Azurix tabs 80mg #30

Instruction for Azurix

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Azurix is ​​an anti-gout drug; xanthine oxidase inhibitor.

Release form and composition

The drug is produced in the form of film-coated tablets: biconvex, oblong, with rounded ends, yellow, on a cross-section - an almost white or white core (10, 14, 15 or 30 pieces in a blister strip; in a cardboard box 1, 2, 3, 4 or 5 packages and instructions for use of Azurix).
1 tablet contains:
    active substance: febuxostat - 80 or 120 mg;
    additional components: sodium croscarmellose, mannitol, sodium bicarbonate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, colloidal silicon dioxide (aerosil), talc;
    film shell: macrogol 6000 (polyethylene glycol 6000), hypromellose (hydroxypropyl methylcellulose), talc, titanium dioxide, iron oxide yellow dye.

Pharmacodynamics

Azurix is ​​a drug that affects the metabolism of uric acid, used to treat gout. Uric acid is the end product of purine metabolism in the human body, which is formed as a result of a sequential series of such biotransformations: hypoxanthine - xanthine - uric acid. The active substance of Azurix, febuxostat, is a derivative of 2-arylthiazole and belongs to strong selective non-purine inhibitors of xanthine oxidase - the in vitro inhibition constant is less than 1 nM. Xanthine oxidase is an enzyme that catalyzes both stages of purine metabolism: the oxidation of hypoxanthine to xanthine and the further oxidation of xanthine to uric acid.
Febuxostat, selectively inhibiting xanthine oxidase, suppressing both the oxidized and reduced forms, provides a decrease in the level of uric acid in the blood serum. The active substance in therapeutic concentrations does not inhibit the activity of other enzymes that take part in the exchange of purines or pyrimidines, such as guanine deaminase, orotate phosphoribosyltransferase, hypoxanthine guanine phosphoribosyltransferase, purine nucleoside phosphorylase or orothi dinaminoboxyl monoboxylate.

Pharmacokinetics

After oral administration, febuxostat is rapidly and significantly (more than 84% of the administered dose) absorbed from the gastrointestinal tract (GIT). With a single intake of the substance at a dose of 120 mg or multiple doses of 80 mg in combination with food rich in fats, its maximum concentration (Cmax) in blood plasma decreased by 38 and 49%, respectively, and the area under the concentration-time curve ( AUC) - by 16 and 18%. However, this did not lead to a significant change in the clinical efficacy of reducing serum uric acid concentration (with repeated use of febuxostat at a dose of 80 mg). Thus, Azurix can be used regardless of food intake.
After oral use, Cmax of the active substance is noted after 1-1.5 hours. This figure is 2.8-3.2 μg / ml with a single dose of 80 mg and 5-5.3 μg / ml with a single dose of 120 mg. The absolute bioavailability of febuxostat in tablet form has not been studied. Against the background of repeated oral administration of the drug in doses of 10–240 mg, the accumulation of the active substance was not observed.
The apparent volume of distribution (Vd) at steady state can vary from 29 to 75 liters after oral administration of febuxostat at a dose of 10–300 mg. The substance binds to blood plasma proteins (primarily albumin) by 99.2%, while the degree of binding does not change if the dose is increased from 80 to 120 mg. The plasma protein binding of active metabolites of febuxostat can range from 82 to 91%.
The metabolic transformation of the drug is carried out through conjugation with the participation of uridine diphosphate glucuronyl transferase (UDFGT) and oxidation produced by enzymes of the cytochrome P450 system (CUR). A total of 4 pharmacologically active hydroxyl metabolites of febuxostat were isolated, 3 of which were found in human blood plasma. During in vitro studies on liver microsomes in humans, it was demonstrated that oxidized metabolites are formed mainly by the action of isoenzymes CYP2C9, CYP2C8, CYP1A2 or CYP1A1. Febuxostat glucuronide, in turn, is formed mainly with the participation of isoenzymes such as UGT 1A9, UGT 1A8 and UGT 1A1.
The active substance and its metabolites are excreted 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: 3% - unchanged, 30% - in the form of acylglucuronide, 13% - in the form of oxidized metabolites and their conjugates, and 3% - in the form of other metabolites. About 45% of febuxostat is excreted through the intestines: 12% - unchanged, 25% - in the form of oxidized metabolites and their conjugates, 1% - in the form of acylglucuronide, and 7% in the form of other metabolites. The apparent half-life (T1 / 2) of febuxostat can be 5-8 hours.
With repeated oral administration, the AUC and Cmax of febuxostat were 12% and 24% higher in women than in men, respectively. But these indicators, adjusted for the patient's body weight, remained similar for both groups. As a consequence, gender-specific dose changes are not required.

Indications for use

    therapy of chronic hyperuricemia against the background of conditions accompanied by the deposition of urate crystals, including in the presence of gouty arthritis and / or tophus, including data in the anamnesis;
    treatment and prevention of hyperuricemia, against the background of cytostatic therapy of hemoblastosis, in the presence of a moderate or high risk of developing tumor disintegration syndrome - only for a dosage of 120 mg.

Contraindications

Absolute:
    pregnancy and lactation;
    age under 18;
    hypersensitivity to any of the constituents of the anti-gout agent.
Relative (taking Azurix tablets with caution is required):
    history of allergic reactions;
    violations of the liver;
    severe renal failure, with creatinine clearance (CC) below 30 ml / min;
    congestive heart failure;
    ischemic heart disease (CHD);
    Lesch-Nyhen syndrome;
    diseases of the thyroid gland (with prolonged use of febuxostat due to a possible increase in the concentration of thyroid-stimulating hormone);
    conditions after organ transplantation (due to insufficient experience of use);
    combined administration with mercaptopurine / azathioprine.

Instructions for use: method and dosage

Azurix tablets are taken orally 1 time per day, regardless of food intake.
In the treatment of gout, the drug is recommended to be used in an initial daily dose of 80 mg. After 2–4 weeks from the beginning of the course, the level of uric acid in the blood serum should be monitored. If the concentration of the latter is higher than 6 mg / dL (357 μmol / L), the daily dose of Azurix can be increased to 120 mg. Since the decrease in serum uric acid levels is reached rather quickly during the period of taking febuxostat, its concentration should be monitored two weeks after the start of administration. The goal of therapy is to reduce the uric acid content and further maintain it at a level below 6 mg / dL (357 μmol / L).
It is recommended to take Azurix in order to prevent the development of acute attacks of gout for at least 6 months.
With tumor disintegration syndrome, the drug is prescribed in a daily dose of 120 mg. It is recommended to start using the drug 2 days before the start of cytotoxic therapy. The duration of taking Azurix should be at least 7 days and may be 9 days in accordance with the course of chemotherapy and clinical evaluation of efficacy.

Side effects

Adverse effects observed in clinical trials and during post-marketing surveillance in patients with gout during therapy with febuxostat:
    endocrine system: infrequently - an increase in the plasma concentration of thyroid-stimulating hormone in the blood;
    nervous system: often - headache; infrequently - hyposthesia, hemiparesis, paresthesia, dizziness, drowsiness, hyposmia (weakening of the sense of smell), impaired taste perception;
    immune system: rarely - hypersensitivity reactions, anaphylactic reactions;
    blood and lymphatic system: rarely - thrombocytopenia, pancytopenia;
    metabolism and nutritional disorders: often - gout attacks (in most cases, they were observed soon after the start of the course, as well as during the first months of treatment, later the frequency of development decreased); infrequently - weight gain, decreased appetite, hyperlipidemia, diabetes mellitus; rarely - increased appetite, weight loss, anorexia;
    sense organs: rarely - tinnitus, blurred vision;
    mental disorders: infrequently - insomnia, decreased libido; rarely - nervousness;
    respiratory system, chest and mediastinal organs: infrequently - a feeling of discomfort in the chest area, cough, dyspnea, chest pain, upper respiratory tract infections, bronchitis;
    cardiovascular system (CVS): infrequently - a feeling of heat, flushing of the face, palpitations, increased blood pressure (BP), changes in the electrocardiogram (ECG), atrial fibrillation; for a dosage of 120 mg - sinus tachycardia, left bundle branch block, hemorrhages;
    digestive system: often - diarrhea, abnormal liver function (these disorders recorded in phase III studies were most often observed when combined with colchicine), nausea; infrequently - dryness of the oral mucosa, vomiting, constipation, bloating, abdominal discomfort / pain, frequent stools, dyspeptic symptoms, flatulence, gastroesophageal reflux disease, cholelithiasis; rarely - ulcerative stomatitis, pancreatitis, jaundice, hepatitis, liver damage;
    musculoskeletal system: infrequently - muscle weakness, muscle tension, muscle spasm, musculoskeletal pain, myalgia, arthralgia, arthritis, bursitis; rarely - muscle / joint stiffness, rhabdomyolysis;
    skin and subcutaneous tissue: often - skin rash (including the various types of rashes listed below with a lower frequency of development); infrequently - petechiae, discoloration of the skin, pruritus, skin lesions, urticaria, dermatitis, papular rash, maculopapular rash, macular rash; rarely - hyperhidrosis, alopecia, measles-like rash, erythematous rash, itchy rash, pustular rash, vesicular rash, follicular rash, exfoliative rash, drug reaction with eosinophilia and systemic symptoms, erythema syndrome, severe forms of JS toxicodermal necrolysis;
    reproductive system: infrequently - erectile dysfunction;
    general disorders: often - edema; infrequently - increased fatigue; rarely - thirst;
    kidneys and urinary tract: infrequently - proteinuria, pollakiuria, hematuria, nephrolithiasis, renal failure; rarely - urge to urinate, tubulointerstitial nephritis;
    research results: infrequently - increased plasma amylase activity, a decrease in the number of leukocytes and / or platelets / lymphocytes, an increase in the level of creatinine and creatine in the blood plasma, an increase in the concentration of urea / triglycerides / cholesterol in the blood plasma; decrease in hematocrit / hemoglobin, increased activity in blood plasma of lactate dehydrogenase, increased potassium levels; rarely - an increase in the activity of alkaline phosphatase in plasma, an increase in glucose concentration, a decrease in the number of erythrocytes, a prolongation of the activated partial thromboplastin time.
In the course of post-marketing surveillance, there have been rare reports of the development of severe hypersensitivity reactions (allergic reactions) to febuxostat, including toxicodermal necrolysis, Stevens-Johnson syndrome, anaphylactic reactions and shock. Toxicodermal necrolysis and Stevens-Johnson syndrome are characterized by the occurrence of a progressive skin rash in combination with bullous lesions of the skin or mucous membranes, including irritation of the mucous membranes of the eyes. Symptoms of hypersensitivity reactions to Azurix may also include skin reactions characterized by an infiltrated maculopapular rash, generalized / exfoliative rash, fever, facial edema, thrombocytopenia and eosinophilia, and damage to individual or multiple organs (liver, kidneys, including stubular nephritis interstitial tubule).
In most cases, the appearance of these side effects was noted during the first month of taking Azurix. Patients who experienced these complications, in some cases, had a history of indications of hypersensitivity reactions and / or renal failure during the use of allopurinol. During the period of therapy, patients need to be closely monitored for signs / symptoms of allergic reactions and hypersensitivity reactions, and patients should also be informed about the possible symptoms of these disorders. If the above conditions appear, it is required to immediately stop taking the drug (since early withdrawal of febuxostat is associated with a better prognosis), re-administration of Azurix is ​​contraindicated.
In a double pivotal Phase III FLORENCE study comparing the effect of febuxostat and allopurinol, in patients receiving chemotherapy for hematologic malignancies with moderate / high risk of tumor collapse syndrome, adverse reactions were observed in only 6.4% of patients in each group. Overall, no additional suspicions were raised about the safety of febuxostat in patients with gout during the study. The exceptions were the following undesirable reactions from the CVS: infrequently - ventricular tachycardia, left bundle branch block; sometimes bleeding.

Overdose

A sign of an overdose of Azurix may be an increase in its side effects.
If an overdose is suspected, symptomatic and supportive therapy is prescribed.

Special instructions

The use of Azurix should be started only in the period after the relief of an acute attack of gout. At the beginning of the course of therapy, due to the release of urates from tissue depots and the resulting increase in the level of serum uric acid concentration in the blood, there is a risk of developing an acute attack. To prevent an exacerbation of the disease, it is recommended, in the absence of contraindications, to take non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine with the drug for at least 6 months. If the attack has developed against the background of drug treatment, it is necessary to continue treatment and at the same time conduct appropriate therapy for exacerbation of gout. The frequency and severity of attacks of this disease are reduced with prolonged use of febuxostat.
In the presence of accelerated formation of urates (for example, in Lesch-Nychen syndrome or against the background of malignant tumors), the risk of a significant increase in the absolute concentration of xanthines in the urine, with subsequent deposition of the latter in the urinary tract, is aggravated. However, this phenomenon was not observed with febuxostat in patients with tumor disintegration syndrome in the FLORENCE study. Due to limited observational data, it is not recommended to take Azurix for patients with Lesch-Nychen syndrome.
In the APEX and FACT studies in the general febuxostat group, when compared with the allopurinol group (in contrast to the CONFIRMS study), an increase in the number of CVS disorders was recorded [setting of endpoints in the antiplatelet therapy co-analysis group (GCAAT), including death due to cardiovascular -vascular disease, stroke without fatal outcome, non-fatal myocardial infarction] - 1.3% compared to 0.3% per year.
The incidence of CVS complications according to the combined data from phase III clinical trials (FACT, APEX and CONFIRMS studies) was 0.7% compared to 0.6% per year. In long-term, large-scale studies, reported rates of cardiovascular abnormalities in GSAAT were 1.2% and 0.6% per year, respectively, for febuxostat and allopurinol. The differences were not statistically significant, and a causal relationship between these disorders and febuxostat was not determined. The following diseases in history were classified as risk factors for these events: congestive heart failure, myocardial infarction and / or atherosclerosis.
Reception of Azurix in patients with coronary artery disease or congestive heart failure is not recommended.
The use of the drug in patients who receive cytostatic therapy of hemoblastosis, with a moderate or severe threat of tumor disintegration syndrome, if clinically indicated, should be carried out under the supervision of a cardiologist.

Influence on the ability to drive vehicles and complex mechanisms

Patients who drive vehicles or work with any other complex and potentially dangerous equipment should be careful during therapy with Azurix, since the drug can cause dizziness, paresthesia, drowsiness and blurred vision.

Application during pregnancy and lactation

Taking Azurix during pregnancy is contraindicated due to insufficient data confirming the efficacy and safety of treatment with febuxostat during this period.
According to the limited experience of using the drug during pregnancy, its adverse effects on its course and the health of the fetus / newborn were not recorded. In animal studies, no direct / indirect negative effects of Azurix on the development of the embryo / fetus or the course of pregnancy and childbirth were observed.
It has not been established whether febuxostat is excreted in breast milk. In animal studies, it was found that the substance is excreted in breast milk and negatively affects the development of nursed young, and therefore, a potential threat to infants cannot be ruled out. The use of Azurix during lactation is contraindicated.
The effect of the drug on human reproductive function is unknown.

Childhood use

Azurix is ​​not intended for pediatric use.

With impaired renal function

In the presence of mild or moderate renal failure, dose adjustment of Azurix is ​​not required.
Patients with severe renal failure (with CC below 30 ml / min) should use an anti-gout agent with caution, since its efficacy and safety in this group of patients have not been sufficiently studied.

For violations of liver function

Patients with impaired liver function Azurix should be taken with caution.
With repeated use of febuxostat in a daily dose of 80 mg, there were no significant changes in the Cmax and AUC values ​​of this active substance and its metabolites in patients with mild to moderate hepatic insufficiency (class A and B on the Child-Pugh scale) when compared with volunteers with normal kidney function. Pharmacokinetic studies of febuxostat in patients with severe liver failure (class C on the Child-Pugh scale) have not been conducted.
For patients with mild hepatic impairment, it is recommended to take Azurix in a daily dose of 80 mg for the treatment of gout. The experience of using the drug against a background of moderate hepatic failure is limited.
During combined phase III clinical trials with febuxostat, mild liver dysfunctions were reported in 5% of patients. It is recommended to assess the functional liver parameters before the start of admission, as well as during the course - if indicated.

Use in the elderly

Against the background of repeated use of Azurix in elderly patients, there were no significant changes in the AUC of the active substance and its metabolites compared with young healthy volunteers. No dose adjustment is required for patients of this age group.

Drug interactions

    cytostatics: the interaction of these drugs with febuxostat has not been studied; febuxostat at a dose of 120 mg during the FLORENCE study was used for tumor disintegration syndrome in patients receiving various types of cytostatic therapy (including monoclonal antibodies), however, it is impossible to exclude the potential interaction of febuxostat when combined with any cytotoxic drugs;
    mercaptopurine / azathioprine: this combination is not recommended, since the suppression of xanthine oxidase by febuxostat can cause an increase in the concentration of mercaptopurine / azathioprine in the blood plasma, and, as a result, lead to an aggravation of their toxic effect; the study of the interaction of febuxostat and drugs metabolized by xanthine oxidase has not been conducted; if it is necessary to combine the use of febuxostat with mercaptopurine / azathioprine, it is necessary to reduce the dose of the latter to reduce the toxic effect on the hematopoietic system and to closely monitor the patient's condition;
    glucuronidation inhibitors - naproxen and other NSAIDs / cyclooxygenase-2 (COX-2) inhibitors; probenecid: agents that suppress the glucuronidation process are theoretically capable of influencing the excretion of febuxostat, since its metabolism depends on the activity of UDPGT; when conducting clinical trials against the background of the combined use of febuxostat with naproxen or other NSAIDs / COX-2 inhibitors, there was no clinically significant increase in the incidence of side effects; no change in doses of febuxostat or naproxen is required;
    glucuronidation inducers: strong UDFGT inducers can activate the metabolism of febuxostat and reduce its effectiveness; with this combination, after 1–2 weeks after its start, it is recommended to control the level of uric acid in the blood plasma; in case of cancellation of the glucuronidation inducer, an increase in the plasma concentration of febuxostat may be observed;
    theophylline: an increase in the concentration of this substance in the blood plasma was observed when it was used simultaneously with other xanthine oxidase inhibitors; with a combination of febuxostat in a daily dose of 80 mg and theophylline in a single dose of 400 mg in healthy volunteers, there were no changes in the parameters of pharmacokinetics or tolerance of theophylline, thus, this combination does not pose a threat to an increase in the concentration of this substance in the blood plasma; there is no information on taking febuxostat 120 mg concurrently with theophylline;
    rosiglitazone / CYP2C8 isoenzyme substrates: no dose adjustment is necessary for both agents; according to research results, the use of febuxostat at a dose of 120 mg and rosiglitazone once at a dose of 4 mg did not lead to a change in the pharmacokinetics of rosiglitazone and its metabolite N-dismethyl rosiglitazone;
    desipramine / CYP2D6 isoenzyme substrates: dose changes are not required, because during the research it was found that in vivo febuxostat has a weak inhibitory effect on the CYP2D6 isoenzyme;
    colchicine / indomethacin / hydrochlorothiazide / warfarin: When used with colchicine, indomethacin, or hydrochlorothiazide, the dose of febuxostat should not be changed; when febuxostat in a daily dose of 80/120 mg was combined with warfarin, its effect on the pharmacokinetic characteristics of the latter, the international normalized ratio (INR) and factor VII activity was not observed, and therefore, there is no need to adjust the dose of warfarin;
    antacids (containing magnesium or aluminum hydroxide): when taken in combination with antacids, the absorption of febuxostat slows down (by about 1 hour) and decreases by 32% Cmax, but its AUC does not change significantly, therefore, febuxostat can be combined with antacids.

Terms and conditions of storage

Store at a temperature not exceeding 25 ° C, out of the reach of children.
Shelf life is 3 years.

Reviews

There are practically no reviews of Azurix on specialized medical websites and forums, since the drug only passed state registration in April, and in July 2018 it was introduced to the Russian pharmaceutical market.
Experts note the effectiveness of this drug and consider it a worthy substitute for allopurinol in the treatment of gout, since Azurix is ​​the first Russian generic drug with the active ingredient febuxostat. They also indicate the good tolerance of febuxostat, which it has demonstrated in all clinical trials, and the low incidence of side effects.
Patients mainly complain about the absence of Azurix in pharmacies.

Terms of sell

You don't need a doctor's prescription to buy Azurix.