaneous use of febuxostat 80 mg once a day and a single dose of theophylline 400 mg in healthy volunteers, so special caution is not required when using febuxostat 80 mg and theophylline simultaneously. The concomitant use of febuxostat 120 mg and theophylline has not been studied. Naproxen and other glucuronidation inhibitorsmetabolism of febuxostat depends on the activity of the enzyme uridine diphosphate-glucuronyltransferase (UDPHT). Drugs that inhibit the glucuronidation process, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenicide, can theoretically affect the elimination of febuxostat. In healthy volunteers, when febuxostat and naproxen were administered simultaneously at a dose of 250 mg 2 times a day, the Cmax of febuxostat increased by 28%, AUC – by 41% and Half – life-by 26%. In clinical studies, the concomitant use of febuxostat and naproxen or other NSAIDs/COX-2 inhibitors was not associated with a clinically significant increase in the incidence of adverse events. No dose adjustment is required for concomitant use of febuxostat and naproxen. Inducers of glucuronidation Simultaneous use of febuxostat with strong inducers of glucuronidation may increase its metabolism and reduce its effectiveness. With simultaneous use, it is necessary to monitor the concentration of uric acid in the blood serum 1-2 weeks after the start of therapy. If the glucuronidation inducer is discontinued, the Cmax of febuxostat may increase. Colchicine / Indometacin / hydrochlorothiazide / Warfarinfebuxostat can be used simultaneously with colchicine or Indometacin without dose adjustment. There is also no need to adjust the dose of febuxostat when co-administered with hydrochlorothiazide. Concomitant use of febuxostat (80 mg or 120 mg once daily) with warfarin did not affect the pharmacokinetics of warfarin, INR (international normalized ratio), or factor VII activity in healthy volunteers. No dose adjustment of warfarin is required when febuxostat is co-administered with warfarin. Desipramine / substrates of the CYP 2D6 isoenzyme According to in vitro data, febuxostat is a weak inhibitor of the CYP 2d6 isoenzyme. In a study in healthy volunteers, the AUC of desipramine (a substrate of the CYP 2D6 isoenzyme) increased by 22% against the background of the use of febuxostat at a dose of 120 mg once a day, which indicates a weak inhibitory effect of febuxostat on the CYP 2d6 isoenzyme in vivo. Thus, no dose adjustment is required when febuxostat and CYP 2 D6 substrates are co-administered. Antacidswhen administered concomitantly with antacids containing magnesium hydroxide or aluminum hydroxide, there was a decrease in the absorption of febuxostat (approximately 1 hour) and a decrease in Cmax by 32%, but the AUC of febuxostat did not change significantly. Thus, febuxostat can be taken simultaneously with antacids.

How to take, course of use and dosage

Inside. The drug Adenurik® is taken once a day, regardless of food intake. The recommended starting dose is 80 mg of febuxostat once daily. After 2-4 weeks, it is recommended to monitor the concentration of uric acid in the blood serum; if the indicator exceeds 6 mg / dl (357 mmol/l), the dose of the drug can be increased to 120 mg once a day. A decrease in the concentration of uric acid in the blood serum against the background of the use of the drug Adenurik® occurs quite quickly, and therefore the control of uric acid concentration can be carried out two weeks after the start of taking the drug. The goal of treatment is to reduce and maintain serum uric acid concentrations below 6 mg / dl (357 mmol / L). Prevention of acute gout attacks is recommended for at least 6 months. Tumour breakdown syndrome The recommended dose is 120 mg of febuxostat once daily, regardless of food intake. Adenuric® should be started two days before the start of cytostatic therapy. The duration of use of the drug Adenurik® should be at least 7 days. Depending on the duration of the course of chemotherapy, the duration of use of Adenuric® can be increased to 9 days. Elderly patientscorrection of the drug dose is not required. Patients with hepatic insufficiencyprevention of patients with mild hepatic insufficiency (class A on the Child-Pugh scale: 5-6 points), the recommended dose of the drug is 80 mg 1 time per day. The experience of using the drug in patients with moderate hepatic insufficiency is limited. Tumor breakdown syndrome In the FLORENCE study, no dose adjustment of febuxostat was required depending on liver function (patients with severe hepatic insufficiency were not included in the study). No studies have been conducted on the efficacy and safety of febuxostat in patients with severe hepatic insufficiency (Child-Pugh class C: 10-15 points). Patients with renal insufficiency In patients with mild to moderate renal insufficiency, no dose adjustment is required. In patients with severe renal insufficiency (creatinine clearance

Overdose

In case of overdose of the drug, symptomatic and supportive therapy is indicated. Symptoms: increased side effects.

Special instructions

Acute attack of goutthe use of Adenuric® should be initiated only after the acute attack of gout has been stopped. Initiation of the drug Adenuric® can provoke the development of an acute attack of gout due to the release of urates from tissue depots and the subsequent increase in the concentration of uric acid in the blood serum. Concomitant use of NSAIDs or colchicine for at least 6 months is recommended to prevent gout attacks in the absence of contraindications. If an attack develops with the use of Adenuric®, the use of the drug should be continued and at the same time appropriate treatment of an acute attack of gout should be carried out. With prolonged use of Adenuric®, the frequency and severity of gout attacks are reduced. Xanthine deposition In rare cases, patients with accelerated urate formation (for example, on the background of malignant neoplasms or with Lesh-Nihan syndrome) may significantly increase the absolute concentration of xanthines in the urine, which may be accompanied by their deposition in the urinary tract. When using febuxostat in the FLORENCE study in patients with tumor collapse syndrome, this phenomenon was not observed. Due to limited data, the use of Adenuric® in patients with Lesh-Nihan syndrome is not recommended. Mercaptopurine/Azathioprine Simultaneous use with mercaptopurine, azathioprine is not recommended. If concomitant use is necessary, a reduction in the dose of mercaptopurine/azathioprine and careful medical supervision are recommended to reduce the toxic effect on the hematopoietic system. Theophylline When febuxostat 80 mg once daily and a single dose of theophylline 400 mg were administered concomitantly in healthy volunteers, no changes in pharmacokinetic parameters were observed. Thus, the concomitant use of febuxostat at a dose of 80 mg and theophylline does not carry the risk of increasing the concentration of theophylline in blood plasma. The concomitant use of febuxostat 120 mg and theophylline has not been studied. Patients who have undergone organ transplantationthe use of Adenuric® in patients who have undergone organ transplantation is not recommended due to lack of experience with its use. Allergic and hypersensitivity reactions Severe allergic reactions (hypersensitivity reactions), including Stevens-Johnson syndrome, toxicodermal necrolysis, anaphylactic reactions, and shock, have been reported infrequently during post-marketing use. In most cases, these reactions developed during the first month of using the drug Adenurik®. Some patients had a history of renal failure and / or hypersensitivity reactions associated with the use of allopurinol. In some cases, severe hypersensitivity reactions, including drug reaction syndrome with eosinophilia and systemic symptoms (DRESS), were accompanied by fever, changes in blood parameters, and impaired liver or kidney function.Patients should be informed about possible signs and symptoms of allergic reactions (hypersensitivity reactions), and should be closely monitored for the development of symptoms of allergic reactions/hypersensitivity reactions. In case of severe allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, the use of Adenuric® should be stopped immediately (earlier withdrawal is associated with a better prognosis). Repeated use of the drug is not recommended. Cardiovascular diseasesapplication of Adenuric® is not recommended in patients with coronary heart disease or congestive heart failure. In the APEX and FACT studies (as opposed to the CONFIRMS study), the total febuxostat group compared to the allopurinol group showed an increase in the number of cardiovascular disorders determined in accordance with the system developed by the joint antiplatelet therapy analysis group (GSAAT) and including death from cardiovascular causes, non-fatal myocardial infarction, stroke without a fatal outcome – 1.3 compared to 0.3 cases per 100 patient-years. According to the combined data of phase III clinical trials (APEX, FACT, and CONFIRMS studies), the incidence of cardiovascular disorders was 0.7 compared to 0.6 cases per 100 patient-years. In long-term, large-scale studies, the incidence of HSAAT cardiovascular disorders was 1.2 and 0.6 cases per 100 patient-years for febuxostat and allopurinol, respectively. The differences were not statistically significant, and a causal relationship between these disorders and febuxostat intake was not established. As risk factors for the development of these events, patients were found to have a history of the following conditions: atherosclerosis and/or myocardial infarction, or congestive heart failure. Prevention and treatment of hyperuricemia in patients at risk of developing tumour collapse syndrome or in patients receiving cytostatic therapy for hemoblastosis with a moderate to severe risk of developing tumour collapse syndrome, the use of Adenuric®, if indicated, should be carried out under the supervision of a cardiologist. Liver Diseasesaccording to the combined data of phase III clinical trials,5% of patients with febuxostat experienced mild hepatic dysfunction. Before prescribing Adenuric®, it is recommended to evaluate liver function, and if indicated, also during use. Thyroid diseases In extended long-term open-label studies with prolonged use of febuxostat in 5.5% of patients, an increase in the concentration of thyroid-stimulating hormone (>5.5 MIU/ml) was noted, and therefore patients with impaired thyroid function should be prescribed Adenuric® with caution. Adenuric ® contains lactose, so its use in patients with lactase deficiency, hereditary lactose intolerance, glucose-galactose malabsorption syndrome is contraindicated. Effects on the ability to drive motor vehicles and control mechanisms When taking the drug Adenurik®, drowsiness, dizziness, paresthesia and blurred vision may occur, and, as a result, a decrease in reaction and ability to concentrate, therefore, during the use of the drug Adenurik®, care should be taken when driving vehicles and engaging in other potentially dangerous activities that require concentration and speed of psychomotor reactions.

Form of production

Film-coated tablets.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep the medicine out of the reach of children!

Shelf

life is 3 years.

Active ingredient

Febuxostat

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

Adults as prescribed by a doctor

Indications

Gout