Adenuric tablets 120mg, No. 28

• Treatment of chronic hyperuricemia in conditions accompanied by the deposition of urate crystals (in the presence of tophus and / or gouty arthritis, including a history).

• Treatment and prevention of hyperuricemia in adult patients during cytostatic therapy of hemoblastosis with a moderate to high risk of tumor disintegration syndrome (only for a dose of 120 mg).

It is taken internally.

The dose is 80-120 mg 1 time / day. The duration of treatment is set individually, depending on the indications. The goal of treatment is to reduce and maintain serum uric acid concentrations below 6 mg / dL (357 ?mol / L).

Light yellow to yellow film-coated tablets, oblong, embossed '120' on one side.

1 tab.

febuxostat 120mg; 80mg

• Pregnancy, breastfeeding period;

• children under 18 years of age;

• hypersensitivity to febuxostat.

pharmachologic effect

Selective non-purine xanthine oxidase inhibitor, 2-arylthiazole derivative. 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 the selective inhibition of xanthine oxidase (oxidized and reduced forms) by febuxostat, the concentration of uric acid in the blood serum decreases. The in vitro inhibition constant is less than 1 nM. At therapeutic concentrations, febuxostat 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 nucleosylase.

The use of febuxostat leads to a more effective decrease in the concentration of uric acid and maintenance of its level in the blood serum compared with allopurinol. 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 (the decrease in the concentration of uric acid in the group of patients with normal renal function is 58%, in the group with severe renal failure - 55%).

With the use of febuxostat for the prevention and treatment of tumor disintegration syndrome, a more intense and rapid decrease in the concentration of uric acid in the blood serum was observed compared with allopurinol.

Pharmacokinetics

After oral administration, febuxostat is rapidly and almost completely (at least 84% of the dose taken) absorbed from the gastrointestinal tract. With repeated administration of febuxostat at a dose of 80 mg or a single dose of 120 mg simultaneously with the intake of fatty foods, the Cmax of febuxostat in blood plasma decreased by 49% and 38%, respectively, and the AUC - by 18% and 16%. However, this did not affect the clinical efficacy of reducing the concentration of uric acid in the blood serum (with repeated administration of febuxostat at a dose of 80 mg), in this regard, febuxostat can be taken regardless of food intake. Cmax is reached within 1.0-1.5 hours after a single or multiple oral administration and is 2.8-3.2 mcg / ml when taken at a dose of 80 mg and 5-5.3 mcg / ml when taken at a dose of 120 mg.

With repeated oral administration of febuxostat at doses of 10-240 mg 1 time per day, no cumulation was observed.In healthy volunteers, with a single or multiple oral administration of febuxostat, Cmax and AUC increase linearly with increasing doses in the range from 10 mg to 120 mg, and in the dose range from 120 mg to 300 mg, there is an increase in AUC to a greater extent than dose-proportional. The apparent Vd at steady state varies from 29 L to 75 L after ingestion 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%. Febuxostat is metabolized by conjugation with the participation of UDP-HT and oxidation with the participation of enzymes of the cytochrome P450 system.

4 pharmacologically active hydroxyl metabolites were isolated, of which 3 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 isoenzymes CYP1A1, CYP1A2, CYP2C8 or CYP2C9, while febuxostat glucuronide is formed mainly under the influence of isoenzymes UGT 1A1, UGT 1A8 and UGT 1A9. Febuxostat and its metabolites are eliminated from the body through the intestines and kidneys.

After oral administration of febuxostat labeled with a radioisotope 14C at a dose of 80 mg, approximately 49% is excreted 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 febuxostat is excreted through the intestine: as unchanged substance - 12%, acylglucuronide - 1%, oxidized metabolites and their conjugates - 25%, other metabolites - 7%. Apparent T1 / 2 is 5-8 hours.

Side effect

On the part of the hematopoietic system: infrequently - a decrease in the number of platelets, leukocytes, lymphocytes, a decrease in the concentration of hemoglobin, a decrease in hematocrit; rarely - pancytopenia, thrombocytopenia, a decrease in the number of red blood cells.

From the immune system: hypersensitivity reactions.

From the nervous system: often - headache; infrequently - dizziness, paresthesia, hemiparesis, drowsiness, change in taste, hypesthesia, hyposmia (weakening of the sense of smell).

From the endocrine system: infrequently - an increase in the concentration of TSH in the blood plasma.

From the side of metabolism: often - gout attacks; infrequently - diabetes mellitus, hyperlipidemia, decreased appetite, weight gain, increased plasma urea concentration, increased plasma triglyceride concentration, increased plasma cholesterol concentration, increased plasma potassium; rarely - an increase in the concentration of glucose in the blood plasma, 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.

On the part of the organ of hearing and labyrinth disorders: rarely - tinnitus.

From the side of the cardiovascular system: infrequently - atrial fibrillation, palpitations, ECG changes, left bundle branch block, sinus tachycardia, increased blood pressure, flushes of blood to the face, fever, hemorrhages.

From the respiratory system: infrequently - dyspnea, bronchitis, upper respiratory tract infections, cough.

From the digestive system: often - diarrhea (more often with the simultaneous use of colchicine), nausea; infrequently - abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dryness of the oral mucosa, dyspeptic symptoms, constipation, frequent stools, flatulence, abdominal discomfort, increased amylase activity in blood plasma; rarely - pancreatitis, ulcerative stomatitis.

From the liver and biliary tract: often - liver dysfunction (more often with the simultaneous use of colchicine); infrequently - cholelithiasis, increased activity of alkaline phosphatase, LDH in blood plasma; rarely - hepatitis, jaundice, liver damage.

On the part of the skin and subcutaneous tissues: often - a rash (including the various types of rashes mentioned below with a lower frequency); infrequently - dermatitis, urticaria, pruritus, skin discoloration, skin lesions, petechiae, macular rash, maculopapular rash, papular rash; rarely - severe generalized rash, erythema, exfoliative rash, follicular rash, vesicular rash, pustular rash, itchy rash, erythematous rash, measles-like rash, alopecia, hyperhidrosis.

Allergic reactions: rarely - angioedema, severe allergic reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylactic reactions and shock, drug reaction with eosinophilia and systemic symptoms.

From the musculoskeletal system: infrequently - arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle spasm, muscle tension, bursitis; rarely - rhabdomyolysis, increased concentration of CPK in the blood plasma, joint stiffness, muscle stiffness.

From the urinary system: infrequently - renal failure, nephrolithiasis, hematuria, pollakiuria, proteinuria, increased levels of creatine and creatinine in the blood plasma; rarely - tubulointerstitial nephritis, urge to urinate.

From the reproductive system: infrequently - erectile dysfunction.

General reactions: often - edema; infrequently - increased fatigue, chest pain, discomfort in the chest area; rarely, thirst. In clinical studies, in patients who received phlebuxostat for hemoblastosis, in 6.4% of cases, tumor disintegration syndrome was observed with the development of mild to moderate adverse events.

Application during pregnancy and lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Application in children

The drug is contraindicated for use in children and adolescents under the age of 18 years.

special instructions

Use with caution in the following diseases and conditions: severe renal failure (CC <30 ml / min) (efficacy and safety have not been studied enough); liver failure; a history of serious allergic reactions (hypersensitivity reactions); Ischemic heart disease; congestive heart failure; diseases of the thyroid gland; simultaneous use with mercaptopurine / azathioprine (it is possible to increase the concentration of these substances in the blood plasma and increase their toxicity); conditions after organ transplantation (experience with febuxostat is limited); Lesch-Nihan syndrome (experience with febuxostat is limited). Febuxostat should only be started after an acute gout attack has subsided.The use of febucostat can provoke the development of an acute attack of gout due to the release of urate from tissue depots and a subsequent increase in the concentration of uric acid in the blood serum. For the prevention of gout attacks, the simultaneous use of NSAIDs or colchicine is recommended for at least 6 months. Concomitant use with mercaptopurine, azathioprine is not recommended. If it is necessary to simultaneously use it to reduce the toxic effect on the hematopoietic system, a decrease in the dose of mercaptopurine / azathioprine and careful medical supervision are recommended. Patients should be informed about the possible signs and symptoms of allergic reactions (hypersensitivity reactions), and should be closely monitored for the development of symptoms of allergic / hypersensitivity reactions.In the event of severe allergic / hypersensitivity reactions, including Stevens-Johnson syndrome, the use of febuxostat should be discontinued immediately (earlier withdrawal is associated with a better prognosis). If the patient has previously experienced severe allergic or hypersensitivity reactions, including Stevens-Johnson syndrome, acute anaphylactic reactions / shock, re-use of the drug is not recommended. In patients undergoing cytostatic therapy of hemoblastosis with a moderate to severe risk of tumor disintegration syndrome (with clinical manifestations from the heart), febuxosat should be used under appropriate supervision. At the beginning of the use of febuxostat and periodically in the presence of clinical manifestations, it is recommended to monitor liver function.

Influence on the ability to drive vehicles and mechanisms

When using febuxostat, drowsiness, dizziness, paresthesia and blurred vision may appear, and, as a result, a decrease in reaction and ability to concentrate, therefore, during the period of treatment, care should be taken when driving vehicles and engaging in other potentially hazardous activities that require concentration and the speed of psychomotor reactions.

Drug interactions

Taking into account the mechanism of action of febuxostat, based on inhibition of xanthine oxidase, simultaneous use is not recommended with mercaptopurine, azathioprine. Inhibition of xanthine oxidase by febuxostat can lead to an increase in the concentration of mercaptopurine, azathioprine in blood plasma and an increase in their toxic effect. A potential interaction of febuxostat with concurrently used cytotoxic chemotherapy cannot be ruled out. According to in vitro data, febuxostat is a weak inhibitor of the isoenzyme CYP2C8. With the simultaneous use of febuxostat and rosiglitazone (or other substrates of the CYP2C8 isoenzyme), dose adjustment is not required. The simultaneous use of febuxostat and naproxen or other NSAIDs / COX-2 inhibitors was not accompanied by a clinically significant increase in the incidence of side effects.No dose adjustment is required with the simultaneous use of febuxostat and naproxen. Simultaneous use of febuxostat with strong inducers of glucuronidation may increase its metabolism and decrease its effectiveness. With the abolition of the inducer of glucuronidation, an increase in Cmax of febuxostat is possible. Desipramine / CYP2D6 isoenzyme substrates In vitro data indicate that febuxostat is a weak inhibitor of CYP2D6 isoenzyme. With the simultaneous use of febuxostat and substrates of the isoenzyme CYP2D6, dose adjustment is not required. With simultaneous use with antacids containing magnesium hydroxide or aluminum hydroxide, there is a decrease in absorption of febuxostat (approximately 1 hour) and a decrease in Cmax by 32%, however, the AUC of febuxostat does not change significantly. Thus, febuxostat can be taken concurrently with antacids.